Cleveland Clinic Journal of Medicine

Medical professionalism in the United States is facing a crisis, just as serious as the crisis facing the health care system, and the two crises are interrelated.

To understand today’s crisis in medical professionalism requires knowing what a profession is and what role it plays in modern society. Freidson¹ considered a profession to be one of three options modern society has for controlling and organizing work. The other two options are the free market and management by organizations such as government or private businesses. Freidson suggested that medical work was totally unsuited for control by the market or by government or business and, therefore, the practice of medicine could only be conducted properly as a profession.

According to Freidson,¹ a profession is highly specialized and grounded in a body of knowledge and skills that is given special status in the labor force, its members are certified through a formal educational program controlled by the profession, and qualified members are granted exclusive jurisdiction and a sheltered position in the labor market. Perhaps most important, professionals have an ideology that assigns a higher priority to doing useful and needed work than to economic rewards, an ideology that focuses more on the quality and social benefits of work than its profitability.

Although this ideology is the most important part of medical professionalism, it is what is now most at risk. The science and technology of medicine and the special place that medical practice holds in the labor market are not presently threatened. The expanding professional health care responsibilities of nurses and the increase in other health workers such as physician assistants and technicians are changing the mix of the health care workforce, but the central role of the physician as the manager and provider of medical services is not likely to be challenged.

Endangered are the ethical foundations of medicine, including the commitment of physicians to put the needs of patients ahead of personal gain, to deal with patients honestly, competently, and compassionately, and to avoid conflicts of interest that could undermine public trust in the altruism of medicine. It is this commitment, what Freidson called the “soul” of the profession,¹ that is eroding, even while its scientific and technical authority grows stronger. Ironically, medical science and technology are flourishing, even as the moral foundations of the medical profession lose their influence on the behavior of physicians.

This undermining of professional values was an inevitable result of the change in the scientific, economic, legal, and social environment in which medicine is now being practiced. A major reason for the decline of medical professional values is the growing commercialization of the US health care system.² Health care has become a $2 trillion industry,² largely shaped by the entry and growth of innumerable private investor-owned businesses that sell health insurance and deliver medical care with a primary concern for the maximization of their income. To survive in this new medical market, most nonprofit medical institutions act like their for-profit competitors, and the behavior of nonprofits and for-profits has become less and less distinguishable. In no other health care system in the world do investors and business considerations play such an important role. In no other country are the organizations that provide medical care so driven by income and profit-generating considerations. This uniquely US development is an important cause of the health cost crisis that is destabilizing the entire economy, and it has played a major part in eroding the ethical commitments of physicians.

Many physicians have contributed to this transformation by accepting the view that medical practice is also in essence a business. Medical practice is now widely viewed as a demanding and technical business that requires extensive, credentialed education and great personal responsibilities—but a business nevertheless. This change in attitude has important consequences. In business, increasing shareholder value through increased revenue and increased profit is the primary goal. However, medical professionalism requires that physicians give even greater primacy to the medical needs of patients and to the public health of the society in which their patients live. When physicians think of themselves as being primarily in business, professional values recede and the practice of medicine changes.

Physicians have always been concerned with earning a comfortable living, and there have always been some who were driven by greed, but the current focus on moneymaking and the seductions of financial rewards have changed the climate of US medical practice at the expense of professional altruism and the moral commitment to patients.³ The vast amount of money in the US medical care system and the manifold opportunities for physicians to earn high incomes have made it almost impossible for many to function as true fiduciaries for patients.

The essence of medicine is so different from that of ordinary business that they are inherently at odds. Business concepts of good management may be useful in medical practice, but only to a degree. The fundamental ethos of medical practice contrasts sharply with that of ordinary commerce, and market principles do not apply to the relationship between physician and patient.⁴ Such insights have not stopped the advance of the “medical-industrial complex,”⁵ or prevented the growing domination of market ideology over medical professionalism.

Other forces in the new environment have also been eroding medical professionalism. The growth of technology and specialization is attracting more physicians into specialties and away from primary care.⁶ The greater economic rewards of procedural specialties are particularly appealing to new graduates who enter practice burdened with large educational debts. Specialization is not necessarily incompatible with ethical professional practice, but it often reduces the opportunities for personal interactions between physicians and patients and thus weakens the bond between physicians and patients. It is too easy for even the best specialists to behave simply as skilled technicians, focused exclusively on their patients’ narrow medical problems and unmindful of their professional obligations to the whole person they are serving.

The law also has played a major role in the decline of medical professionalism. The 1975 Supreme Court ruling that the professions were not protected from antitrust law⁷ undermined the traditional restraint that medical professional societies had always placed on the commercial behavior of physicians, such as advertising and investing in the products they prescribe or facilities they recommend. Having lost some initial legal battles and fearing the financial costs of losing more, organized medicine now hesitates to require physicians to behave differently from business people. It asks only that physicians’ business activities should be legal, disclosed to patients, and not inconsistent with patients’ interests. Until forced by antitrust concerns to change its ethical code in 1980, the American Medical Association had held that “in the practice of medicine a physician should limit the source of his professional income to medical services actually rendered by him, or under his supervision, to his patients” and that “the practice of medicine should not be commercialized, nor treated as a commodity in trade.”⁸ These sentiments reflecting the spirit of professionalism are now gone.

Professionalism is also compromised by the failure of physicians to exercise self-regulation that would be supported by law. Many physicians are reluctant to identify incompetent or unethical colleagues. Such behavior also undermines the public’s trust in the profession.

Yet another deprofessionalizing force has been the growing influence of the pharmaceutical industry on the practice of medicine. This industry now uses its enormous financial resources to help shape the postgraduate and continuing medical education of physicians in ways that serve its marketing purposes.⁹ Physicians and medical educational institutions aid and abet this influence by accepting, sometimes even soliciting, financial help and other favors from the industry, thus relinquishing what should be their professional responsibility for self-education. A medical profession that is being educated by an industry that sells the drugs physicians prescribe and other tools physicians use is abdicating its ethical commitment to serve as the independent fiduciary for its patients.¹⁰

The preservation of independent professionalism and its ethical commitment to patients still are very important because physicians are at the center of the health care system and the public must be able to depend on and trust physicians. There is currently much concern about the paternalism and elitism of medicine, and this concern is often used to justify policies seeking to establish so-called consumer-directed health care.¹¹ Although there undoubtedly is a need for patients to have more information and responsibility for their health care choices, without trustworthy and accountable professional guidance from physicians, the health care system could not function. In the absence of physicians’ commitment to professional values, health care becomes just another industry that may, by continuing along its present course, be heading toward bankruptcy.

Physicians should not accept the industrialization of medical care, but should work instead toward major reforms that will restore the health care system to its proper role as a social service that society provides to all. Virtually every other advanced nation has achieved that goal. An essential part of the needed reforms is a rededication of physicians to the ethical professional principles on which the practice of medicine should rest. Such reforms will require public and political initiatives¹² and the active participation of the medical profession.

Medical professionalism cannot survive in the current commercialized health care market. The continued privatization of health care and the continued prevalence and intrusion of market forces in the practice of medicine will not only bankrupt the health care system, but also will inevitably undermine the ethical foundations of medical practice and dissolve the moral precepts that have historically defined the medical profession. Physicians who care about these values must support major reform of both the insurance and the delivery sides of the health care system.² It is the one policy option most likely to preserve the integrity and values of the medical profession.

ADDENDUM

The foregoing commentary, published last year in JAMA, explains why I am concerned about the “ethical challenges in surgical innovation,” the subject of this conference. Although the legal status of patent applications for surgical methods (“process patents”) has not yet been fully defined,¹³ such applications fortunately are relatively rare. The great majority of surgical techniques are not patented and are freely available to surgeons—as they should be. However, the devices, equipment, and implants that may be an essential part of new surgical techniques can be and are patented, and may therefore be profitable. If these patented items are developed by a staff physician or are the product of collaboration between such a physician and a company, should financial benefits accrue to the physician involved? Some say yes. They seem convinced that without some sort of financial incentive—royalties, direct payments from the manufacturer, or equity interest in the manufacturer—physicians would simply not be motivated to do innovative work, and the “translational” research essential for medical progress would languish.

I strongly disagree with this view, but unfortunately it has gained considerable influence in academic medicine in recent years, despite the fact that it conflicts with medical professional ethics. Court interpretation of antitrust law in 1975⁷ forced the American Medical Association to abandon its long-standing ethical injunction against practicing physicians earning income from financial interests in the medical products they use or prescribe. However, antitrust legislation is not relevant here, and no legal restraints prevent medical schools, teaching hospitals, and similar medical institutions from regulating or even prohibiting such outside earnings by their full-time salaried staff. These earnings constitute a clear conflict of interest, and there is a growing national consensus that such conflicts not only should be publicly disclosed but should be regulated by the institutions employing the physicians. If the institutions do not do this job, many now believe the government should.

What is the evidence that personal financial rewards are necessary incentives for physicians to work on “translational” research? I submit that there is little or none—only an assumption. But the fact is that even before commercialization began to transform health care 3 or 4 decades ago, and even before salaried academic physicians began to earn substantial outside income from their financial ties to device and drug manufacturers, “translational” research was thriving. In the 2 or 3 decades after World War II, salaried academic physicians conducted applied medical and surgical research, often in cooperation with industry but usually without any personal gain. It is true that today there is much more “translational” research going on, but that is probably explained by the greater number of researchers working now and the much greater public and private investment in research. It does not follow that the recent growth in applied biomedical investigation would not have occurred without personal financial incentives to academic physicians and surgeons. Such an assumption not only ignores medical history but demeans the professional values that we physicians swear to live by.

If we continue to encourage, or even allow, practicing physicians and surgeons to be entrepreneurs and have financial interests in the products they use and prescribe, we will surely undermine the ethical traditions of our profession, as I have argued in the above JAMA commentary. But beyond this ethical catastrophe, such policy would surely destroy the credibility and integrity of the whole US medical research enterprise, with dire consequences for society. I believe it is time for our best clinical research institutions to insist that research cooperation with industry be conducted in a much more professional and controlled manner. Academic-industrial cooperation can often facilitate advances in research, but any financial gains for the academic side should flow to institutions, not individuals, and should be strictly regulated by law to ensure that the public interest is protected and the integrity of the medical profession preserved.

I refuse to believe that academic physicians will stop their search for innovative devices and methods for treating their patients if they are not given extra financial rewards beyond their salaries. Of course, they need to be paid well and they need the time and resources required for their research, but that should be the responsibility of their institutions, not of industry. The present shortage of time and resources for research in not-for-profit medical institutions must be addressed, but turning the responsibility over to the free market of medical entrepreneurialism is not the answer. It will lead only to a dead end for our profession and for the public stake in medical research. This is a challenge that the best and strongest US medical institutions must face up to, but government will also need to help. Our country depends on a vibrant but socially responsible and trustworthy medical research sector. That is an objective that unregulated commercial markets and private interests cannot achieve. We need academic institutions, supported by public policies, to lead the way.

Medical professionalism in the United States is facing a crisis, just as serious as the crisis facing the health care system, and the two crises are interrelated.

To understand today’s crisis in medical professionalism requires knowing what a profession is and what role it plays in modern society. Freidson¹ considered a profession to be one of three options modern society has for controlling and organizing work. The other two options are the free market and management by organizations such as government or private businesses. Freidson suggested that medical work was totally unsuited for control by the market or by government or business and, therefore, the practice of medicine could only be conducted properly as a profession.

According to Freidson,¹ a profession is highly specialized and grounded in a body of knowledge and skills that is given special status in the labor force, its members are certified through a formal educational program controlled by the profession, and qualified members are granted exclusive jurisdiction and a sheltered position in the labor market. Perhaps most important, professionals have an ideology that assigns a higher priority to doing useful and needed work than to economic rewards, an ideology that focuses more on the quality and social benefits of work than its profitability.

Although this ideology is the most important part of medical professionalism, it is what is now most at risk. The science and technology of medicine and the special place that medical practice holds in the labor market are not presently threatened. The expanding professional health care responsibilities of nurses and the increase in other health workers such as physician assistants and technicians are changing the mix of the health care workforce, but the central role of the physician as the manager and provider of medical services is not likely to be challenged.

Endangered are the ethical foundations of medicine, including the commitment of physicians to put the needs of patients ahead of personal gain, to deal with patients honestly, competently, and compassionately, and to avoid conflicts of interest that could undermine public trust in the altruism of medicine. It is this commitment, what Freidson called the “soul” of the profession,¹ that is eroding, even while its scientific and technical authority grows stronger. Ironically, medical science and technology are flourishing, even as the moral foundations of the medical profession lose their influence on the behavior of physicians.

This undermining of professional values was an inevitable result of the change in the scientific, economic, legal, and social environment in which medicine is now being practiced. A major reason for the decline of medical professional values is the growing commercialization of the US health care system.² Health care has become a $2 trillion industry,² largely shaped by the entry and growth of innumerable private investor-owned businesses that sell health insurance and deliver medical care with a primary concern for the maximization of their income. To survive in this new medical market, most nonprofit medical institutions act like their for-profit competitors, and the behavior of nonprofits and for-profits has become less and less distinguishable. In no other health care system in the world do investors and business considerations play such an important role. In no other country are the organizations that provide medical care so driven by income and profit-generating considerations. This uniquely US development is an important cause of the health cost crisis that is destabilizing the entire economy, and it has played a major part in eroding the ethical commitments of physicians.

Many physicians have contributed to this transformation by accepting the view that medical practice is also in essence a business. Medical practice is now widely viewed as a demanding and technical business that requires extensive, credentialed education and great personal responsibilities—but a business nevertheless. This change in attitude has important consequences. In business, increasing shareholder value through increased revenue and increased profit is the primary goal. However, medical professionalism requires that physicians give even greater primacy to the medical needs of patients and to the public health of the society in which their patients live. When physicians think of themselves as being primarily in business, professional values recede and the practice of medicine changes.

Physicians have always been concerned with earning a comfortable living, and there have always been some who were driven by greed, but the current focus on moneymaking and the seductions of financial rewards have changed the climate of US medical practice at the expense of professional altruism and the moral commitment to patients.³ The vast amount of money in the US medical care system and the manifold opportunities for physicians to earn high incomes have made it almost impossible for many to function as true fiduciaries for patients.

The essence of medicine is so different from that of ordinary business that they are inherently at odds. Business concepts of good management may be useful in medical practice, but only to a degree. The fundamental ethos of medical practice contrasts sharply with that of ordinary commerce, and market principles do not apply to the relationship between physician and patient.⁴ Such insights have not stopped the advance of the “medical-industrial complex,”⁵ or prevented the growing domination of market ideology over medical professionalism.

Other forces in the new environment have also been eroding medical professionalism. The growth of technology and specialization is attracting more physicians into specialties and away from primary care.⁶ The greater economic rewards of procedural specialties are particularly appealing to new graduates who enter practice burdened with large educational debts. Specialization is not necessarily incompatible with ethical professional practice, but it often reduces the opportunities for personal interactions between physicians and patients and thus weakens the bond between physicians and patients. It is too easy for even the best specialists to behave simply as skilled technicians, focused exclusively on their patients’ narrow medical problems and unmindful of their professional obligations to the whole person they are serving.

The law also has played a major role in the decline of medical professionalism. The 1975 Supreme Court ruling that the professions were not protected from antitrust law⁷ undermined the traditional restraint that medical professional societies had always placed on the commercial behavior of physicians, such as advertising and investing in the products they prescribe or facilities they recommend. Having lost some initial legal battles and fearing the financial costs of losing more, organized medicine now hesitates to require physicians to behave differently from business people. It asks only that physicians’ business activities should be legal, disclosed to patients, and not inconsistent with patients’ interests. Until forced by antitrust concerns to change its ethical code in 1980, the American Medical Association had held that “in the practice of medicine a physician should limit the source of his professional income to medical services actually rendered by him, or under his supervision, to his patients” and that “the practice of medicine should not be commercialized, nor treated as a commodity in trade.”⁸ These sentiments reflecting the spirit of professionalism are now gone.

Professionalism is also compromised by the failure of physicians to exercise self-regulation that would be supported by law. Many physicians are reluctant to identify incompetent or unethical colleagues. Such behavior also undermines the public’s trust in the profession.

Yet another deprofessionalizing force has been the growing influence of the pharmaceutical industry on the practice of medicine. This industry now uses its enormous financial resources to help shape the postgraduate and continuing medical education of physicians in ways that serve its marketing purposes.⁹ Physicians and medical educational institutions aid and abet this influence by accepting, sometimes even soliciting, financial help and other favors from the industry, thus relinquishing what should be their professional responsibility for self-education. A medical profession that is being educated by an industry that sells the drugs physicians prescribe and other tools physicians use is abdicating its ethical commitment to serve as the independent fiduciary for its patients.¹⁰

The preservation of independent professionalism and its ethical commitment to patients still are very important because physicians are at the center of the health care system and the public must be able to depend on and trust physicians. There is currently much concern about the paternalism and elitism of medicine, and this concern is often used to justify policies seeking to establish so-called consumer-directed health care.¹¹ Although there undoubtedly is a need for patients to have more information and responsibility for their health care choices, without trustworthy and accountable professional guidance from physicians, the health care system could not function. In the absence of physicians’ commitment to professional values, health care becomes just another industry that may, by continuing along its present course, be heading toward bankruptcy.

Physicians should not accept the industrialization of medical care, but should work instead toward major reforms that will restore the health care system to its proper role as a social service that society provides to all. Virtually every other advanced nation has achieved that goal. An essential part of the needed reforms is a rededication of physicians to the ethical professional principles on which the practice of medicine should rest. Such reforms will require public and political initiatives¹² and the active participation of the medical profession.

Medical professionalism cannot survive in the current commercialized health care market. The continued privatization of health care and the continued prevalence and intrusion of market forces in the practice of medicine will not only bankrupt the health care system, but also will inevitably undermine the ethical foundations of medical practice and dissolve the moral precepts that have historically defined the medical profession. Physicians who care about these values must support major reform of both the insurance and the delivery sides of the health care system.² It is the one policy option most likely to preserve the integrity and values of the medical profession.

ADDENDUM

The foregoing commentary, published last year in JAMA, explains why I am concerned about the “ethical challenges in surgical innovation,” the subject of this conference. Although the legal status of patent applications for surgical methods (“process patents”) has not yet been fully defined,¹³ such applications fortunately are relatively rare. The great majority of surgical techniques are not patented and are freely available to surgeons—as they should be. However, the devices, equipment, and implants that may be an essential part of new surgical techniques can be and are patented, and may therefore be profitable. If these patented items are developed by a staff physician or are the product of collaboration between such a physician and a company, should financial benefits accrue to the physician involved? Some say yes. They seem convinced that without some sort of financial incentive—royalties, direct payments from the manufacturer, or equity interest in the manufacturer—physicians would simply not be motivated to do innovative work, and the “translational” research essential for medical progress would languish.

I strongly disagree with this view, but unfortunately it has gained considerable influence in academic medicine in recent years, despite the fact that it conflicts with medical professional ethics. Court interpretation of antitrust law in 1975⁷ forced the American Medical Association to abandon its long-standing ethical injunction against practicing physicians earning income from financial interests in the medical products they use or prescribe. However, antitrust legislation is not relevant here, and no legal restraints prevent medical schools, teaching hospitals, and similar medical institutions from regulating or even prohibiting such outside earnings by their full-time salaried staff. These earnings constitute a clear conflict of interest, and there is a growing national consensus that such conflicts not only should be publicly disclosed but should be regulated by the institutions employing the physicians. If the institutions do not do this job, many now believe the government should.

What is the evidence that personal financial rewards are necessary incentives for physicians to work on “translational” research? I submit that there is little or none—only an assumption. But the fact is that even before commercialization began to transform health care 3 or 4 decades ago, and even before salaried academic physicians began to earn substantial outside income from their financial ties to device and drug manufacturers, “translational” research was thriving. In the 2 or 3 decades after World War II, salaried academic physicians conducted applied medical and surgical research, often in cooperation with industry but usually without any personal gain. It is true that today there is much more “translational” research going on, but that is probably explained by the greater number of researchers working now and the much greater public and private investment in research. It does not follow that the recent growth in applied biomedical investigation would not have occurred without personal financial incentives to academic physicians and surgeons. Such an assumption not only ignores medical history but demeans the professional values that we physicians swear to live by.

If we continue to encourage, or even allow, practicing physicians and surgeons to be entrepreneurs and have financial interests in the products they use and prescribe, we will surely undermine the ethical traditions of our profession, as I have argued in the above JAMA commentary. But beyond this ethical catastrophe, such policy would surely destroy the credibility and integrity of the whole US medical research enterprise, with dire consequences for society. I believe it is time for our best clinical research institutions to insist that research cooperation with industry be conducted in a much more professional and controlled manner. Academic-industrial cooperation can often facilitate advances in research, but any financial gains for the academic side should flow to institutions, not individuals, and should be strictly regulated by law to ensure that the public interest is protected and the integrity of the medical profession preserved.

I refuse to believe that academic physicians will stop their search for innovative devices and methods for treating their patients if they are not given extra financial rewards beyond their salaries. Of course, they need to be paid well and they need the time and resources required for their research, but that should be the responsibility of their institutions, not of industry. The present shortage of time and resources for research in not-for-profit medical institutions must be addressed, but turning the responsibility over to the free market of medical entrepreneurialism is not the answer. It will lead only to a dead end for our profession and for the public stake in medical research. This is a challenge that the best and strongest US medical institutions must face up to, but government will also need to help. Our country depends on a vibrant but socially responsible and trustworthy medical research sector. That is an objective that unregulated commercial markets and private interests cannot achieve. We need academic institutions, supported by public policies, to lead the way.

Medical professionalism in the United States is facing a crisis, just as serious as the crisis facing the health care system, and the two crises are interrelated.

To understand today’s crisis in medical professionalism requires knowing what a profession is and what role it plays in modern society. Freidson¹ considered a profession to be one of three options modern society has for controlling and organizing work. The other two options are the free market and management by organizations such as government or private businesses. Freidson suggested that medical work was totally unsuited for control by the market or by government or business and, therefore, the practice of medicine could only be conducted properly as a profession.

According to Freidson,¹ a profession is highly specialized and grounded in a body of knowledge and skills that is given special status in the labor force, its members are certified through a formal educational program controlled by the profession, and qualified members are granted exclusive jurisdiction and a sheltered position in the labor market. Perhaps most important, professionals have an ideology that assigns a higher priority to doing useful and needed work than to economic rewards, an ideology that focuses more on the quality and social benefits of work than its profitability.

Although this ideology is the most important part of medical professionalism, it is what is now most at risk. The science and technology of medicine and the special place that medical practice holds in the labor market are not presently threatened. The expanding professional health care responsibilities of nurses and the increase in other health workers such as physician assistants and technicians are changing the mix of the health care workforce, but the central role of the physician as the manager and provider of medical services is not likely to be challenged.

Endangered are the ethical foundations of medicine, including the commitment of physicians to put the needs of patients ahead of personal gain, to deal with patients honestly, competently, and compassionately, and to avoid conflicts of interest that could undermine public trust in the altruism of medicine. It is this commitment, what Freidson called the “soul” of the profession,¹ that is eroding, even while its scientific and technical authority grows stronger. Ironically, medical science and technology are flourishing, even as the moral foundations of the medical profession lose their influence on the behavior of physicians.

This undermining of professional values was an inevitable result of the change in the scientific, economic, legal, and social environment in which medicine is now being practiced. A major reason for the decline of medical professional values is the growing commercialization of the US health care system.² Health care has become a $2 trillion industry,² largely shaped by the entry and growth of innumerable private investor-owned businesses that sell health insurance and deliver medical care with a primary concern for the maximization of their income. To survive in this new medical market, most nonprofit medical institutions act like their for-profit competitors, and the behavior of nonprofits and for-profits has become less and less distinguishable. In no other health care system in the world do investors and business considerations play such an important role. In no other country are the organizations that provide medical care so driven by income and profit-generating considerations. This uniquely US development is an important cause of the health cost crisis that is destabilizing the entire economy, and it has played a major part in eroding the ethical commitments of physicians.

Many physicians have contributed to this transformation by accepting the view that medical practice is also in essence a business. Medical practice is now widely viewed as a demanding and technical business that requires extensive, credentialed education and great personal responsibilities—but a business nevertheless. This change in attitude has important consequences. In business, increasing shareholder value through increased revenue and increased profit is the primary goal. However, medical professionalism requires that physicians give even greater primacy to the medical needs of patients and to the public health of the society in which their patients live. When physicians think of themselves as being primarily in business, professional values recede and the practice of medicine changes.

Physicians have always been concerned with earning a comfortable living, and there have always been some who were driven by greed, but the current focus on moneymaking and the seductions of financial rewards have changed the climate of US medical practice at the expense of professional altruism and the moral commitment to patients.³ The vast amount of money in the US medical care system and the manifold opportunities for physicians to earn high incomes have made it almost impossible for many to function as true fiduciaries for patients.

The essence of medicine is so different from that of ordinary business that they are inherently at odds. Business concepts of good management may be useful in medical practice, but only to a degree. The fundamental ethos of medical practice contrasts sharply with that of ordinary commerce, and market principles do not apply to the relationship between physician and patient.⁴ Such insights have not stopped the advance of the “medical-industrial complex,”⁵ or prevented the growing domination of market ideology over medical professionalism.

Other forces in the new environment have also been eroding medical professionalism. The growth of technology and specialization is attracting more physicians into specialties and away from primary care.⁶ The greater economic rewards of procedural specialties are particularly appealing to new graduates who enter practice burdened with large educational debts. Specialization is not necessarily incompatible with ethical professional practice, but it often reduces the opportunities for personal interactions between physicians and patients and thus weakens the bond between physicians and patients. It is too easy for even the best specialists to behave simply as skilled technicians, focused exclusively on their patients’ narrow medical problems and unmindful of their professional obligations to the whole person they are serving.

The law also has played a major role in the decline of medical professionalism. The 1975 Supreme Court ruling that the professions were not protected from antitrust law⁷ undermined the traditional restraint that medical professional societies had always placed on the commercial behavior of physicians, such as advertising and investing in the products they prescribe or facilities they recommend. Having lost some initial legal battles and fearing the financial costs of losing more, organized medicine now hesitates to require physicians to behave differently from business people. It asks only that physicians’ business activities should be legal, disclosed to patients, and not inconsistent with patients’ interests. Until forced by antitrust concerns to change its ethical code in 1980, the American Medical Association had held that “in the practice of medicine a physician should limit the source of his professional income to medical services actually rendered by him, or under his supervision, to his patients” and that “the practice of medicine should not be commercialized, nor treated as a commodity in trade.”⁸ These sentiments reflecting the spirit of professionalism are now gone.

Professionalism is also compromised by the failure of physicians to exercise self-regulation that would be supported by law. Many physicians are reluctant to identify incompetent or unethical colleagues. Such behavior also undermines the public’s trust in the profession.

Yet another deprofessionalizing force has been the growing influence of the pharmaceutical industry on the practice of medicine. This industry now uses its enormous financial resources to help shape the postgraduate and continuing medical education of physicians in ways that serve its marketing purposes.⁹ Physicians and medical educational institutions aid and abet this influence by accepting, sometimes even soliciting, financial help and other favors from the industry, thus relinquishing what should be their professional responsibility for self-education. A medical profession that is being educated by an industry that sells the drugs physicians prescribe and other tools physicians use is abdicating its ethical commitment to serve as the independent fiduciary for its patients.¹⁰

The preservation of independent professionalism and its ethical commitment to patients still are very important because physicians are at the center of the health care system and the public must be able to depend on and trust physicians. There is currently much concern about the paternalism and elitism of medicine, and this concern is often used to justify policies seeking to establish so-called consumer-directed health care.¹¹ Although there undoubtedly is a need for patients to have more information and responsibility for their health care choices, without trustworthy and accountable professional guidance from physicians, the health care system could not function. In the absence of physicians’ commitment to professional values, health care becomes just another industry that may, by continuing along its present course, be heading toward bankruptcy.

Physicians should not accept the industrialization of medical care, but should work instead toward major reforms that will restore the health care system to its proper role as a social service that society provides to all. Virtually every other advanced nation has achieved that goal. An essential part of the needed reforms is a rededication of physicians to the ethical professional principles on which the practice of medicine should rest. Such reforms will require public and political initiatives¹² and the active participation of the medical profession.

Medical professionalism cannot survive in the current commercialized health care market. The continued privatization of health care and the continued prevalence and intrusion of market forces in the practice of medicine will not only bankrupt the health care system, but also will inevitably undermine the ethical foundations of medical practice and dissolve the moral precepts that have historically defined the medical profession. Physicians who care about these values must support major reform of both the insurance and the delivery sides of the health care system.² It is the one policy option most likely to preserve the integrity and values of the medical profession.

ADDENDUM

The foregoing commentary, published last year in JAMA, explains why I am concerned about the “ethical challenges in surgical innovation,” the subject of this conference. Although the legal status of patent applications for surgical methods (“process patents”) has not yet been fully defined,¹³ such applications fortunately are relatively rare. The great majority of surgical techniques are not patented and are freely available to surgeons—as they should be. However, the devices, equipment, and implants that may be an essential part of new surgical techniques can be and are patented, and may therefore be profitable. If these patented items are developed by a staff physician or are the product of collaboration between such a physician and a company, should financial benefits accrue to the physician involved? Some say yes. They seem convinced that without some sort of financial incentive—royalties, direct payments from the manufacturer, or equity interest in the manufacturer—physicians would simply not be motivated to do innovative work, and the “translational” research essential for medical progress would languish.

I strongly disagree with this view, but unfortunately it has gained considerable influence in academic medicine in recent years, despite the fact that it conflicts with medical professional ethics. Court interpretation of antitrust law in 1975⁷ forced the American Medical Association to abandon its long-standing ethical injunction against practicing physicians earning income from financial interests in the medical products they use or prescribe. However, antitrust legislation is not relevant here, and no legal restraints prevent medical schools, teaching hospitals, and similar medical institutions from regulating or even prohibiting such outside earnings by their full-time salaried staff. These earnings constitute a clear conflict of interest, and there is a growing national consensus that such conflicts not only should be publicly disclosed but should be regulated by the institutions employing the physicians. If the institutions do not do this job, many now believe the government should.

What is the evidence that personal financial rewards are necessary incentives for physicians to work on “translational” research? I submit that there is little or none—only an assumption. But the fact is that even before commercialization began to transform health care 3 or 4 decades ago, and even before salaried academic physicians began to earn substantial outside income from their financial ties to device and drug manufacturers, “translational” research was thriving. In the 2 or 3 decades after World War II, salaried academic physicians conducted applied medical and surgical research, often in cooperation with industry but usually without any personal gain. It is true that today there is much more “translational” research going on, but that is probably explained by the greater number of researchers working now and the much greater public and private investment in research. It does not follow that the recent growth in applied biomedical investigation would not have occurred without personal financial incentives to academic physicians and surgeons. Such an assumption not only ignores medical history but demeans the professional values that we physicians swear to live by.

If we continue to encourage, or even allow, practicing physicians and surgeons to be entrepreneurs and have financial interests in the products they use and prescribe, we will surely undermine the ethical traditions of our profession, as I have argued in the above JAMA commentary. But beyond this ethical catastrophe, such policy would surely destroy the credibility and integrity of the whole US medical research enterprise, with dire consequences for society. I believe it is time for our best clinical research institutions to insist that research cooperation with industry be conducted in a much more professional and controlled manner. Academic-industrial cooperation can often facilitate advances in research, but any financial gains for the academic side should flow to institutions, not individuals, and should be strictly regulated by law to ensure that the public interest is protected and the integrity of the medical profession preserved.

I refuse to believe that academic physicians will stop their search for innovative devices and methods for treating their patients if they are not given extra financial rewards beyond their salaries. Of course, they need to be paid well and they need the time and resources required for their research, but that should be the responsibility of their institutions, not of industry. The present shortage of time and resources for research in not-for-profit medical institutions must be addressed, but turning the responsibility over to the free market of medical entrepreneurialism is not the answer. It will lead only to a dead end for our profession and for the public stake in medical research. This is a challenge that the best and strongest US medical institutions must face up to, but government will also need to help. Our country depends on a vibrant but socially responsible and trustworthy medical research sector. That is an objective that unregulated commercial markets and private interests cannot achieve. We need academic institutions, supported by public policies, to lead the way.

How should we introduce and evaluate new procedures?

By Joel D. Cooper, MD

Time magazine published an article in 1995 titled “Are Surgeons Too Creative?” that examined the question of whether operations should be regulated the way that medications are.¹ The piece featured two patients. One, a patient with emphysema who underwent lung volume reduction surgery at our institution during the early days of this procedure, had a good outcome. The other was a neurosurgical patient who had a bad outcome.

The public is somewhat sympathetic to this article’s premise, which can be viewed as a call to require a similar level of evidence for surgical procedures as for new drugs. This sympathy arises from the expense of new technologies, pressure from payors to control costs and increase profits, hospital budget restraints, and the reality of increasingly well-informed patients.

Yet there are distinct differences between drugs and surgery. A new drug does not change over time. A new drug is associated with a variable biologic response whose assessment often requires large numbers of patients and considerable follow-up. And a new drug may manifest unforeseen late side effects and toxicities far removed from the time of initial use. In contrast, none of these characteristics applies to surgical procedures. A surgical intervention changes over time as the technique and experience evolve and as refinements are made in patient selection and in pre- and postoperative management. With this evolution comes a change in risk over time. Patient selection for surgery is as much an art as a science; each patient requires assessment of both the potential benefits and risks of the procedure, which argues against offering an operation by prescription. Moreover, with surgery, the facilities and the operator’s skill and experience levels vary from one center to another.

INTRODUCTION OF NEW PROCEDURES: COVERAGE VS VALIDATION

Introduction of a new surgical procedure depends on the nature of the procedure and the other interventions that may be available for the condition. In assessing how new procedures should be introduced, I believe we need to distinguish between coverage and validation. Coverage—ie, payment for the procedure—is an economic issue, whereas validation involves an ethical and scientific evaluation of the role of the procedure.

Coverage by an insurer should have at least theoretical justification and presumption of benefit. For instance, the rationale behind a heart transplant for a patient with a failing heart is obvious. Coverage generally requires preliminary evidence of efficacy, possibly in an animal model, although no animal models may exist for some conditions. Most important, a different standard for providing initial coverage should be applied if no alternative therapy exists for a condition that is severe, debilitating, and potentially life-threatening; if a new procedure treats a condition for which a standard therapy already exists, the standard for coverage must be higher. Finally, coverage in all cases should require ongoing reassessment of the procedure.

In contrast, validation is a scientific analysis of results over time, including long-term results, and can be accomplished by well-controlled case series, particularly if the magnitude of the benefit is both frequent and significant and especially if no alternative therapy exists. Randomized clinical trials are the gold standard for appropriate interventions but are not always applicable.

A 1996 study by Majeed et al² provides a good example of validation-oriented surgical research. In this blinded trial, 200 patients scheduled for cholecystectomy were randomized to either laparoscopic or open (small-incision) procedures. The study found no differences between the groups in terms of hospital stay or postprocedure pain or recovery. In an accompanying commentary,³Lancet editor Richard Horton praised the design and conduct of the study, noting that it was very much the exception in surgical research, which he argued was preoccupied with case series. Horton offered the following speculation about this preoccupation:

Perhaps many surgeons do not see randomised trials as feasible strategy to resolve questions about surgical management. Cynics might even claim that the personal attributes that go to make a successful surgeon differ from those needed for collaborative multicentre research.³

IS THE ‘SURGICAL SCIENTIST’ AN OXYMORON?

Barnaby Reeves, writing in The Lancet 3 years later, offered a more diplomatic take on the difficulty of evaluating surgical procedures:

What makes a surgical technique new is not always easy to define because surgical procedures generally evolve in small steps, which makes it difficult to decide when a procedure has changed sufficiently to justify formal evaluation.⁴

Reeves went on to argue that doing an evaluation too early may preclude acceptance, since the technique may not have evolved sufficiently and surgeons may not have mastered it; conversely, doing an evaluation too late may make the evaluation moot, since the technique may have already become established and withholding it may be deemed unethical. Additionally, he noted that the quality of surgical evaluation is complicated by the possibility that some surgeons have better mastery of—and therefore better outcomes with—one procedure while other surgeons have better mastery and outcomes with an alternative procedure.⁴

These concerns were well captured by the late Dr. Judah Folkman, whom I once heard say, “When a basic scientist is informed that another investigator cannot reproduce his work, it has a chilling effect; for the surgeon, however, it is a source of pride.”

Even as we recognize these challenges specific to surgical evaluation, we are still left with the task of determining when a randomized controlled trial is appropriate and when a case-control series may suffice.

There are three broad sets of circumstances in which a randomized trial is essential:

• For preventive procedures, ie, when the operation is done to reduce the potential for a future adverse event. An example would be evaluating carotid endarterectomy to reduce the potential for stroke in asymptomatic patients with 60% or greater stenosis. Only a randomized trial could have shown a difference in favor of endarterectomy over aspirin plus best medical therapy.
• To compare a procedure with alternative medical or surgical interventions. I would argue that laparoscopic surgery should have been introduced with randomized trials, as it begs one to suspend judgment and accept that small incisions are invariably and de facto better than a large incision.
• For trials in oncology, where the outcome depends on long-term results, such as survival or time to recurrence. Examples would include comparisons of surgery alone versus surgery plus chemotherapy for prevention of cancer recurrence.

Similarly, there are several scenarios in which a case-control series is appropriate and adequate:

• When no alternative therapy exists. Falling into this category, in my view, are lung transplant, which we introduced successfully at the University of Toronto in 1983, and lung volume reduction surgery, which we introduced in 1993.
• When the natural history of the condition is well documented and the impact of the intervention is obvious.
• When the magnitude of the procedure’s effect is measurable, significant, and expected.

RANDOMIZED TRIALS IN SURGERY

Advantages of randomized trials

Randomized clinical trials confer a number of advantages. They eliminate bias. They ensure a balance between treatment groups in terms of known or unknown prognostic factors. And, importantly, they have a major impact on payors.

A tale of two Medicare payment decisions

The impact of clinical trials on payors is exemplified by the contrasting stories of two procedures: transmyocardial laser revascularization and lung volume reduction surgery.

Transmyocardial laser revascularization (TMR) involves the creation of channels in the myocardium with a laser to relieve angina. Although TMR is a dubious intervention with no physiologic rationale (similar to internal mammary artery ligation for angina5) and no proven improvement in life expectancy (only a reduction in pain), it was approved for reimbursement by Medicare because it was investigated in a randomized trial.⁶ However, the “randomized trial” was not truly a randomized investigation because the control patients received only medical therapy and did not go to the operating room to receive a sham operation.⁶ Despite this flaw, the perceived authority of the trial was sufficient to influence Medicare.

In contrast, Medicare refused to pay for lung volume reduction surgery until it was subjected to a randomized trial, despite the fact that the procedure had produced tremendous benefit in hundreds of patients at multiple centers who otherwise could not have achieved such benefit. Only after $50 million was spent on a randomized controlled trial, the National Emphysema Treatment Trial (NETT),^7–9 did Medicare agree to pay for lung volume reduction surgery. The trial showed that over 5 years, the procedure was associated with significant improvements in life expectancy, exercise tolerance, and quality of life, but the study took 8 years to conduct and by then it was a bit too late, as detailed in the following section.

NETT: A case study in how a trial can be counterproductive

Lung volume reduction surgery is an operation based on the recognition that the crippling effects of emphysema are hyperinflation of the chest, flattening of the diaphragm, and inability to move air in and out of the chest. The notion that the chest can be reconfigured in the patient with emphysema by removing the distending overinflated emphysema led us to develop the volume reduction operation.

The NETT was initiated by Medicare, and the protocol denied compassionate crossover of patients.⁷ In an attempt to establish clinical equipoise, surgeons who participated were not allowed to perform any volume reduction operations on non-Medicare patients or on Medicare patients not enrolled in the trial. After 2 years of slow patient enrollment, the clinical trial committee, in an effort to increase enrollment, eliminated the original entrance criteria specifying certain degrees of hyperinflation and diffusing capacity. An excess of mortality was discovered 2 years later in a subgroup randomized to volume reduction surgery;⁸ not surprisingly, further analysis showed that the excess mortality was largely confined to patients who would have been excluded based on the original entrance criteria. This is a matter of public record but was never acknowledged in published reports of the trial. Final 5-year NETT results showed that in patients with upper lobe emphysema, lung volume reduction surgery improved survival, increased exercise capacity, and improved quality of life.⁹ By the trial’s completion, however, the procedure’s reputation had been tarnished irreparably by bad publicity from the deaths attributable to the misguided changes to the original eligibility criteria.

Disadvantages of randomized trials

The NETT exemplifies many of the drawbacks of randomized trials in surgery, particularly the need to wait long periods while they are being conducted. During the 8 years in which the NETT was ongoing, the number of lung volume reduction operations declined, with the typical center performing fewer than 6 cases per year, on average. That limitation is certainly not conducive to the development of a new procedure for a disabling condition in patients with no ready alternative.

Other disadvantages of randomized trials in surgery are their considerable expense and the fact that they often are not generalizable and often are not appropriate. Moreover, when they are flawed, randomized trials propagate, sometimes for decades, misleading information that is nonetheless considered “authoritative.” For instance, lung cancer kills more men and women in the United States than the next three cancers combined, yet, on the basis of a flawed randomized trial,¹⁰ the American Cancer Society advises smokers to wait for symptoms before undergoing chest radiography, instead of recommending annual screening chest radiography. This is a major reason why two-thirds of lung cancer cases are discovered too late to save the patient.

‘Better to know nothing than to know what ain’t so’

Indeed, this potential for randomized clinical trials, when flawed, to propagate misleading information makes the perceived authoritativeness of randomized trials both an advantage and a disadvantage. As Berger and colleagues noted a few years ago, overuse of randomized trials for evaluating emerging operations could have led to the demise of heart transplantation, mechanical circulatory assist devices, cardiac valve procedures, coronary bypass grafting, and repair of congenital lesions.¹¹

For this reason, one of our responsibilities when reading the literature and conducting studies is not just to answer unanswered questions but to question unquestioned answers. As 19th-century humorist Josh Billings put it, “It’s better to know nothing than to know what ain’t so.”

A PERSONAL PERSPECTIVE

In my view, health care providers should restrict the application of new procedures to a limited number of centers of excellence that have appropriate resources and experience. Those centers should be required to document and report specified information regarding morbidity, mortality, and objective measures of outcome; if they do not comply, they should lose the privilege of doing such research. The data should be reviewed by an independent, nongovernmental scientific panel. In this way, the procedure can be offered to appropriate patients, insurers and patients can be protected against abuse, and the necessary data can be collected for objective analysis.

By Ralph V. Clayman, MD

Change in the surgical world involves three aspects, which I refer to as the three Ds: discovery, development, and dissemination. Change requires proof that the new method is superior to the old. When we, as innovators, develop something “new,” I believe that our immediate subsequent task is to do everything we can to prove that this “new” finding is of no value whatsoever before we determine that it is worth advancing.

Getting to Malcolm Gladwell’s tipping point—the act or event after which nothing is ever the same— requires a team of people, usually from different disciplines, coming together to concentrate on a problem, or an individual whose experiences in different fields provides the ability to “see” the next level. In my opinion, one person working in one discipline rarely leads to breakthrough progress in medicine.

These observations about surgical innovation stem largely from my experience in the development of laparoscopic nephrectomy, in which I was privileged to play a role while at Washington University in St. Louis, which I will outline here.

THE HISTORY BEHIND LAPAROSCOPIC NEPHRECTOMY

After doing preliminary work in dogs, the German surgeon Gustav Simon performed the first human nephrectomy in 1869, in a woman with a ureteral vaginal fistula. The operation was a success: it took him 50 minutes to complete the procedure, and 6 months later the patient went home.

From that point in 1869 until 1990, progress in nephrectomy was minimal, with open surgery remaining the gold standard. While the surgeon’s tools remained largely unchanged, the advances that did occur were in anesthesia, analgesia, and antibiotics, which allowed patients to better survive the onslaught of the operation.

In an unrelated arena, laparoscopy was developed in 1901 by another German surgeon, Georg Kelling, who pumped air into the peritoneal cavity of a dog in a successful effort to stop bleeding from the stomach. Within the pneumoperitoneum, Kelling was able to examine the canine organs with a cystoscope at pressures as high as 140 mm Hg. This discovery was not applied clinically, however, until 9 years later when the Swedish gastroenterologist H.C. Jacobeus used Kelling’s pneumoperitoneum concept and a cystoscope to visualize the peritoneal cavity to search for cancer. The technique advanced little in the subsequent decades —apart from Semm’s seminal laparoscopic removal of the appendix in the 1960s—until 1985, when the first laparoscopic gallbladder removal ignited the era of laparoscopic cholecystectomy.

Three technological developments spurred this recent surge in laparoscopy: (1) the ability to affix a camera to the endoscope, (2) the ability to display the camera’s images on a video screen, and (3) the development of self-feeding clip appliers to allow occlusion of vascular or ductal structures.

THE EVOLUTION OF LAPAROSCOPIC NEPHRECTOMY

Discovery

I became interested in the possibility of laparoscopic nephrectomy during the laparoscopic cholecystectomy craze in the late 1980s. At that time, I was working with Dr. Nat Soper, performing laparoscopic cholecystectomies in pigs to show that the procedure could be done safely with electrocautery rather than a laser. As it turns out, the anatomy of the porcine kidney is such that the colonic reflection lies medial rather than lateral to the organ. As such, the kidney is quite visible as soon as one enters the abdomen. Indeed, the kidney seemed to be saying to us, “Hey, what about me? I could come out through that hole too.” That is basically how the idea arose.

So, along with Dr. Lou Kavoussi and many others in our research team, we attempted laparoscopic nephrectomy in the pig and succeeded: the kidney could be removed through a small hole by entrapping it in a sack, breaking it up in the sack, and pulling it out.¹² The team involved in this discovery were specialists in urology and general surgery as well as biomedical engineers from industry, specifically a team from Cook Urological led by Mr. Fred Roemer.

After performing this technique numerous times in the laboratory, we reduced the operation’s duration to 90 minutes, at which point we believed the procedure had advanced sufficiently to be considered for clinical use.

Development

The patient we selected for the initial clinical case was an 85-year-old woman with a 3-cm mass in her kidney. She was deemed to be “too sick to operate on,” so she was presented to me as a candidate for the new laparoscopic procedure.

Amazing as it may seem in our current medical climate, at that time (1990) we were faced with the question of whether or not to seek institutional review board (IRB) approval. The argument could be made that since radical nephrectomy had been practiced for 120 years and laparoscopy had been around for nearly 100 years, the combination of these two well-accepted procedures might require nothing more than physician-patient informed consent. However, the concept of “informed consent” in this context was problematic: what could we tell the patient about a procedure that had never been done before except that if it was not working out we would convert to the standard open procedure?

A senior colleague—actually my boss at that time, Dr. Bill Catalona—sagely advised me to get IRB approval, noting, “If the operation works out well, you’ll be fine, but if it doesn’t work out well, they’ll kill you if you don’t have approval.” So we fortunately ended up seeking (and receiving) IRB approval, as well as providing, as best we could, informed consent to the patient and her best friend.

Our next consideration was designating a team member to determine if and when conversion to open surgery would be necessary. We needed a “referee” to aid in objectively determining a point at which we should convert. For our team, that person was Dr. Teri Monk, our anesthesiologist, who had no previous experience with our laboratory work but understood what we were attempting.

So we proceeded with the first clinical laparoscopic nephrectomy on June 25, 1990. The kidney was embolized the morning of the procedure. Five laparoscopic ports were placed. The clip appliers proved too small for renal vein occlusion, so the main renal vein had to be traced to its branches; in total we clipped five separate sets of renal vascular branches. The kidney was ensnared and morcellated, which took 7 minutes. Total operative time was 6.8 hours. The complications that arose were not anticipated:

• Intraoperative oliguria due to the prolonged pneumoperitoneum
• Fluid overload (postoperative congestive heart failure) due to providing fluids to the patient as though this were an open procedure
• Dilutional anemia, again due to providing excessive fluids for a closed procedure.

Postoperative pain medications consisted of one dose of morphine sulfate. The patient was discharged on postoperative day 6 and resumed normal activities by postoperative day 10.¹³

Dissemination

Before a new procedure is disseminated, evidence of the four Es—efficiency, effectiveness, equanimity, and economy—must be obtained. In retrospective reviews, laparoscopic removal was associated with a slightly longer operating time but much less blood loss, a shorter hospital stay, and fewer complications. The immediate cancer cure rate was the same for open and laparoscopic nephrectomy, and over time the laparoscopic procedure has been shown to be just as good as open surgery at 5 and now 10 years. Also, with time, laparoscopic nephrectomy was shown to reduce institutional costs.

The next question was the proper way to disseminate this knowledge. At Washington University we took the traditional route of providing courses, offering 17 courses on laparoscopic surgery to nearly 1,000 urologists from 1985 to 2002. But as Winfield and associates later showed, only 54% of urologists who completed a 2.5-day hands-on, laboratory-based laparoscopic course actually ended up introducing laparoscopy into their practice.¹⁴

The challenge of dissemination is still with us, and we need to find better methods of transferring new skills to our surgical colleagues. In this regard, longer experiences, such as weeklong mini-fellowships and the development of procedure-specific surgical simulators, hold great promise.

UNANSWERED CHALLENGES, UNMET NEEDS

With the advent of any technology comes a cornucopia of unanswered questions and challenges. In the areas of discovery and development, a key question is whether every procedure performed using a new Food and Drug Administration (FDA)-approved technology requires a separate approval by the IRB and ethics committee. For instance, if robotic prostatectomy is approved and performed, are separate approvals needed for robotic nephrectomy, robotic pyeloplasty, and robotic vasectomy? Where would or should the approvals end?

With respect to dissemination, many questions remain: How is a new technology taught effectively? How is surgical competency tested? How is clinical performance or proficiency evaluated?

One problem specific to dissemination is a lack of funding. While ample funding is available for discovery and development, as they bring prestige and profit, dollars are scarce for dissemination, or the teaching and testing of competency and proficiency with new procedures. 

Evidence of our failure to educate the postgraduate surgeon abounds in terms of poor outcomes and malpractice suits. The response of government all too often is the knee-jerk reaction to protect (ie, regulate), not educate. To be sure, we can do better, but only if our society commits to the process—not with words, but with funded educational action.

With regard to the last, I believe there is an unmet need for the development of accurate, validated surgical simulators. As a society, we need to find a way to fund the development of simulators for each surgical subspecialty and then use these devices to objectively test an individual surgeon’s manipulative skill as well as cognitive ability when he or she seeks certification or recertification—and perhaps, albeit in an abbreviated 5-minute format, before beginning each operative day. We owe this to ourselves, but most of all to our patients, who in all confidence place their lives in our hands.

By Thomas M. Krummel, MD

If we surgeons take a step back and consider for a moment what has changed in the operating room (OR) in the past 50 to 60 years, the clear answer is, “Just about everything.” The monitors, pumps, transport devices, and OR tables and lights have all changed dramatically, as have the tools, catheters, sutures, energy sources, scopes, staplers, ports, valves, and joints. If we consider technologies outside the OR that guide what we do inside the OR, the changes are just as striking. Circulatory assist devices for the failing heart and widespread use of dialysis for the failing kidney postdate 1950, as does all of our modern imaging capability—ultrasonography, computed tomography, magnetic resonance imaging, positron emission tomography, functional imaging. As for pharmacotherapy in 1950, there were three antibiotics, no antivirals, one antifungal, and three chemotherapeutic agents. Open drop ether was the anesthetic of choice. Not only have the tools and technologies changed, but virtually every procedure has been changed. Both our profession and the industry that has developed these devices and tools can be rightfully proud.

It is likewise necessary to recognize that our patients have been partners in this innovation. Many of them have given informed consent to participate in research and experimental procedures with the expectation that the benefits might accrue only to future patients and not to themselves. That is a hell of a contribution, and we can be proud of our patients’ partnership.

THE GOOD, THE BAD, AND THE UGLY OF INNOVATION

The history of progress in surgical care is always about innovation, and such progress almost always begins with an unsolved patient problem, regardless of the solution that is developed, be it a tool, a device, a technology, or a surgical procedure. At the same time, any discussion of the ethics of surgical innovation should recognize that while efforts to solve patient problems over the years have had many good results, they have also had some bad results and even the occasional ugly result.

This conference has already focused on much of the good that has come from surgical innovation, including transplantation, remarkable advances in cardiac and gastrointestinal surgery, a host of devices, and too many other benefits to list. Yet missteps have been made along the way, such as bloodletting, gastric freezing as a therapy for ulcer, and carotid denervation for treatment of asthma in children.

Then there are the ugly incidents, and these notably include a number of cases involving children, an issue of special interest to me as a pediatric surgeon. Consider the following examples:

• Edward Jenner’s notorious cowpox experiment in the late 18th century was conducted in an 8-year-old boy.
• A well-documented literature shows that orphans were used as subjects for tuberculosis and syphilis inoculations.
• The more recent case of Jesse Gelsinger involved a teenager with a nonlethal condition who died in a clinical trial of gene therapy, after which an undisclosed financial interest on the part of one of the treating physicians was revealed.

It should give us pause to note that many of these practices that look foolish in hindsight probably seemed more rational at the time they were undertaken.

CHILDREN: THE ORPHANS OF INNOVATION

Children have been the orphans of innovation, as technology development specifically for children has traditionally been a low priority. There are several reasons for this:

• FDA standards for approving therapies in children are high. For instance, the vast majority of chemotherapeutic drugs are not approved for use in children because conducting a trial specifically in children is deemed too expensive.
• Pediatric markets for therapies are small.
• The payor mix is poor.

The benefts of duality

Nevertheless, children have benefited enormously from the duality of technology development, in which a technology developed for one population—either adult or pediatric—ends up benefiting both populations. For instance, no one would have invented the pulse oximeter to care for a child, yet now it is the only device with which infants and children are monitored in the operating room and during transport.

Likewise, in some cases the solutions to pediatric problems have had reciprocal benefits in adults. Ligation of the patent ductus arteriosus and the Blalock-Taussig shunt for tetralogy of Fallot opened the door to our understanding of surgery on the great vessels and ultimately enabled the development of cardiac surgery. Similarly, the early impetus for Thomas Starzl’s groundbreaking work in transplantation was focused on children with biliary atresia even though this work is now much more widely applied in adults.

ETHICAL PRINCIPLES APPLY EQUALLY TO ADULTS AND CHILDREN

The principles of medical ethics that began with Hammurabi in 1750 BC and progressed through Hippocrates’ work circa 400 BC, the 1946 Nuremberg medical trial, the 1964 Declaration of Helsinki,¹⁵ Henry Beecher’s classic exposé in 1966,¹⁶ and the 1979 Belmont Report¹⁷ are just as valid for children as they are for adults.

Francis Moore, the great surgeon who created the environment and the team at Brigham and Women’s Hospital that facilitated the first twin-twin transplant, identified six important components of ethical surgical innovation:^18,19

• A solid scientific background (basic laboratory research)
• A skilled and experienced team (“field strength,” as Moore called it)
• An ethical climate within the institution
• An open display for ongoing discussion
• Public evaluation
• Public and professional discussion.

The principles behind these components remain as true today as they were 20 years ago when Moore outlined them.

SPECIAL CONSIDERATIONS IN PEDIATRIC SURGERY: A CASE STUDY IN MATERNAL-FETAL MEDICINE

The Belmont Report, mentioned above, was developed by the US government in 1979 to form the basis of regulations for federally funded research involving human subjects.¹⁷ The report identified three basic principles that must underlie such research:

• Respect for persons—protecting the autonomy of all subjects, treating them with courtesy, and allowing for informed consent
• Beneficence—maximizing benefits from the research initiative while minimizing risks to the subjects
• Justice—ensuring reasonable, nonexploitative, and well-considered procedures that are administered fairly.

In pediatric surgery, everyone agrees that the “best interests of the child” must be protected, but the issue of autonomy (a key element of the first Belmont principle) is more difficult to define, of course, when the patient is a child rather than an adult. The question of autonomy is especially tricky in the evolving field of maternal-fetal medicine: what if the patient is a fetus and the mother is an innocent bystander?

Over the past 20 years, tremendous progress has been made in our understanding of diseases of the fetus, particularly diseases that limit fetal viability and diseases that cause serious organ damage but which may be more responsive to postnatal therapy if they are treated prenatally. Michael Harrison, N. Scott Adzick, and a few of their disciples have laid the ethical groundwork for consideration of the fetus as a patient.

Considerations in maternal-fetal medicine

I will conclude with a case in maternal-fetal medicine for us to consider and perhaps debate in the panel discussion at the end of this session. As you consider this case, keep in mind several important observations relating to maternal-fetal medicine:

• The mother’s health interests cannot be underestimated.
• Most “fixable” fetal lesions (ie, those that interfere with development and cannot be fixed postnatally, but for which intervention in utero may result in normal development) are very rare. They include obstructive uropathy, lung lesions causing hydrops, congenital diaphragmatic hernia, sacrococcygeal teratoma, hydrocephalus, twin-twin transfusion syndrome, congenital high airway obstruction, hydrothorax, myelomeningocele, and congenital heart disease.
• The field is evolving, and the efficacy of therapy is supported by variable level I, II, and III evidence.
• The law has not kept (and perhaps cannot keep) pace with developments in this field.

Case study

A 24-year-old healthy woman has a fetus of 28 weeks’ gestational age with progressive lower urinary tract obstruction with megacystis, bilateral hydronephrosis, and oligohydramnios. In other words, there is diminished volume in the uterine cavity that causes compression of the fetal chest and subsequent respiratory compromise that will be fatal if not addressed. The karyotype is a normal 46,XY male. Serial urine sampling reveals electrolyte and protein profiles with a good prognosis.

Prenatal counseling with fetal therapy specialists suggests that this is the “perfect case” for a vesicoamniotic shunt. This is the least invasive, most successful fetal surgical intervention. It is done under local anesthesia and involves transabdominal transuterine percutaneous placement of a double-lumen pigtail catheter in the fetal bladder. There has never been a reported maternal death, and morbidities have been minimal. Renal and pulmonary function both are improved by approximately 80% in fetuses treated with this intervention, and survival is improved.

The father is eager to proceed. The mother is ambivalent. Should the mother be pressured to proceed, for the good of the child?

Questions to ponder

The following questions are intended to be provocative, with no clear-cut answers:

• Should (or does) the fetus have independent moral status? Is it full, graded, or none? Does it matter?
• What are the beneficence-based obligations to the fetus? At 28 weeks’ gestation, the fetus is viable outside the uterus. The fetus is otherwise well, without a lethal karyotype, and has currently good renal function.
• What are the beneficence-based and autonomy-based obligations to the mother? What are the mother’s obligations to the fetus?
• What if the mother ultimately decides to proceed and the insurance company denies coverage? What are the social responsibilities to care, cost, and research?

These questions lend themselves to discussion. As much as we surgeons like to be certain about what we do, we would do well to heed the quote from Voltaire that the great surgeon Norman Shumway hung on his office door: “Doubt is not a very agreeable state, but certainty is a ridiculous one.”

By Philip R. Schauer, MD

Obesity is a staggering problem: 100 million Americans are overweight, 85 million more are obese, and another 15 million are morbidly obese (ie, ≥ 100 lbs above ideal body weight). The incidence of obesity is rising rapidly and threatens to shorten the life spans of today’s young generations relative to their parents. Unlike other conditions, such as cardiovascular disease and cancer, obesity has seen no widespread progress in management in recent years.

Recognition of obesity as a medical problem is a challenge in itself. Many people consider obesity to be a character flaw or a behavioral issue and fail to recognize it as a disease entity. Yet obesity is the root cause of many metabolic conditions and diseases with metabolic components, including type 2 diabetes, heart disease, blood pressure, metabolic syndrome, acid reflux, gout, arthritis, and sleep apnea.

The approach to obesity treatment can be conceptualized as a pyramid, with the aggressiveness of the intervention based on the patient’s body mass index (BMI). At the base of the pyramid, for patients with lower BMIs, are minimally invasive (and minimally effective) interventions involving changes in diet, physical activity, and other lifestyle factors. As BMI increases, so does the intensity of treatment, to include pharmacotherapy and eventually bariatric surgery. Traditionally, surgery has been considered only at the very top of the pyramid, for morbidly obese patients, and is usually not offered as an option for the vast majority of people with this condition.

The sad reality is that the various combinations of these therapies are effective in fewer than 1% of the approximately 100 million Americans who are obese. Because surgery has been shown to be the most effective therapy for obesity, the remainder of my discussion will focus on surgery, with an eye toward potential new indications for bariatric procedures and the questions they raise.

SURGICAL APPROACHES TO OBESITY

Bariatric surgery has evolved over the past 50 years. Although there are about a dozen different permutations of bariatric procedures performed in the United States today, they fall into one of three major types of operations, as outlined below:

Gastric banding reduces appetite and satiety by adjusting and tightening the gastric band. This procedure has been in existence for 10 to 15 years and represents about 25% of operations for obesity in the United States.

The biliopancreatic diversion procedure diverts most of the small bowel and radically reduces absorption of calories. Patients undergoing this procedure lose weight because few calories are absorbed into the body. This approach, while quite effective, is somewhat radical and represents only about 2% of the operations for obesity in the United States.

The Roux-en-Y gastric bypass procedure has been the dominant procedure over the past 15 to 20 years. A combination of the above two procedures, it involves reducing the gastric reservoir and bypassing the stomach and upper intestine. The reduction in gastric volume reduces calorie intake by enhancing satiety, and the limited foregut bypass moderately reduces absorption.

No randomized trials, but much support from observational studies

Virtually none of these procedures evolved with randomized controlled trals. Instead, they evolved incrementally, primarily on the basis of knowledge gained from case procedures. Despite the lack of randomized trials, these operations have been shown to be effective, particularly in patients with multiple metabolic abnormalities associated with severe obesity. A large body of data from case-control and cohort studies demonstrates not only dramatic improvement in metabolic abnormalities with the use of various bariatric procedures, but also improvements in quality of life and survival.^20–26 The two most recent of these studies, published in 2007, found reductions in mortality of 29% (adjusted) and 40% among surgical patients compared with well-matched obese controls during mean follow-up of more than 7 years.^25,26 Reductions in the incidence of cardiovascular mortality and, secondly, cancer-related mortality were the two major contributors to the overall mortality reduction in these two studies. Consistent with this latter finding, obesity is starting to be thought of as a disease that may lead to cancer.

NEW FRONTIERS FOR BARIATRIC PROCEDURES

The current indications for bariatric surgery have existed intact for about 25 years, and were based on limited evidence available at the time. They are basically as follows, assuming acceptable operative risk and appropriate patient expectations:

• BMI greater than 40 kg/m²
• BMI greater than 35 kg/m² with significant obesity-related comorbidities.

Payors adhere strictly to these indications, such that they will not pay for bariatric surgery in a patient with a BMI less than 35 kg/m². This raises questions about the appropriateness of such a firm threshold and whether expansion of these strict indications may be reasonable.

Even without broadened indications, the volume of bariatric procedures in the United States has grown dramatically in recent years. Whereas only 10,000 to 20,000 of these operations were performed annually in the 1990s, approximately 200,000 such procedures were performed in 2007, and this number is expected to double over the next 5 years or so.

This growth in volume has been paralleled by burgeoning media interest in bariatric procedures, particularly in the last few years. More attention can be expected as we increasingly recognize the potential of bariatric procedures for indications beyond strictly the treatment of morbid obesity. At least two new frontiers loom: metabolic surgery and endoscopic surgery.

Metabolic surgery

Procedures that incorporate a bypass—the Roux-en-Y gastric bypass and the biliopancreatic diversion —have been associated with a reversal of metabolic diseases such as type 2 diabetes.^27–32  Many patients with type 2 diabetes who have undergone these procedures have been able to be weaned off insulin and insulin-sensitizing medications while maintaining normal blood glucose levels. The effect has been profound and immediate, occurring even before the patient loses weight. In one series of patients with type 2 diabetes who had undergone a bypass operation, 30% left the hospital in a euglycemic state.²⁹

These observations have been made primarily in the morbidly obese population, who are the primary candidates for bariatric bypass procedures. However, because of the rapid improvement in metabolic abnormalities that has been observed, interest has arisen in applying these procedures to populations that are not morbidly obese. Bypassing of the foregut appears to be critical, perhaps because it tempers the release of hormonally active peptides from the gastrointestinal tract.³³ In any case, the gut is regaining recognition as a major metabolic organ.

In light of these hypotheses, the duodenal-jejunal bypass is a bariatric procedure that may be beneficial for a patient with type 2 diabetes who is not morbidly obese. In this operation, the stomach volume is preserved but the foregut is bypassed. In a small experimental series from Brazil, patients with type 2 diabetes who were normal weight or only slightly overweight had resolution of their diabetes following this procedure, without any weight loss.³⁴

New applications for endoscopy

Another area of development is endoluminal and transgastric bariatric surgery. Endoluminal surgery is performed entirely within the lumen of the gastrointestinal tract using flexible endoscopy. Transgastric surgery is performed within the peritoneal cavity, which is accessed via a hollow viscus. Both approaches use natural orifices to gain surgical access, thereby avoiding access incisions and scars.³⁵

The benefits of such an approach are numerous:

(1) fewer complications and side effects; (2) less invasiveness, and thus the ability to perform in the outpatient setting; (3) reduced procedure costs; and (4) better access to treatment. The implication in terms of indications is the potential to use such procedures to prevent progression to morbid obesity.

Examples of these procedures are proliferating:

Gastrojejunostomy reduction is an endoscopic procedure that involves reducing the dilated opening of the gastric pouch after gastric bypass surgery. New endoscopic suturing or stapling devices enable the outlet reduction without requiring surgery. The result is enhancement of weight loss without a major operation.

Endoluminal suturing uses endoscopic instruments to suture the stomach to reduce its volume. When this procedure is perfected, the patient should be able to leave the endoscopy suite and return home within a few hours.

The duodenal sleeve is an avant garde concept in which an internal sleeve is threaded into the stomach and down the intestines.³⁶ The sleeve covers the absorptive surface of the small bowel, preventing absorption of nutrients to cause weight loss. This procedure has been shown to have a strong antidiabetic effect as well.

Clinical applications of these operations are emerging. An endoluminal sutured gastroplasty procedure to shrink stomach volume has been shown in a small clinical trial to cause loss of significant excess body weight; the operation leaves no scars and is associated with a low risk of bleeding or any type of surgical complication.³⁷ A similar procedure is in development that involves staples instead of sutures.

How best to validate innovations moving forward?

As we move into these new eras of metabolic surgery and endoluminal and transgastric bariatric surgery, interesting questions arise. We as innovators and caregivers are ethically obligated to demonstrate reasonable safety and efficacy before such new procedures are performed widely. Although some of these emerging procedures involve new devices that will go through the FDA review process, many are existing procedures for which indications may be expanded, while others are permutations of existing procedures for which no formal rules for validation exist. For new procedures that differ substantially from existing proven procedures but which do not require new devices, should we not be ethically bound to demonstrate safety and efficacy even though they do not require FDA review? These are the challenges that await as innovation takes bariatric surgery to new frontiers.

By Christopher Thompson, MD, MHES

Although the endoscope has changed very little since the first fiberscope was developed 50 years ago, the accessories and other instruments used in conjunction with the endoscope have changed remarkably. These include clips for hemostasis, ultrasonographic technology, and instruments for tissue dissection.

These advances in endoscopy, combined with advances in laparoscopic surgery, have led to the convergence of these two fields, culminating in the new field of natural orifice transluminal endoscopic surgery (NOTES). In NOTES, the surgeon enters a natural orifice and punctures through a viscus to perform surgery, removes the endoscope, and closes the area without leaving a scar.

HISTORY OF NOTES AT A GLANCE

NOTES was patented as a concept in 1992. Its first application was as an exploratory procedure in the pig in 2004.³⁸ Soon thereafter, therapeutic NOTES procedures in animals were reported, including tubal ligation, organ resection, cholecystectomy, and splenectomy.

Particularly notable in the development of NOTES is the extremely short interval between early animal experiments (2004) and the first human procedures, which took place as early as 2005 when surgeons in India used the technique to perform a human appendectomy. Since then, more than 300 NOTES procedures have been performed in humans throughout the United States, Europe, Latin America, and Asia, for applications ranging from percutaneous endoscopic gastrostomy rescue to transvaginal cholecystectomy.

This rapid adoption of NOTES in humans is concerning, as it raises clear questions about whether there has been time for adequate oversight and safety assessment. For instance, at a surgical conference in April 2008, questions and debate swirled around whether a large Brazilian registry of more than 200 NOTES cases did or did not include two deaths. Other ethical issues raised by NOTES are discussed further below.

DRIVING FORCES BEHIND NOTES

The medical rationale

Abdominal wounds can cause pain, are unaesthetic, and are prone to wound infections, ruptures, and hernias. They sometimes cause adhesions or may lead to abdominal wall syndromes with scar neuromas that cause pain later. They also require general anesthesia. Beyond these shortcomings of incision-based procedures, NOTES offers potential reductions in length of stay and therefore in cost. Moreover, certain patient populations may specifically stand to benefit from NOTES, such as obese patients, those with abdominal mesh in place, and those undergoing palliative procedures. This is the essence of the medical rationale for NOTES, which is somewhat thin.

Professional organizations and courses

In July 2005, leaders from the American Society of Gastrointestinal Endoscopy and the Society of American Gastrointestinal and Endoscopic Surgeons convened a working group to support and plan for the responsible development of NOTES.³⁹ The group formed the Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR), an organization that has since sponsored several conferences on NOTES and procured millions of dollars in grants for NOTES research in animals. (In the interest of full disclosure, I am one of the founding members of NOSCAR.)

Additionally, leading institutions in this field have held numerous hands-on courses on NOTES throughout the United States, Europe, Latin America, and Asia. These courses, including those held by my laboratory at Harvard University, are designed to teach colleagues at other institutions how to set up an appropriate animal laboratory and to promote and encourage proper research in NOTES. There have been unintended consequences, however, as we have learned that some course attendees have returned to their home countries and immediately started using the techniques in humans.

New technology

At the July 2005 working group meeting that launched NOSCAR, we determined that several technological advances were needed before NOTES could be safely applied to humans. These included development of multitasking platforms, better devices for tissue apposition and fixation, better imaging and spatial orientation, and improved means of retraction.³⁹ Industry responded with novel devices and end effectors such as guide tubes, direct drive systems, endoscopic suturing devices, magnetic retraction, devices for closing luminal defects, flexible staplers, and computerized robotics.

Other driving forces

Additional forces have undoubtedly contributed to the rapid development of NOTES:

• The slowdown in innovation in general surgery in recent years has left a vacuum to be filled.
• An abundance of venture capital has been available to rush into that vacuum.
• Perceived patient demand (owing to cosmetic advantages) has been a driver, especially in cities such as Rio de Janeiro, Milan, and New York.
• The fear of being left behind is a factor that cannot be underestimated. Surgeons who failed to convert to laparoscopic techniques from open techniques in the early 1990s for procedures such as cholecystectomy, fundoplication, and splenectomy were losing their patient bases. Many surgeons fear a similar phenomenon today if they do not adopt NOTES into their practices.

ETHICAL ISSUES RAISED BY NOTES

As NOTES moves toward further evaluation in humans, several ethical questions need to be grappled with:

• Must there be a significant potential for improvement in care before an innovation advances to human research?
• Is the cosmetic benefit of NOTES sufficient, considering the substantially increased risk? For instance, laparoscopic cholecystectomy is well established, whereas NOTES cholecystectomy carries an increased risk of bile duct injuries and other injuries. Is NOTES worth the risk?
• What about the corporate agenda behind new technologies and its associated influence on the media?
• Are hospital IRBs adequate to the task of evaluating and monitoring these questions, and will they be independent of the impact of hospitals’ larger agendas?

Finally, the problem of premature adoption of this technology is particularly concerning. I heard a surgeon explain at a course that he performed NOTES on a few pigs at a previous course and then returned home to Peru and immediately started performing it on patients at his ambulatory surgery center. There is also the temptation for well-respected surgeons to go to other countries to practice their NOTES skills before returning to the United States, in hopes that their experience will help them attain IRB approval. Practices like these raise questions about what ethical responsibilities lie with those of us who have pioneered the technology and are trying to develop and disseminate it responsibly. We can try to vigilantly watch course attendees from certain countries, but there is little we can do in the absence of regulation and enforcement in those countries. These are difficult ethical challenges.

Panel discussion

Moderated by Jonathan D. Moreno, PhD

Dr. Jonathan Moreno: I would like to begin with any questions that the panelists have for one another.

Dr. Philip Schauer: I would be curious to hear how my colleagues define incremental changes in a procedure. In other words, what constitutes a new procedure versus a modification of an existing one?

In bariatric surgery we are grappling with a procedure called the sleeve gastrectomy, which poses challenges comparable to lung volume reduction surgery as described by Dr. Cooper. Many of us believe that this procedure is just a slight modification of a gastroplasty, yet payors consider it an entirely different procedure, and some want 5 to 10 years of follow-up data before they will pay for the operation.

Dr. Joel Cooper: That is not an easy question, but I would approach it from the standpoint of what you would tell the patient. When we were first developing lung volume reduction, we performed it only in patients who had absolutely no other alternative. Only later in its development did we offer it as an alternative to transplantation. How do you approach the patient when you can already achieve a very good result with an existing procedure and you can tell the patient, with some assurance, what to expect with that procedure? In the case of NOTES, I do not think that the cosmetics are sufficient justification.

The second aspect is regulatory. I am not a supporter of the FDA’s practices for the introduction of new procedures, but I believe strongly that universities have been derelict in setting the standard for the introduction of new procedures, particularly minimally invasive procedures. They have been using these procedures as marketing tools to vie with private hospitals for dollars and patients. I cannot say whether the rapid promulgation of these procedures at too early a stage actually can be prevented, but I do not recall the chairmen of major surgery departments getting together to issue public statements about the proper protocol for introducing new techniques. As Pogo said, “We have met the enemy and he is us.”

This may not answer your question, but I believe there should be no payment for any new or novel procedure for a certain period after its introduction, and certainly the hospitals should not be able to profit from it, although the expenses of a new procedure may be recouped. That alone would perhaps put the brake on some of the marketing and the financial incentives, and it might separate, to some degree, the development of new procedures from economic interests.

WHO SHOULD OBTAIN INFORMED CONSENT?

Dr. Moreno: Should informed consent be obtained only by a knowledgeable third party rather than the surgeon-innovator?

Dr. Thomas Krummel: The question is whether there is a disinterested third party who truly is knowledgeable; in cases where there is such a person, I see no downside to having that person involved. However, the notion of having someone who is not associated with clinicians or surgeons obtaining informed consent makes me uncomfortable. Informed consent is not a piece of paper. It is a trust between physician and patient, and to ignore that could leave you in a heap of trouble.

Dr. Cooper: I agree, but another process is important as well. In proposing lung transplantation before there had been any successful transplants, we defined in advance the standards, indications, and contraindications that we thought should apply. We did this in the absence of any particular patient, and it relieved us of the difficulty of making arbitrary decisions that may have led to unfairly accommodating one patient over another. Once the standards have been set in this way, they can be applied—whether by the investigator or by a committee—in an objective way to the group of patients that is most appropriate in the early phases of development.

Dr. Ralph Clayman: It is difficult for the inventors of an operation to dampen their enthusiasm for their creation to a point where they are as objective as they should be. Joel is bringing up situations for which there are no alternatives. My realm is an area in which there were well-established alternatives for everything we have done laparoscopically or percutaneously, and it was difficult to decide the indications or contraindications early on. Often, the early indications only had to clear the threshold of not seeming ridiculous.

The early development of percutaneous stone removal at the University of Minnesota took place entirely outside the purview of an IRB. Percutaneous nephroscopy had been around since 1955, and we extended it to plucking out a stone. That is how that entire field developed. Early on, we were not going to go after a stone that was as big as a fist because we did not have a way to break it up. As time went by, however, it evolved to the point where there was no stone in the kidney—regardless of its size, location, or hardness— that could not be removed through a small hole in the back. But that entire evolution proceeded without IRB approval.

For laparoscopic nephrectomy, for which there were well-known alternatives, who should have obtained the informed consent? Should it have been me, bringing along the “white coat” factor and not being able to really explain the potential problems since nobody had yet gone there, despite my rapport with the patient? Or should it have been a third party with whom I had discussed the procedure and its possible problems? I do not know the answer, but it raises an interesting point, especially in this age of IRBs and ethics committees.

Dr. Krummel: It is not unlike what we have tried at Stanford when we are not sure of the boundary for IRB consultation. The surgical chairs are willing to convene and essentially police one another, so that when the neurosurgeon proposes a brain transplant, there probably will be a pretty interesting conversation before it gets the green light.

Dr. Cooper: My experiences with IRB involvement differed quite a bit between my work in lung transplantation and my work in volume reduction surgery, but the differences owe a lot to the countries where I was practicing at the time. I did my early work in transplantation in Canada, where I did ask for approval from my hospital’s ethics committee and other relevant committees. In Canada, the hospital had a global budget, and it made a decision that it was willing to use part of its budget for transplantation. We received no fees for years, until the operation was proven to be effective, but that did not stop us from developing the procedure.

I had returned to the United States when I began my work with lung volume reduction, and I did not ask the IRB for permission to do that procedure. My justification was that, theoretically, volume reduction was similar to accepted practices for removal of nonfunctioning lung to improve respiratory mechanics (bullectomy) and that we would simply be applying the concept to a different group of patients. However, unlike in Canada, I did not have institutional financial support for doing this new procedure, so how was I going to do it if the hospital could not receive payment for it? I went to the IRB, but instead of asking for permission to do the procedure I asked for permission to study the procedure and to collect data on it. In that way, I was notifying the IRB of my action and thus giving it an opportunity to act. If I had gone to the IRB to approve the procedure, however, the operation would have been labeled experimental by insurance companies, who would have then found a way to deny payment. At least that was how it was in those days.

Question from audience: What makes you think that in 10 years there won’t be 100 million obese Americans watching television ads for noninvasive bariatric surgery promising to rid them of their obesity problem? What will keep that from happening?

Dr. Krummel: Nothing. What makes you think it is not happening now? Just look at the ads for the Lap-Band in the lay press.

Dr. Clayman: We already have direct marketing of drugs and direct marketing of facilities. What Joel said is true: “the enemy is us.” When I was in training, the idea that a physician would advertise was considered unethical. I still consider it thus. But everybody is doing it, so should that make it acceptable? I think not.

The same thing is true of the huge amount of money spent marketing drugs on television. Why should a single nickel be spent to advertise health care beyond generically informing the public of important health care issues and initiatives? You cannot go to an airport without seeing a surgical robotics program being advertised or a hospital being advertised. You cannot turn on National Public Radio without hearing well-financed spots touting the achievements of a hospital. You cannot watch television without seeing ads for erectile dysfunction medications or other new drugs. It is a waste of dollars. If we took all of that money and redirected it, we could probably solve much of the indigent health care problem, but we as a society have chosen not to do that. 

SHOULD THE BAR BE RAISED FOR SURGICAL TRIALS?

Dr. Moreno: Let’s consider some additional questions. Why shouldn’t the government raise the bar on the level of evidence needed to gain regulatory approval for new devices? Why not require randomized trials, as is done for drugs?

Dr. Cooper: Procedures that lend themselves to a randomized trial should be studied at a limited number of centers with mandatory reporting and preset indications for promulgation and payment. I believe that universities have been derelict in their duty to require this level of evidence.

This question is always nuanced, however. Consider the case of laparoscopic procedures. They offer the advantage of smaller incisions, yet how many patients have had to die or suffer serious consequences for the sake of these smaller incisions? On the other hand, how many patients may have been saved from pulmonary embolism, wound infections, or a prolonged hospital stay as a result of laparoscopic techniques? Only a randomized trial could demonstrate whether or not there has been an overall payback from new procedures such as this, although even then the payback may be present for some types of patients but not others.

Dr. Schauer: The problem is expense. Perhaps it is all a matter of economics. Return on investment for the drug industry is something like 10 to 1, but return on investment for the medical device industry is generally much lower. Therefore, conducting large randomized controlled trials is extremely expensive and much more complicated for a device or procedure. This may explain why the standard for trials is different for the two industries.

Dr. Krummel: Virtually all fetal surgical procedures have been subjected to a trial, several of them randomized. The National Institutes of Health paid for many of these trials. One such study prevented rapid uptake of the congenital diaphragmatic hernia operation, which has never been proven in a randomized trial to be better than our current therapy. It is a good example of a randomized trial making a difference.

Dr. Clayman: As Joel pointed out, surgery is constantly evolving, whereas a drug remains unchanged throughout its lifespan. If we had started a prospective randomized trial after we had done our first laparoscopic nephrectomy, the procedure would have died because we were not nearly as facile with our first 10 as we were after our first 100. The technology continues to develop, and the surgeon continues to develop his or her skills, which makes a study of this nature overly dynamic. Perhaps the best you can do is a retrospective, matched, controlled study with the same surgeon, comparing his or her results after 40 or 50 laparoscopic procedures with results after his or her 50 most recent open procedures.

Dr. Cooper: How do you put a brake on the system? Would some sort of limited trial perhaps put a brake on the too-rapid promulgation that we often see?

Dr. Clayman: In the general surgery realm, laparoscopic cholecystectomy came out of private practice. It did not come out of the university with its faculty and laboratories dedicated to exploration and investigation. It never was properly vetted in the scientific realm but rather came to the light of day as an “economic” edge.

Dr. Krummel: I would not underestimate the talent and creativity of those that we train who go out into private practice. Much innovation has come from very active practitioners.

Dr. Clayman: Right, but they do not have the infrastructure that we are blessed with at universities both to create and to validate.

Dr. Schauer: I agree that academia does not have a monopoly on creative ideas. But perhaps academia should play a major role in defining validation-type studies. That is one area where we may be especially well suited to meet an important need.

THE INNOVATION-TRAINING INTERFACE

Question from audience: I have a dilemma as a residency program director. Our residents want to learn the new technology—laparoscopic surgery, robotic surgery, etc—but we have them in our program for such a limited time. How do you justify teaching them new technology and at the same time still teach them basic, traditional surgical procedures, especially with the reduction in residents’ hours? It is fine to be able to do a nephrectomy laparoscopically, but if you get in trouble, you still have to know how to do a good open nephrectomy. How do you address this?

Dr. Schauer: I think the answer largely is fellowship training. Emerging procedures probably should be introduced in fellowship programs until they reach the point where they are so standardized that they become a major part of practice. For example, cholecystectomy quickly became part of general surgery practice, but laparoscopic colectomy took several years to evolve and was taught primarily in fellowship or advanced training, after which it gradually filtered down to residency programs.

Dr. Krummel: All of us who are responsible for training are wrestling with this problem. Residents are expected to learn more yet do so in less time. One approach would be early specialization, so that instead of 5 years of general surgery, you would have 3 years of general surgery and then 3 years of, for instance, thoracic surgery. Also, Ralph mentioned earlier the advantage of skills labs. We increasingly see that type of approach as a backbone for providing broad training without putting patients at harm.

As for teaching the use of new technology, first you have to teach the existing base of practicing surgeons. Here again there is much to be said for skills labs, and I give credit to the American College of Surgeons for its drive to establish and accredit centers around the country as a way to teach this base of surgeons.

Dr. Schauer: If I may expand this question beyond residency and fellowship training, how do we balance the desire to share new innovations with our colleagues against the need to temper their desire to prematurely jump into an area where they do not yet really belong? Chris, I know this applies to your challenges in disseminating knowledge about NOTES.

Dr. Christopher Thompson: Yes, courses on NOTES are also being held in conjunction with all the major society meetings, and we are seeing many enthusiastic trainees at these hands-on courses. The original intent was to give attendees instruction on setting up their own animal labs, yet some trainees took it beyond this limited purpose. As a result, some in our field believe that we should not allow foreign physicians to come here to be trained in NOTES, for fear they will go back to their home countries and use it on humans. I am not certain that that approach is the best way to go, but there has been much discussion about how to handle this. It is a real conundrum. Certainly there are a number of surgical residents and gastroenterology fellows who are clamoring to get into the lab right now and learn these techniques.

Dr. Clayman: This goes back to our earlier discussion about from where new technologies should emerge. What frightens me are the consequences of creative activity occurring outside the university, where there are no laboratories or animal or cadaver models for refining or testing a technique. To me, it was frightening to see laparoscopic cholecystectomy suddenly emerge as a craze without the proper animal and clinical studies having been done. That is not the way I believe clinical research should go forward. I once heard a prominent urologic surgeon say at a major surgical meeting, after a presentation on the impact of percutaneous stone surgery on the canine kidney, “Now that I’ve done a thousand of these in humans, it’s reassuring to know that it’s safe to do in dogs.” That is not the way it should happen, and every time it does happen that way, we pay a large price, some of us as individuals and all of us as a society.

Dr. Cooper: The answer therefore is to use our academic facilities to facilitate the training of those in community practice. We should continue to offer training because we have the resources to make it available.

Dr. Clayman: Yes, and this is why I emphasized earlier that support for surgical training centers is so essential. I see all the dollars spent on health care advertising and wonder why these dollars are not instead poured into surgical training, or research facilities, or training simulators.

The way we should train surgeons in new technologies is to train them on simulators equipped with a properly vetted curriculum. This is the future for training, because once you put instruments through small ports, everything becomes measurable—economy of motion, past pointing, and efficiency; simulators with a curriculum will also be able to assess the trainee’s cognitive abilities. When an individual performs well on the simulator, he or she can then come into the operating room and work with surgeons experienced in the procedure. The use of simulators in this manner should ultimately improve the overall quality and safety of each surgical specialty.

Question from audience: I am curious how the panel members interpret early randomized trial data showing an increased cost without an improvement in care with the use of surgical robots in certain procedures. Should we persist or consider an investment in the future as robotic technology improves and surgeons further adapt to it?

Dr. Cooper: I think the robot should be used only for those procedures for which it has unique capability and can perform a task better than we can. It appears that the robot performs better than the ear, nose, and throat surgeon for operations on the base of the tongue. The same may be true of prostate surgery, but I am not certain. But to do a laparoscopic Nissen repair with a robot…as Dr. Nat Soper of Northwestern University has said, “If I needed a robot, I shouldn’t be doing laparoscopic Nissens.”

The robot provides light, it gives you magnification, and it reduces tremor. We should concentrate on its use for operations where these attributes are particularly valuable. But we should be wary of its use as an expensive marketing tool.

Dr. Clayman: The robot provides you with superhuman capabilities: 10 to 30X magnification, no tremor, a 540-degree wrist, instrumentation with 6 degrees of freedom, and motion scaling. It allows you to be a better surgeon than you are without it. I agree that it is expensive. It is woefully overpriced at this point, but I believe the expense will come down with time. It is no different than the first computers, which were terribly expensive. The robot enables surgeons to do a better job than they would without it if we are talking about reconstructive-type surgery.

Ergonomically, the robot is very positive for the surgeon. For the first time, the surgeon is actually allowed to sit down in a comfortable environment and can work for 4 hours straight, get up at the end of the surgery, and feel fine. If you are older than 50 and you operate standing at the table staring at a television screen on the other side for 4 to 6 hours, you are going to ache afterwards. I believe surgeons work better if they are comfortable.

Dr. Schauer: At least within my field of general surgery, there has been no evidence that this superhuman ability has translated into superhuman results, in terms of reduced operating time, fewer complications, or better efficacy. We should probably develop the metrics to measure progress. How do the theoretical benefits translate into clinical benefit?

Dr. Clayman: It is not theoretical in radical prostatectomy if you look at the data. The potency rates for patients who undergo robotic surgery for these procedures are now almost 90%, which is something that no surgeon performing open prostatectomy has ever achieved. Fortunately, the continence mechanism is so strong in most adults that it does not matter whether prostatectomy is done with a robot or open surgery—patients are probably going to be all right. But the bottom line is that robotic surgery is a bit better. Most surgeons would use it if it were free. The problem is that it is so expensive right now and it is breaking the backs of many hospitals.

Dr. Schauer: You make a good point. Demonstrating metrics is important, and prostatectomy is a good example. But I am not aware of any other procedures for which benefit from robotic surgery has been documented.

Dr. Krummel: The history of robotic surgery is so interesting because the killer application was supposed to be coronary work—percutaneous bypass surgery. But then the heart port went to pot and patients with anterior wall lesions ended up not being a big enough group. It turns out that it is still difficult to do and there is not a lot of room. So prostatectomy has ended up as the initial killer application.

Keep in mind that the current robot is not an end device. We will see more. There are now robotic steerable catheters that I think will be adopted into NOTES procedures. This theme of immediate benefit versus follow-on iterations is the story of device development in this country.

How should we introduce and evaluate new procedures?

By Joel D. Cooper, MD

Time magazine published an article in 1995 titled “Are Surgeons Too Creative?” that examined the question of whether operations should be regulated the way that medications are.¹ The piece featured two patients. One, a patient with emphysema who underwent lung volume reduction surgery at our institution during the early days of this procedure, had a good outcome. The other was a neurosurgical patient who had a bad outcome.

The public is somewhat sympathetic to this article’s premise, which can be viewed as a call to require a similar level of evidence for surgical procedures as for new drugs. This sympathy arises from the expense of new technologies, pressure from payors to control costs and increase profits, hospital budget restraints, and the reality of increasingly well-informed patients.

Yet there are distinct differences between drugs and surgery. A new drug does not change over time. A new drug is associated with a variable biologic response whose assessment often requires large numbers of patients and considerable follow-up. And a new drug may manifest unforeseen late side effects and toxicities far removed from the time of initial use. In contrast, none of these characteristics applies to surgical procedures. A surgical intervention changes over time as the technique and experience evolve and as refinements are made in patient selection and in pre- and postoperative management. With this evolution comes a change in risk over time. Patient selection for surgery is as much an art as a science; each patient requires assessment of both the potential benefits and risks of the procedure, which argues against offering an operation by prescription. Moreover, with surgery, the facilities and the operator’s skill and experience levels vary from one center to another.

INTRODUCTION OF NEW PROCEDURES: COVERAGE VS VALIDATION

Introduction of a new surgical procedure depends on the nature of the procedure and the other interventions that may be available for the condition. In assessing how new procedures should be introduced, I believe we need to distinguish between coverage and validation. Coverage—ie, payment for the procedure—is an economic issue, whereas validation involves an ethical and scientific evaluation of the role of the procedure.

Coverage by an insurer should have at least theoretical justification and presumption of benefit. For instance, the rationale behind a heart transplant for a patient with a failing heart is obvious. Coverage generally requires preliminary evidence of efficacy, possibly in an animal model, although no animal models may exist for some conditions. Most important, a different standard for providing initial coverage should be applied if no alternative therapy exists for a condition that is severe, debilitating, and potentially life-threatening; if a new procedure treats a condition for which a standard therapy already exists, the standard for coverage must be higher. Finally, coverage in all cases should require ongoing reassessment of the procedure.

In contrast, validation is a scientific analysis of results over time, including long-term results, and can be accomplished by well-controlled case series, particularly if the magnitude of the benefit is both frequent and significant and especially if no alternative therapy exists. Randomized clinical trials are the gold standard for appropriate interventions but are not always applicable.

A 1996 study by Majeed et al² provides a good example of validation-oriented surgical research. In this blinded trial, 200 patients scheduled for cholecystectomy were randomized to either laparoscopic or open (small-incision) procedures. The study found no differences between the groups in terms of hospital stay or postprocedure pain or recovery. In an accompanying commentary,³Lancet editor Richard Horton praised the design and conduct of the study, noting that it was very much the exception in surgical research, which he argued was preoccupied with case series. Horton offered the following speculation about this preoccupation:

Perhaps many surgeons do not see randomised trials as feasible strategy to resolve questions about surgical management. Cynics might even claim that the personal attributes that go to make a successful surgeon differ from those needed for collaborative multicentre research.³

IS THE ‘SURGICAL SCIENTIST’ AN OXYMORON?

Barnaby Reeves, writing in The Lancet 3 years later, offered a more diplomatic take on the difficulty of evaluating surgical procedures:

What makes a surgical technique new is not always easy to define because surgical procedures generally evolve in small steps, which makes it difficult to decide when a procedure has changed sufficiently to justify formal evaluation.⁴

Reeves went on to argue that doing an evaluation too early may preclude acceptance, since the technique may not have evolved sufficiently and surgeons may not have mastered it; conversely, doing an evaluation too late may make the evaluation moot, since the technique may have already become established and withholding it may be deemed unethical. Additionally, he noted that the quality of surgical evaluation is complicated by the possibility that some surgeons have better mastery of—and therefore better outcomes with—one procedure while other surgeons have better mastery and outcomes with an alternative procedure.⁴

These concerns were well captured by the late Dr. Judah Folkman, whom I once heard say, “When a basic scientist is informed that another investigator cannot reproduce his work, it has a chilling effect; for the surgeon, however, it is a source of pride.”

Even as we recognize these challenges specific to surgical evaluation, we are still left with the task of determining when a randomized controlled trial is appropriate and when a case-control series may suffice.

There are three broad sets of circumstances in which a randomized trial is essential:

• For preventive procedures, ie, when the operation is done to reduce the potential for a future adverse event. An example would be evaluating carotid endarterectomy to reduce the potential for stroke in asymptomatic patients with 60% or greater stenosis. Only a randomized trial could have shown a difference in favor of endarterectomy over aspirin plus best medical therapy.
• To compare a procedure with alternative medical or surgical interventions. I would argue that laparoscopic surgery should have been introduced with randomized trials, as it begs one to suspend judgment and accept that small incisions are invariably and de facto better than a large incision.
• For trials in oncology, where the outcome depends on long-term results, such as survival or time to recurrence. Examples would include comparisons of surgery alone versus surgery plus chemotherapy for prevention of cancer recurrence.

Similarly, there are several scenarios in which a case-control series is appropriate and adequate:

• When no alternative therapy exists. Falling into this category, in my view, are lung transplant, which we introduced successfully at the University of Toronto in 1983, and lung volume reduction surgery, which we introduced in 1993.
• When the natural history of the condition is well documented and the impact of the intervention is obvious.
• When the magnitude of the procedure’s effect is measurable, significant, and expected.

RANDOMIZED TRIALS IN SURGERY

Advantages of randomized trials

Randomized clinical trials confer a number of advantages. They eliminate bias. They ensure a balance between treatment groups in terms of known or unknown prognostic factors. And, importantly, they have a major impact on payors.

A tale of two Medicare payment decisions

The impact of clinical trials on payors is exemplified by the contrasting stories of two procedures: transmyocardial laser revascularization and lung volume reduction surgery.

Transmyocardial laser revascularization (TMR) involves the creation of channels in the myocardium with a laser to relieve angina. Although TMR is a dubious intervention with no physiologic rationale (similar to internal mammary artery ligation for angina5) and no proven improvement in life expectancy (only a reduction in pain), it was approved for reimbursement by Medicare because it was investigated in a randomized trial.⁶ However, the “randomized trial” was not truly a randomized investigation because the control patients received only medical therapy and did not go to the operating room to receive a sham operation.⁶ Despite this flaw, the perceived authority of the trial was sufficient to influence Medicare.

In contrast, Medicare refused to pay for lung volume reduction surgery until it was subjected to a randomized trial, despite the fact that the procedure had produced tremendous benefit in hundreds of patients at multiple centers who otherwise could not have achieved such benefit. Only after $50 million was spent on a randomized controlled trial, the National Emphysema Treatment Trial (NETT),^7–9 did Medicare agree to pay for lung volume reduction surgery. The trial showed that over 5 years, the procedure was associated with significant improvements in life expectancy, exercise tolerance, and quality of life, but the study took 8 years to conduct and by then it was a bit too late, as detailed in the following section.

NETT: A case study in how a trial can be counterproductive

Lung volume reduction surgery is an operation based on the recognition that the crippling effects of emphysema are hyperinflation of the chest, flattening of the diaphragm, and inability to move air in and out of the chest. The notion that the chest can be reconfigured in the patient with emphysema by removing the distending overinflated emphysema led us to develop the volume reduction operation.

The NETT was initiated by Medicare, and the protocol denied compassionate crossover of patients.⁷ In an attempt to establish clinical equipoise, surgeons who participated were not allowed to perform any volume reduction operations on non-Medicare patients or on Medicare patients not enrolled in the trial. After 2 years of slow patient enrollment, the clinical trial committee, in an effort to increase enrollment, eliminated the original entrance criteria specifying certain degrees of hyperinflation and diffusing capacity. An excess of mortality was discovered 2 years later in a subgroup randomized to volume reduction surgery;⁸ not surprisingly, further analysis showed that the excess mortality was largely confined to patients who would have been excluded based on the original entrance criteria. This is a matter of public record but was never acknowledged in published reports of the trial. Final 5-year NETT results showed that in patients with upper lobe emphysema, lung volume reduction surgery improved survival, increased exercise capacity, and improved quality of life.⁹ By the trial’s completion, however, the procedure’s reputation had been tarnished irreparably by bad publicity from the deaths attributable to the misguided changes to the original eligibility criteria.

Disadvantages of randomized trials

The NETT exemplifies many of the drawbacks of randomized trials in surgery, particularly the need to wait long periods while they are being conducted. During the 8 years in which the NETT was ongoing, the number of lung volume reduction operations declined, with the typical center performing fewer than 6 cases per year, on average. That limitation is certainly not conducive to the development of a new procedure for a disabling condition in patients with no ready alternative.

Other disadvantages of randomized trials in surgery are their considerable expense and the fact that they often are not generalizable and often are not appropriate. Moreover, when they are flawed, randomized trials propagate, sometimes for decades, misleading information that is nonetheless considered “authoritative.” For instance, lung cancer kills more men and women in the United States than the next three cancers combined, yet, on the basis of a flawed randomized trial,¹⁰ the American Cancer Society advises smokers to wait for symptoms before undergoing chest radiography, instead of recommending annual screening chest radiography. This is a major reason why two-thirds of lung cancer cases are discovered too late to save the patient.

‘Better to know nothing than to know what ain’t so’

Indeed, this potential for randomized clinical trials, when flawed, to propagate misleading information makes the perceived authoritativeness of randomized trials both an advantage and a disadvantage. As Berger and colleagues noted a few years ago, overuse of randomized trials for evaluating emerging operations could have led to the demise of heart transplantation, mechanical circulatory assist devices, cardiac valve procedures, coronary bypass grafting, and repair of congenital lesions.¹¹

For this reason, one of our responsibilities when reading the literature and conducting studies is not just to answer unanswered questions but to question unquestioned answers. As 19th-century humorist Josh Billings put it, “It’s better to know nothing than to know what ain’t so.”

A PERSONAL PERSPECTIVE

In my view, health care providers should restrict the application of new procedures to a limited number of centers of excellence that have appropriate resources and experience. Those centers should be required to document and report specified information regarding morbidity, mortality, and objective measures of outcome; if they do not comply, they should lose the privilege of doing such research. The data should be reviewed by an independent, nongovernmental scientific panel. In this way, the procedure can be offered to appropriate patients, insurers and patients can be protected against abuse, and the necessary data can be collected for objective analysis.

By Ralph V. Clayman, MD

Change in the surgical world involves three aspects, which I refer to as the three Ds: discovery, development, and dissemination. Change requires proof that the new method is superior to the old. When we, as innovators, develop something “new,” I believe that our immediate subsequent task is to do everything we can to prove that this “new” finding is of no value whatsoever before we determine that it is worth advancing.

Getting to Malcolm Gladwell’s tipping point—the act or event after which nothing is ever the same— requires a team of people, usually from different disciplines, coming together to concentrate on a problem, or an individual whose experiences in different fields provides the ability to “see” the next level. In my opinion, one person working in one discipline rarely leads to breakthrough progress in medicine.

These observations about surgical innovation stem largely from my experience in the development of laparoscopic nephrectomy, in which I was privileged to play a role while at Washington University in St. Louis, which I will outline here.

THE HISTORY BEHIND LAPAROSCOPIC NEPHRECTOMY

After doing preliminary work in dogs, the German surgeon Gustav Simon performed the first human nephrectomy in 1869, in a woman with a ureteral vaginal fistula. The operation was a success: it took him 50 minutes to complete the procedure, and 6 months later the patient went home.

From that point in 1869 until 1990, progress in nephrectomy was minimal, with open surgery remaining the gold standard. While the surgeon’s tools remained largely unchanged, the advances that did occur were in anesthesia, analgesia, and antibiotics, which allowed patients to better survive the onslaught of the operation.

In an unrelated arena, laparoscopy was developed in 1901 by another German surgeon, Georg Kelling, who pumped air into the peritoneal cavity of a dog in a successful effort to stop bleeding from the stomach. Within the pneumoperitoneum, Kelling was able to examine the canine organs with a cystoscope at pressures as high as 140 mm Hg. This discovery was not applied clinically, however, until 9 years later when the Swedish gastroenterologist H.C. Jacobeus used Kelling’s pneumoperitoneum concept and a cystoscope to visualize the peritoneal cavity to search for cancer. The technique advanced little in the subsequent decades —apart from Semm’s seminal laparoscopic removal of the appendix in the 1960s—until 1985, when the first laparoscopic gallbladder removal ignited the era of laparoscopic cholecystectomy.

Three technological developments spurred this recent surge in laparoscopy: (1) the ability to affix a camera to the endoscope, (2) the ability to display the camera’s images on a video screen, and (3) the development of self-feeding clip appliers to allow occlusion of vascular or ductal structures.

THE EVOLUTION OF LAPAROSCOPIC NEPHRECTOMY

Discovery

I became interested in the possibility of laparoscopic nephrectomy during the laparoscopic cholecystectomy craze in the late 1980s. At that time, I was working with Dr. Nat Soper, performing laparoscopic cholecystectomies in pigs to show that the procedure could be done safely with electrocautery rather than a laser. As it turns out, the anatomy of the porcine kidney is such that the colonic reflection lies medial rather than lateral to the organ. As such, the kidney is quite visible as soon as one enters the abdomen. Indeed, the kidney seemed to be saying to us, “Hey, what about me? I could come out through that hole too.” That is basically how the idea arose.

So, along with Dr. Lou Kavoussi and many others in our research team, we attempted laparoscopic nephrectomy in the pig and succeeded: the kidney could be removed through a small hole by entrapping it in a sack, breaking it up in the sack, and pulling it out.¹² The team involved in this discovery were specialists in urology and general surgery as well as biomedical engineers from industry, specifically a team from Cook Urological led by Mr. Fred Roemer.

After performing this technique numerous times in the laboratory, we reduced the operation’s duration to 90 minutes, at which point we believed the procedure had advanced sufficiently to be considered for clinical use.

Development

The patient we selected for the initial clinical case was an 85-year-old woman with a 3-cm mass in her kidney. She was deemed to be “too sick to operate on,” so she was presented to me as a candidate for the new laparoscopic procedure.

Amazing as it may seem in our current medical climate, at that time (1990) we were faced with the question of whether or not to seek institutional review board (IRB) approval. The argument could be made that since radical nephrectomy had been practiced for 120 years and laparoscopy had been around for nearly 100 years, the combination of these two well-accepted procedures might require nothing more than physician-patient informed consent. However, the concept of “informed consent” in this context was problematic: what could we tell the patient about a procedure that had never been done before except that if it was not working out we would convert to the standard open procedure?

A senior colleague—actually my boss at that time, Dr. Bill Catalona—sagely advised me to get IRB approval, noting, “If the operation works out well, you’ll be fine, but if it doesn’t work out well, they’ll kill you if you don’t have approval.” So we fortunately ended up seeking (and receiving) IRB approval, as well as providing, as best we could, informed consent to the patient and her best friend.

Our next consideration was designating a team member to determine if and when conversion to open surgery would be necessary. We needed a “referee” to aid in objectively determining a point at which we should convert. For our team, that person was Dr. Teri Monk, our anesthesiologist, who had no previous experience with our laboratory work but understood what we were attempting.

So we proceeded with the first clinical laparoscopic nephrectomy on June 25, 1990. The kidney was embolized the morning of the procedure. Five laparoscopic ports were placed. The clip appliers proved too small for renal vein occlusion, so the main renal vein had to be traced to its branches; in total we clipped five separate sets of renal vascular branches. The kidney was ensnared and morcellated, which took 7 minutes. Total operative time was 6.8 hours. The complications that arose were not anticipated:

• Intraoperative oliguria due to the prolonged pneumoperitoneum
• Fluid overload (postoperative congestive heart failure) due to providing fluids to the patient as though this were an open procedure
• Dilutional anemia, again due to providing excessive fluids for a closed procedure.

Postoperative pain medications consisted of one dose of morphine sulfate. The patient was discharged on postoperative day 6 and resumed normal activities by postoperative day 10.¹³

Dissemination

Before a new procedure is disseminated, evidence of the four Es—efficiency, effectiveness, equanimity, and economy—must be obtained. In retrospective reviews, laparoscopic removal was associated with a slightly longer operating time but much less blood loss, a shorter hospital stay, and fewer complications. The immediate cancer cure rate was the same for open and laparoscopic nephrectomy, and over time the laparoscopic procedure has been shown to be just as good as open surgery at 5 and now 10 years. Also, with time, laparoscopic nephrectomy was shown to reduce institutional costs.

The next question was the proper way to disseminate this knowledge. At Washington University we took the traditional route of providing courses, offering 17 courses on laparoscopic surgery to nearly 1,000 urologists from 1985 to 2002. But as Winfield and associates later showed, only 54% of urologists who completed a 2.5-day hands-on, laboratory-based laparoscopic course actually ended up introducing laparoscopy into their practice.¹⁴

The challenge of dissemination is still with us, and we need to find better methods of transferring new skills to our surgical colleagues. In this regard, longer experiences, such as weeklong mini-fellowships and the development of procedure-specific surgical simulators, hold great promise.

UNANSWERED CHALLENGES, UNMET NEEDS

With the advent of any technology comes a cornucopia of unanswered questions and challenges. In the areas of discovery and development, a key question is whether every procedure performed using a new Food and Drug Administration (FDA)-approved technology requires a separate approval by the IRB and ethics committee. For instance, if robotic prostatectomy is approved and performed, are separate approvals needed for robotic nephrectomy, robotic pyeloplasty, and robotic vasectomy? Where would or should the approvals end?

With respect to dissemination, many questions remain: How is a new technology taught effectively? How is surgical competency tested? How is clinical performance or proficiency evaluated?

One problem specific to dissemination is a lack of funding. While ample funding is available for discovery and development, as they bring prestige and profit, dollars are scarce for dissemination, or the teaching and testing of competency and proficiency with new procedures. 

Evidence of our failure to educate the postgraduate surgeon abounds in terms of poor outcomes and malpractice suits. The response of government all too often is the knee-jerk reaction to protect (ie, regulate), not educate. To be sure, we can do better, but only if our society commits to the process—not with words, but with funded educational action.

With regard to the last, I believe there is an unmet need for the development of accurate, validated surgical simulators. As a society, we need to find a way to fund the development of simulators for each surgical subspecialty and then use these devices to objectively test an individual surgeon’s manipulative skill as well as cognitive ability when he or she seeks certification or recertification—and perhaps, albeit in an abbreviated 5-minute format, before beginning each operative day. We owe this to ourselves, but most of all to our patients, who in all confidence place their lives in our hands.

By Thomas M. Krummel, MD

If we surgeons take a step back and consider for a moment what has changed in the operating room (OR) in the past 50 to 60 years, the clear answer is, “Just about everything.” The monitors, pumps, transport devices, and OR tables and lights have all changed dramatically, as have the tools, catheters, sutures, energy sources, scopes, staplers, ports, valves, and joints. If we consider technologies outside the OR that guide what we do inside the OR, the changes are just as striking. Circulatory assist devices for the failing heart and widespread use of dialysis for the failing kidney postdate 1950, as does all of our modern imaging capability—ultrasonography, computed tomography, magnetic resonance imaging, positron emission tomography, functional imaging. As for pharmacotherapy in 1950, there were three antibiotics, no antivirals, one antifungal, and three chemotherapeutic agents. Open drop ether was the anesthetic of choice. Not only have the tools and technologies changed, but virtually every procedure has been changed. Both our profession and the industry that has developed these devices and tools can be rightfully proud.

It is likewise necessary to recognize that our patients have been partners in this innovation. Many of them have given informed consent to participate in research and experimental procedures with the expectation that the benefits might accrue only to future patients and not to themselves. That is a hell of a contribution, and we can be proud of our patients’ partnership.

THE GOOD, THE BAD, AND THE UGLY OF INNOVATION

The history of progress in surgical care is always about innovation, and such progress almost always begins with an unsolved patient problem, regardless of the solution that is developed, be it a tool, a device, a technology, or a surgical procedure. At the same time, any discussion of the ethics of surgical innovation should recognize that while efforts to solve patient problems over the years have had many good results, they have also had some bad results and even the occasional ugly result.

This conference has already focused on much of the good that has come from surgical innovation, including transplantation, remarkable advances in cardiac and gastrointestinal surgery, a host of devices, and too many other benefits to list. Yet missteps have been made along the way, such as bloodletting, gastric freezing as a therapy for ulcer, and carotid denervation for treatment of asthma in children.

Then there are the ugly incidents, and these notably include a number of cases involving children, an issue of special interest to me as a pediatric surgeon. Consider the following examples:

• Edward Jenner’s notorious cowpox experiment in the late 18th century was conducted in an 8-year-old boy.
• A well-documented literature shows that orphans were used as subjects for tuberculosis and syphilis inoculations.
• The more recent case of Jesse Gelsinger involved a teenager with a nonlethal condition who died in a clinical trial of gene therapy, after which an undisclosed financial interest on the part of one of the treating physicians was revealed.

It should give us pause to note that many of these practices that look foolish in hindsight probably seemed more rational at the time they were undertaken.

CHILDREN: THE ORPHANS OF INNOVATION

Children have been the orphans of innovation, as technology development specifically for children has traditionally been a low priority. There are several reasons for this:

• FDA standards for approving therapies in children are high. For instance, the vast majority of chemotherapeutic drugs are not approved for use in children because conducting a trial specifically in children is deemed too expensive.
• Pediatric markets for therapies are small.
• The payor mix is poor.

The benefts of duality

Nevertheless, children have benefited enormously from the duality of technology development, in which a technology developed for one population—either adult or pediatric—ends up benefiting both populations. For instance, no one would have invented the pulse oximeter to care for a child, yet now it is the only device with which infants and children are monitored in the operating room and during transport.

Likewise, in some cases the solutions to pediatric problems have had reciprocal benefits in adults. Ligation of the patent ductus arteriosus and the Blalock-Taussig shunt for tetralogy of Fallot opened the door to our understanding of surgery on the great vessels and ultimately enabled the development of cardiac surgery. Similarly, the early impetus for Thomas Starzl’s groundbreaking work in transplantation was focused on children with biliary atresia even though this work is now much more widely applied in adults.

ETHICAL PRINCIPLES APPLY EQUALLY TO ADULTS AND CHILDREN

The principles of medical ethics that began with Hammurabi in 1750 BC and progressed through Hippocrates’ work circa 400 BC, the 1946 Nuremberg medical trial, the 1964 Declaration of Helsinki,¹⁵ Henry Beecher’s classic exposé in 1966,¹⁶ and the 1979 Belmont Report¹⁷ are just as valid for children as they are for adults.

Francis Moore, the great surgeon who created the environment and the team at Brigham and Women’s Hospital that facilitated the first twin-twin transplant, identified six important components of ethical surgical innovation:^18,19

• A solid scientific background (basic laboratory research)
• A skilled and experienced team (“field strength,” as Moore called it)
• An ethical climate within the institution
• An open display for ongoing discussion
• Public evaluation
• Public and professional discussion.

The principles behind these components remain as true today as they were 20 years ago when Moore outlined them.

SPECIAL CONSIDERATIONS IN PEDIATRIC SURGERY: A CASE STUDY IN MATERNAL-FETAL MEDICINE

The Belmont Report, mentioned above, was developed by the US government in 1979 to form the basis of regulations for federally funded research involving human subjects.¹⁷ The report identified three basic principles that must underlie such research:

• Respect for persons—protecting the autonomy of all subjects, treating them with courtesy, and allowing for informed consent
• Beneficence—maximizing benefits from the research initiative while minimizing risks to the subjects
• Justice—ensuring reasonable, nonexploitative, and well-considered procedures that are administered fairly.

In pediatric surgery, everyone agrees that the “best interests of the child” must be protected, but the issue of autonomy (a key element of the first Belmont principle) is more difficult to define, of course, when the patient is a child rather than an adult. The question of autonomy is especially tricky in the evolving field of maternal-fetal medicine: what if the patient is a fetus and the mother is an innocent bystander?

Over the past 20 years, tremendous progress has been made in our understanding of diseases of the fetus, particularly diseases that limit fetal viability and diseases that cause serious organ damage but which may be more responsive to postnatal therapy if they are treated prenatally. Michael Harrison, N. Scott Adzick, and a few of their disciples have laid the ethical groundwork for consideration of the fetus as a patient.

Considerations in maternal-fetal medicine

I will conclude with a case in maternal-fetal medicine for us to consider and perhaps debate in the panel discussion at the end of this session. As you consider this case, keep in mind several important observations relating to maternal-fetal medicine:

• The mother’s health interests cannot be underestimated.
• Most “fixable” fetal lesions (ie, those that interfere with development and cannot be fixed postnatally, but for which intervention in utero may result in normal development) are very rare. They include obstructive uropathy, lung lesions causing hydrops, congenital diaphragmatic hernia, sacrococcygeal teratoma, hydrocephalus, twin-twin transfusion syndrome, congenital high airway obstruction, hydrothorax, myelomeningocele, and congenital heart disease.
• The field is evolving, and the efficacy of therapy is supported by variable level I, II, and III evidence.
• The law has not kept (and perhaps cannot keep) pace with developments in this field.

Case study

A 24-year-old healthy woman has a fetus of 28 weeks’ gestational age with progressive lower urinary tract obstruction with megacystis, bilateral hydronephrosis, and oligohydramnios. In other words, there is diminished volume in the uterine cavity that causes compression of the fetal chest and subsequent respiratory compromise that will be fatal if not addressed. The karyotype is a normal 46,XY male. Serial urine sampling reveals electrolyte and protein profiles with a good prognosis.

Prenatal counseling with fetal therapy specialists suggests that this is the “perfect case” for a vesicoamniotic shunt. This is the least invasive, most successful fetal surgical intervention. It is done under local anesthesia and involves transabdominal transuterine percutaneous placement of a double-lumen pigtail catheter in the fetal bladder. There has never been a reported maternal death, and morbidities have been minimal. Renal and pulmonary function both are improved by approximately 80% in fetuses treated with this intervention, and survival is improved.

The father is eager to proceed. The mother is ambivalent. Should the mother be pressured to proceed, for the good of the child?

Questions to ponder

The following questions are intended to be provocative, with no clear-cut answers:

• Should (or does) the fetus have independent moral status? Is it full, graded, or none? Does it matter?
• What are the beneficence-based obligations to the fetus? At 28 weeks’ gestation, the fetus is viable outside the uterus. The fetus is otherwise well, without a lethal karyotype, and has currently good renal function.
• What are the beneficence-based and autonomy-based obligations to the mother? What are the mother’s obligations to the fetus?
• What if the mother ultimately decides to proceed and the insurance company denies coverage? What are the social responsibilities to care, cost, and research?

These questions lend themselves to discussion. As much as we surgeons like to be certain about what we do, we would do well to heed the quote from Voltaire that the great surgeon Norman Shumway hung on his office door: “Doubt is not a very agreeable state, but certainty is a ridiculous one.”

By Philip R. Schauer, MD

Obesity is a staggering problem: 100 million Americans are overweight, 85 million more are obese, and another 15 million are morbidly obese (ie, ≥ 100 lbs above ideal body weight). The incidence of obesity is rising rapidly and threatens to shorten the life spans of today’s young generations relative to their parents. Unlike other conditions, such as cardiovascular disease and cancer, obesity has seen no widespread progress in management in recent years.

Recognition of obesity as a medical problem is a challenge in itself. Many people consider obesity to be a character flaw or a behavioral issue and fail to recognize it as a disease entity. Yet obesity is the root cause of many metabolic conditions and diseases with metabolic components, including type 2 diabetes, heart disease, blood pressure, metabolic syndrome, acid reflux, gout, arthritis, and sleep apnea.

The approach to obesity treatment can be conceptualized as a pyramid, with the aggressiveness of the intervention based on the patient’s body mass index (BMI). At the base of the pyramid, for patients with lower BMIs, are minimally invasive (and minimally effective) interventions involving changes in diet, physical activity, and other lifestyle factors. As BMI increases, so does the intensity of treatment, to include pharmacotherapy and eventually bariatric surgery. Traditionally, surgery has been considered only at the very top of the pyramid, for morbidly obese patients, and is usually not offered as an option for the vast majority of people with this condition.

The sad reality is that the various combinations of these therapies are effective in fewer than 1% of the approximately 100 million Americans who are obese. Because surgery has been shown to be the most effective therapy for obesity, the remainder of my discussion will focus on surgery, with an eye toward potential new indications for bariatric procedures and the questions they raise.

SURGICAL APPROACHES TO OBESITY

Bariatric surgery has evolved over the past 50 years. Although there are about a dozen different permutations of bariatric procedures performed in the United States today, they fall into one of three major types of operations, as outlined below:

Gastric banding reduces appetite and satiety by adjusting and tightening the gastric band. This procedure has been in existence for 10 to 15 years and represents about 25% of operations for obesity in the United States.

The biliopancreatic diversion procedure diverts most of the small bowel and radically reduces absorption of calories. Patients undergoing this procedure lose weight because few calories are absorbed into the body. This approach, while quite effective, is somewhat radical and represents only about 2% of the operations for obesity in the United States.

The Roux-en-Y gastric bypass procedure has been the dominant procedure over the past 15 to 20 years. A combination of the above two procedures, it involves reducing the gastric reservoir and bypassing the stomach and upper intestine. The reduction in gastric volume reduces calorie intake by enhancing satiety, and the limited foregut bypass moderately reduces absorption.

No randomized trials, but much support from observational studies

Virtually none of these procedures evolved with randomized controlled trals. Instead, they evolved incrementally, primarily on the basis of knowledge gained from case procedures. Despite the lack of randomized trials, these operations have been shown to be effective, particularly in patients with multiple metabolic abnormalities associated with severe obesity. A large body of data from case-control and cohort studies demonstrates not only dramatic improvement in metabolic abnormalities with the use of various bariatric procedures, but also improvements in quality of life and survival.^20–26 The two most recent of these studies, published in 2007, found reductions in mortality of 29% (adjusted) and 40% among surgical patients compared with well-matched obese controls during mean follow-up of more than 7 years.^25,26 Reductions in the incidence of cardiovascular mortality and, secondly, cancer-related mortality were the two major contributors to the overall mortality reduction in these two studies. Consistent with this latter finding, obesity is starting to be thought of as a disease that may lead to cancer.

NEW FRONTIERS FOR BARIATRIC PROCEDURES

The current indications for bariatric surgery have existed intact for about 25 years, and were based on limited evidence available at the time. They are basically as follows, assuming acceptable operative risk and appropriate patient expectations:

• BMI greater than 40 kg/m²
• BMI greater than 35 kg/m² with significant obesity-related comorbidities.

Payors adhere strictly to these indications, such that they will not pay for bariatric surgery in a patient with a BMI less than 35 kg/m². This raises questions about the appropriateness of such a firm threshold and whether expansion of these strict indications may be reasonable.

Even without broadened indications, the volume of bariatric procedures in the United States has grown dramatically in recent years. Whereas only 10,000 to 20,000 of these operations were performed annually in the 1990s, approximately 200,000 such procedures were performed in 2007, and this number is expected to double over the next 5 years or so.

This growth in volume has been paralleled by burgeoning media interest in bariatric procedures, particularly in the last few years. More attention can be expected as we increasingly recognize the potential of bariatric procedures for indications beyond strictly the treatment of morbid obesity. At least two new frontiers loom: metabolic surgery and endoscopic surgery.

Metabolic surgery

Procedures that incorporate a bypass—the Roux-en-Y gastric bypass and the biliopancreatic diversion —have been associated with a reversal of metabolic diseases such as type 2 diabetes.^27–32  Many patients with type 2 diabetes who have undergone these procedures have been able to be weaned off insulin and insulin-sensitizing medications while maintaining normal blood glucose levels. The effect has been profound and immediate, occurring even before the patient loses weight. In one series of patients with type 2 diabetes who had undergone a bypass operation, 30% left the hospital in a euglycemic state.²⁹

These observations have been made primarily in the morbidly obese population, who are the primary candidates for bariatric bypass procedures. However, because of the rapid improvement in metabolic abnormalities that has been observed, interest has arisen in applying these procedures to populations that are not morbidly obese. Bypassing of the foregut appears to be critical, perhaps because it tempers the release of hormonally active peptides from the gastrointestinal tract.³³ In any case, the gut is regaining recognition as a major metabolic organ.

In light of these hypotheses, the duodenal-jejunal bypass is a bariatric procedure that may be beneficial for a patient with type 2 diabetes who is not morbidly obese. In this operation, the stomach volume is preserved but the foregut is bypassed. In a small experimental series from Brazil, patients with type 2 diabetes who were normal weight or only slightly overweight had resolution of their diabetes following this procedure, without any weight loss.³⁴

New applications for endoscopy

Another area of development is endoluminal and transgastric bariatric surgery. Endoluminal surgery is performed entirely within the lumen of the gastrointestinal tract using flexible endoscopy. Transgastric surgery is performed within the peritoneal cavity, which is accessed via a hollow viscus. Both approaches use natural orifices to gain surgical access, thereby avoiding access incisions and scars.³⁵

The benefits of such an approach are numerous:

(1) fewer complications and side effects; (2) less invasiveness, and thus the ability to perform in the outpatient setting; (3) reduced procedure costs; and (4) better access to treatment. The implication in terms of indications is the potential to use such procedures to prevent progression to morbid obesity.

Examples of these procedures are proliferating:

Gastrojejunostomy reduction is an endoscopic procedure that involves reducing the dilated opening of the gastric pouch after gastric bypass surgery. New endoscopic suturing or stapling devices enable the outlet reduction without requiring surgery. The result is enhancement of weight loss without a major operation.

Endoluminal suturing uses endoscopic instruments to suture the stomach to reduce its volume. When this procedure is perfected, the patient should be able to leave the endoscopy suite and return home within a few hours.

The duodenal sleeve is an avant garde concept in which an internal sleeve is threaded into the stomach and down the intestines.³⁶ The sleeve covers the absorptive surface of the small bowel, preventing absorption of nutrients to cause weight loss. This procedure has been shown to have a strong antidiabetic effect as well.

Clinical applications of these operations are emerging. An endoluminal sutured gastroplasty procedure to shrink stomach volume has been shown in a small clinical trial to cause loss of significant excess body weight; the operation leaves no scars and is associated with a low risk of bleeding or any type of surgical complication.³⁷ A similar procedure is in development that involves staples instead of sutures.

How best to validate innovations moving forward?

As we move into these new eras of metabolic surgery and endoluminal and transgastric bariatric surgery, interesting questions arise. We as innovators and caregivers are ethically obligated to demonstrate reasonable safety and efficacy before such new procedures are performed widely. Although some of these emerging procedures involve new devices that will go through the FDA review process, many are existing procedures for which indications may be expanded, while others are permutations of existing procedures for which no formal rules for validation exist. For new procedures that differ substantially from existing proven procedures but which do not require new devices, should we not be ethically bound to demonstrate safety and efficacy even though they do not require FDA review? These are the challenges that await as innovation takes bariatric surgery to new frontiers.

By Christopher Thompson, MD, MHES

Although the endoscope has changed very little since the first fiberscope was developed 50 years ago, the accessories and other instruments used in conjunction with the endoscope have changed remarkably. These include clips for hemostasis, ultrasonographic technology, and instruments for tissue dissection.

These advances in endoscopy, combined with advances in laparoscopic surgery, have led to the convergence of these two fields, culminating in the new field of natural orifice transluminal endoscopic surgery (NOTES). In NOTES, the surgeon enters a natural orifice and punctures through a viscus to perform surgery, removes the endoscope, and closes the area without leaving a scar.

HISTORY OF NOTES AT A GLANCE

NOTES was patented as a concept in 1992. Its first application was as an exploratory procedure in the pig in 2004.³⁸ Soon thereafter, therapeutic NOTES procedures in animals were reported, including tubal ligation, organ resection, cholecystectomy, and splenectomy.

Particularly notable in the development of NOTES is the extremely short interval between early animal experiments (2004) and the first human procedures, which took place as early as 2005 when surgeons in India used the technique to perform a human appendectomy. Since then, more than 300 NOTES procedures have been performed in humans throughout the United States, Europe, Latin America, and Asia, for applications ranging from percutaneous endoscopic gastrostomy rescue to transvaginal cholecystectomy.

This rapid adoption of NOTES in humans is concerning, as it raises clear questions about whether there has been time for adequate oversight and safety assessment. For instance, at a surgical conference in April 2008, questions and debate swirled around whether a large Brazilian registry of more than 200 NOTES cases did or did not include two deaths. Other ethical issues raised by NOTES are discussed further below.

DRIVING FORCES BEHIND NOTES

The medical rationale

Abdominal wounds can cause pain, are unaesthetic, and are prone to wound infections, ruptures, and hernias. They sometimes cause adhesions or may lead to abdominal wall syndromes with scar neuromas that cause pain later. They also require general anesthesia. Beyond these shortcomings of incision-based procedures, NOTES offers potential reductions in length of stay and therefore in cost. Moreover, certain patient populations may specifically stand to benefit from NOTES, such as obese patients, those with abdominal mesh in place, and those undergoing palliative procedures. This is the essence of the medical rationale for NOTES, which is somewhat thin.

Professional organizations and courses

In July 2005, leaders from the American Society of Gastrointestinal Endoscopy and the Society of American Gastrointestinal and Endoscopic Surgeons convened a working group to support and plan for the responsible development of NOTES.³⁹ The group formed the Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR), an organization that has since sponsored several conferences on NOTES and procured millions of dollars in grants for NOTES research in animals. (In the interest of full disclosure, I am one of the founding members of NOSCAR.)

Additionally, leading institutions in this field have held numerous hands-on courses on NOTES throughout the United States, Europe, Latin America, and Asia. These courses, including those held by my laboratory at Harvard University, are designed to teach colleagues at other institutions how to set up an appropriate animal laboratory and to promote and encourage proper research in NOTES. There have been unintended consequences, however, as we have learned that some course attendees have returned to their home countries and immediately started using the techniques in humans.

New technology

At the July 2005 working group meeting that launched NOSCAR, we determined that several technological advances were needed before NOTES could be safely applied to humans. These included development of multitasking platforms, better devices for tissue apposition and fixation, better imaging and spatial orientation, and improved means of retraction.³⁹ Industry responded with novel devices and end effectors such as guide tubes, direct drive systems, endoscopic suturing devices, magnetic retraction, devices for closing luminal defects, flexible staplers, and computerized robotics.

Other driving forces

Additional forces have undoubtedly contributed to the rapid development of NOTES:

• The slowdown in innovation in general surgery in recent years has left a vacuum to be filled.
• An abundance of venture capital has been available to rush into that vacuum.
• Perceived patient demand (owing to cosmetic advantages) has been a driver, especially in cities such as Rio de Janeiro, Milan, and New York.
• The fear of being left behind is a factor that cannot be underestimated. Surgeons who failed to convert to laparoscopic techniques from open techniques in the early 1990s for procedures such as cholecystectomy, fundoplication, and splenectomy were losing their patient bases. Many surgeons fear a similar phenomenon today if they do not adopt NOTES into their practices.

ETHICAL ISSUES RAISED BY NOTES

As NOTES moves toward further evaluation in humans, several ethical questions need to be grappled with:

• Must there be a significant potential for improvement in care before an innovation advances to human research?
• Is the cosmetic benefit of NOTES sufficient, considering the substantially increased risk? For instance, laparoscopic cholecystectomy is well established, whereas NOTES cholecystectomy carries an increased risk of bile duct injuries and other injuries. Is NOTES worth the risk?
• What about the corporate agenda behind new technologies and its associated influence on the media?
• Are hospital IRBs adequate to the task of evaluating and monitoring these questions, and will they be independent of the impact of hospitals’ larger agendas?

Finally, the problem of premature adoption of this technology is particularly concerning. I heard a surgeon explain at a course that he performed NOTES on a few pigs at a previous course and then returned home to Peru and immediately started performing it on patients at his ambulatory surgery center. There is also the temptation for well-respected surgeons to go to other countries to practice their NOTES skills before returning to the United States, in hopes that their experience will help them attain IRB approval. Practices like these raise questions about what ethical responsibilities lie with those of us who have pioneered the technology and are trying to develop and disseminate it responsibly. We can try to vigilantly watch course attendees from certain countries, but there is little we can do in the absence of regulation and enforcement in those countries. These are difficult ethical challenges.

Panel discussion

Moderated by Jonathan D. Moreno, PhD

Dr. Jonathan Moreno: I would like to begin with any questions that the panelists have for one another.

Dr. Philip Schauer: I would be curious to hear how my colleagues define incremental changes in a procedure. In other words, what constitutes a new procedure versus a modification of an existing one?

In bariatric surgery we are grappling with a procedure called the sleeve gastrectomy, which poses challenges comparable to lung volume reduction surgery as described by Dr. Cooper. Many of us believe that this procedure is just a slight modification of a gastroplasty, yet payors consider it an entirely different procedure, and some want 5 to 10 years of follow-up data before they will pay for the operation.

Dr. Joel Cooper: That is not an easy question, but I would approach it from the standpoint of what you would tell the patient. When we were first developing lung volume reduction, we performed it only in patients who had absolutely no other alternative. Only later in its development did we offer it as an alternative to transplantation. How do you approach the patient when you can already achieve a very good result with an existing procedure and you can tell the patient, with some assurance, what to expect with that procedure? In the case of NOTES, I do not think that the cosmetics are sufficient justification.

The second aspect is regulatory. I am not a supporter of the FDA’s practices for the introduction of new procedures, but I believe strongly that universities have been derelict in setting the standard for the introduction of new procedures, particularly minimally invasive procedures. They have been using these procedures as marketing tools to vie with private hospitals for dollars and patients. I cannot say whether the rapid promulgation of these procedures at too early a stage actually can be prevented, but I do not recall the chairmen of major surgery departments getting together to issue public statements about the proper protocol for introducing new techniques. As Pogo said, “We have met the enemy and he is us.”

This may not answer your question, but I believe there should be no payment for any new or novel procedure for a certain period after its introduction, and certainly the hospitals should not be able to profit from it, although the expenses of a new procedure may be recouped. That alone would perhaps put the brake on some of the marketing and the financial incentives, and it might separate, to some degree, the development of new procedures from economic interests.

WHO SHOULD OBTAIN INFORMED CONSENT?

Dr. Moreno: Should informed consent be obtained only by a knowledgeable third party rather than the surgeon-innovator?

Dr. Thomas Krummel: The question is whether there is a disinterested third party who truly is knowledgeable; in cases where there is such a person, I see no downside to having that person involved. However, the notion of having someone who is not associated with clinicians or surgeons obtaining informed consent makes me uncomfortable. Informed consent is not a piece of paper. It is a trust between physician and patient, and to ignore that could leave you in a heap of trouble.

Dr. Cooper: I agree, but another process is important as well. In proposing lung transplantation before there had been any successful transplants, we defined in advance the standards, indications, and contraindications that we thought should apply. We did this in the absence of any particular patient, and it relieved us of the difficulty of making arbitrary decisions that may have led to unfairly accommodating one patient over another. Once the standards have been set in this way, they can be applied—whether by the investigator or by a committee—in an objective way to the group of patients that is most appropriate in the early phases of development.

Dr. Ralph Clayman: It is difficult for the inventors of an operation to dampen their enthusiasm for their creation to a point where they are as objective as they should be. Joel is bringing up situations for which there are no alternatives. My realm is an area in which there were well-established alternatives for everything we have done laparoscopically or percutaneously, and it was difficult to decide the indications or contraindications early on. Often, the early indications only had to clear the threshold of not seeming ridiculous.

The early development of percutaneous stone removal at the University of Minnesota took place entirely outside the purview of an IRB. Percutaneous nephroscopy had been around since 1955, and we extended it to plucking out a stone. That is how that entire field developed. Early on, we were not going to go after a stone that was as big as a fist because we did not have a way to break it up. As time went by, however, it evolved to the point where there was no stone in the kidney—regardless of its size, location, or hardness— that could not be removed through a small hole in the back. But that entire evolution proceeded without IRB approval.

For laparoscopic nephrectomy, for which there were well-known alternatives, who should have obtained the informed consent? Should it have been me, bringing along the “white coat” factor and not being able to really explain the potential problems since nobody had yet gone there, despite my rapport with the patient? Or should it have been a third party with whom I had discussed the procedure and its possible problems? I do not know the answer, but it raises an interesting point, especially in this age of IRBs and ethics committees.

Dr. Krummel: It is not unlike what we have tried at Stanford when we are not sure of the boundary for IRB consultation. The surgical chairs are willing to convene and essentially police one another, so that when the neurosurgeon proposes a brain transplant, there probably will be a pretty interesting conversation before it gets the green light.

Dr. Cooper: My experiences with IRB involvement differed quite a bit between my work in lung transplantation and my work in volume reduction surgery, but the differences owe a lot to the countries where I was practicing at the time. I did my early work in transplantation in Canada, where I did ask for approval from my hospital’s ethics committee and other relevant committees. In Canada, the hospital had a global budget, and it made a decision that it was willing to use part of its budget for transplantation. We received no fees for years, until the operation was proven to be effective, but that did not stop us from developing the procedure.

I had returned to the United States when I began my work with lung volume reduction, and I did not ask the IRB for permission to do that procedure. My justification was that, theoretically, volume reduction was similar to accepted practices for removal of nonfunctioning lung to improve respiratory mechanics (bullectomy) and that we would simply be applying the concept to a different group of patients. However, unlike in Canada, I did not have institutional financial support for doing this new procedure, so how was I going to do it if the hospital could not receive payment for it? I went to the IRB, but instead of asking for permission to do the procedure I asked for permission to study the procedure and to collect data on it. In that way, I was notifying the IRB of my action and thus giving it an opportunity to act. If I had gone to the IRB to approve the procedure, however, the operation would have been labeled experimental by insurance companies, who would have then found a way to deny payment. At least that was how it was in those days.

Question from audience: What makes you think that in 10 years there won’t be 100 million obese Americans watching television ads for noninvasive bariatric surgery promising to rid them of their obesity problem? What will keep that from happening?

Dr. Krummel: Nothing. What makes you think it is not happening now? Just look at the ads for the Lap-Band in the lay press.

Dr. Clayman: We already have direct marketing of drugs and direct marketing of facilities. What Joel said is true: “the enemy is us.” When I was in training, the idea that a physician would advertise was considered unethical. I still consider it thus. But everybody is doing it, so should that make it acceptable? I think not.

The same thing is true of the huge amount of money spent marketing drugs on television. Why should a single nickel be spent to advertise health care beyond generically informing the public of important health care issues and initiatives? You cannot go to an airport without seeing a surgical robotics program being advertised or a hospital being advertised. You cannot turn on National Public Radio without hearing well-financed spots touting the achievements of a hospital. You cannot watch television without seeing ads for erectile dysfunction medications or other new drugs. It is a waste of dollars. If we took all of that money and redirected it, we could probably solve much of the indigent health care problem, but we as a society have chosen not to do that. 

SHOULD THE BAR BE RAISED FOR SURGICAL TRIALS?

Dr. Moreno: Let’s consider some additional questions. Why shouldn’t the government raise the bar on the level of evidence needed to gain regulatory approval for new devices? Why not require randomized trials, as is done for drugs?

Dr. Cooper: Procedures that lend themselves to a randomized trial should be studied at a limited number of centers with mandatory reporting and preset indications for promulgation and payment. I believe that universities have been derelict in their duty to require this level of evidence.

This question is always nuanced, however. Consider the case of laparoscopic procedures. They offer the advantage of smaller incisions, yet how many patients have had to die or suffer serious consequences for the sake of these smaller incisions? On the other hand, how many patients may have been saved from pulmonary embolism, wound infections, or a prolonged hospital stay as a result of laparoscopic techniques? Only a randomized trial could demonstrate whether or not there has been an overall payback from new procedures such as this, although even then the payback may be present for some types of patients but not others.

Dr. Schauer: The problem is expense. Perhaps it is all a matter of economics. Return on investment for the drug industry is something like 10 to 1, but return on investment for the medical device industry is generally much lower. Therefore, conducting large randomized controlled trials is extremely expensive and much more complicated for a device or procedure. This may explain why the standard for trials is different for the two industries.

Dr. Krummel: Virtually all fetal surgical procedures have been subjected to a trial, several of them randomized. The National Institutes of Health paid for many of these trials. One such study prevented rapid uptake of the congenital diaphragmatic hernia operation, which has never been proven in a randomized trial to be better than our current therapy. It is a good example of a randomized trial making a difference.

Dr. Clayman: As Joel pointed out, surgery is constantly evolving, whereas a drug remains unchanged throughout its lifespan. If we had started a prospective randomized trial after we had done our first laparoscopic nephrectomy, the procedure would have died because we were not nearly as facile with our first 10 as we were after our first 100. The technology continues to develop, and the surgeon continues to develop his or her skills, which makes a study of this nature overly dynamic. Perhaps the best you can do is a retrospective, matched, controlled study with the same surgeon, comparing his or her results after 40 or 50 laparoscopic procedures with results after his or her 50 most recent open procedures.

Dr. Cooper: How do you put a brake on the system? Would some sort of limited trial perhaps put a brake on the too-rapid promulgation that we often see?

Dr. Clayman: In the general surgery realm, laparoscopic cholecystectomy came out of private practice. It did not come out of the university with its faculty and laboratories dedicated to exploration and investigation. It never was properly vetted in the scientific realm but rather came to the light of day as an “economic” edge.

Dr. Krummel: I would not underestimate the talent and creativity of those that we train who go out into private practice. Much innovation has come from very active practitioners.

Dr. Clayman: Right, but they do not have the infrastructure that we are blessed with at universities both to create and to validate.

Dr. Schauer: I agree that academia does not have a monopoly on creative ideas. But perhaps academia should play a major role in defining validation-type studies. That is one area where we may be especially well suited to meet an important need.

THE INNOVATION-TRAINING INTERFACE

Question from audience: I have a dilemma as a residency program director. Our residents want to learn the new technology—laparoscopic surgery, robotic surgery, etc—but we have them in our program for such a limited time. How do you justify teaching them new technology and at the same time still teach them basic, traditional surgical procedures, especially with the reduction in residents’ hours? It is fine to be able to do a nephrectomy laparoscopically, but if you get in trouble, you still have to know how to do a good open nephrectomy. How do you address this?

Dr. Schauer: I think the answer largely is fellowship training. Emerging procedures probably should be introduced in fellowship programs until they reach the point where they are so standardized that they become a major part of practice. For example, cholecystectomy quickly became part of general surgery practice, but laparoscopic colectomy took several years to evolve and was taught primarily in fellowship or advanced training, after which it gradually filtered down to residency programs.

Dr. Krummel: All of us who are responsible for training are wrestling with this problem. Residents are expected to learn more yet do so in less time. One approach would be early specialization, so that instead of 5 years of general surgery, you would have 3 years of general surgery and then 3 years of, for instance, thoracic surgery. Also, Ralph mentioned earlier the advantage of skills labs. We increasingly see that type of approach as a backbone for providing broad training without putting patients at harm.

As for teaching the use of new technology, first you have to teach the existing base of practicing surgeons. Here again there is much to be said for skills labs, and I give credit to the American College of Surgeons for its drive to establish and accredit centers around the country as a way to teach this base of surgeons.

Dr. Schauer: If I may expand this question beyond residency and fellowship training, how do we balance the desire to share new innovations with our colleagues against the need to temper their desire to prematurely jump into an area where they do not yet really belong? Chris, I know this applies to your challenges in disseminating knowledge about NOTES.

Dr. Christopher Thompson: Yes, courses on NOTES are also being held in conjunction with all the major society meetings, and we are seeing many enthusiastic trainees at these hands-on courses. The original intent was to give attendees instruction on setting up their own animal labs, yet some trainees took it beyond this limited purpose. As a result, some in our field believe that we should not allow foreign physicians to come here to be trained in NOTES, for fear they will go back to their home countries and use it on humans. I am not certain that that approach is the best way to go, but there has been much discussion about how to handle this. It is a real conundrum. Certainly there are a number of surgical residents and gastroenterology fellows who are clamoring to get into the lab right now and learn these techniques.

Dr. Clayman: This goes back to our earlier discussion about from where new technologies should emerge. What frightens me are the consequences of creative activity occurring outside the university, where there are no laboratories or animal or cadaver models for refining or testing a technique. To me, it was frightening to see laparoscopic cholecystectomy suddenly emerge as a craze without the proper animal and clinical studies having been done. That is not the way I believe clinical research should go forward. I once heard a prominent urologic surgeon say at a major surgical meeting, after a presentation on the impact of percutaneous stone surgery on the canine kidney, “Now that I’ve done a thousand of these in humans, it’s reassuring to know that it’s safe to do in dogs.” That is not the way it should happen, and every time it does happen that way, we pay a large price, some of us as individuals and all of us as a society.

Dr. Cooper: The answer therefore is to use our academic facilities to facilitate the training of those in community practice. We should continue to offer training because we have the resources to make it available.

Dr. Clayman: Yes, and this is why I emphasized earlier that support for surgical training centers is so essential. I see all the dollars spent on health care advertising and wonder why these dollars are not instead poured into surgical training, or research facilities, or training simulators.

The way we should train surgeons in new technologies is to train them on simulators equipped with a properly vetted curriculum. This is the future for training, because once you put instruments through small ports, everything becomes measurable—economy of motion, past pointing, and efficiency; simulators with a curriculum will also be able to assess the trainee’s cognitive abilities. When an individual performs well on the simulator, he or she can then come into the operating room and work with surgeons experienced in the procedure. The use of simulators in this manner should ultimately improve the overall quality and safety of each surgical specialty.

Question from audience: I am curious how the panel members interpret early randomized trial data showing an increased cost without an improvement in care with the use of surgical robots in certain procedures. Should we persist or consider an investment in the future as robotic technology improves and surgeons further adapt to it?

Dr. Cooper: I think the robot should be used only for those procedures for which it has unique capability and can perform a task better than we can. It appears that the robot performs better than the ear, nose, and throat surgeon for operations on the base of the tongue. The same may be true of prostate surgery, but I am not certain. But to do a laparoscopic Nissen repair with a robot…as Dr. Nat Soper of Northwestern University has said, “If I needed a robot, I shouldn’t be doing laparoscopic Nissens.”

The robot provides light, it gives you magnification, and it reduces tremor. We should concentrate on its use for operations where these attributes are particularly valuable. But we should be wary of its use as an expensive marketing tool.

Dr. Clayman: The robot provides you with superhuman capabilities: 10 to 30X magnification, no tremor, a 540-degree wrist, instrumentation with 6 degrees of freedom, and motion scaling. It allows you to be a better surgeon than you are without it. I agree that it is expensive. It is woefully overpriced at this point, but I believe the expense will come down with time. It is no different than the first computers, which were terribly expensive. The robot enables surgeons to do a better job than they would without it if we are talking about reconstructive-type surgery.

Ergonomically, the robot is very positive for the surgeon. For the first time, the surgeon is actually allowed to sit down in a comfortable environment and can work for 4 hours straight, get up at the end of the surgery, and feel fine. If you are older than 50 and you operate standing at the table staring at a television screen on the other side for 4 to 6 hours, you are going to ache afterwards. I believe surgeons work better if they are comfortable.

Dr. Schauer: At least within my field of general surgery, there has been no evidence that this superhuman ability has translated into superhuman results, in terms of reduced operating time, fewer complications, or better efficacy. We should probably develop the metrics to measure progress. How do the theoretical benefits translate into clinical benefit?

Dr. Clayman: It is not theoretical in radical prostatectomy if you look at the data. The potency rates for patients who undergo robotic surgery for these procedures are now almost 90%, which is something that no surgeon performing open prostatectomy has ever achieved. Fortunately, the continence mechanism is so strong in most adults that it does not matter whether prostatectomy is done with a robot or open surgery—patients are probably going to be all right. But the bottom line is that robotic surgery is a bit better. Most surgeons would use it if it were free. The problem is that it is so expensive right now and it is breaking the backs of many hospitals.

Dr. Schauer: You make a good point. Demonstrating metrics is important, and prostatectomy is a good example. But I am not aware of any other procedures for which benefit from robotic surgery has been documented.

Dr. Krummel: The history of robotic surgery is so interesting because the killer application was supposed to be coronary work—percutaneous bypass surgery. But then the heart port went to pot and patients with anterior wall lesions ended up not being a big enough group. It turns out that it is still difficult to do and there is not a lot of room. So prostatectomy has ended up as the initial killer application.

Keep in mind that the current robot is not an end device. We will see more. There are now robotic steerable catheters that I think will be adopted into NOTES procedures. This theme of immediate benefit versus follow-on iterations is the story of device development in this country.

How should we introduce and evaluate new procedures?

By Joel D. Cooper, MD

Time magazine published an article in 1995 titled “Are Surgeons Too Creative?” that examined the question of whether operations should be regulated the way that medications are.¹ The piece featured two patients. One, a patient with emphysema who underwent lung volume reduction surgery at our institution during the early days of this procedure, had a good outcome. The other was a neurosurgical patient who had a bad outcome.

The public is somewhat sympathetic to this article’s premise, which can be viewed as a call to require a similar level of evidence for surgical procedures as for new drugs. This sympathy arises from the expense of new technologies, pressure from payors to control costs and increase profits, hospital budget restraints, and the reality of increasingly well-informed patients.

Yet there are distinct differences between drugs and surgery. A new drug does not change over time. A new drug is associated with a variable biologic response whose assessment often requires large numbers of patients and considerable follow-up. And a new drug may manifest unforeseen late side effects and toxicities far removed from the time of initial use. In contrast, none of these characteristics applies to surgical procedures. A surgical intervention changes over time as the technique and experience evolve and as refinements are made in patient selection and in pre- and postoperative management. With this evolution comes a change in risk over time. Patient selection for surgery is as much an art as a science; each patient requires assessment of both the potential benefits and risks of the procedure, which argues against offering an operation by prescription. Moreover, with surgery, the facilities and the operator’s skill and experience levels vary from one center to another.

INTRODUCTION OF NEW PROCEDURES: COVERAGE VS VALIDATION

Introduction of a new surgical procedure depends on the nature of the procedure and the other interventions that may be available for the condition. In assessing how new procedures should be introduced, I believe we need to distinguish between coverage and validation. Coverage—ie, payment for the procedure—is an economic issue, whereas validation involves an ethical and scientific evaluation of the role of the procedure.

Coverage by an insurer should have at least theoretical justification and presumption of benefit. For instance, the rationale behind a heart transplant for a patient with a failing heart is obvious. Coverage generally requires preliminary evidence of efficacy, possibly in an animal model, although no animal models may exist for some conditions. Most important, a different standard for providing initial coverage should be applied if no alternative therapy exists for a condition that is severe, debilitating, and potentially life-threatening; if a new procedure treats a condition for which a standard therapy already exists, the standard for coverage must be higher. Finally, coverage in all cases should require ongoing reassessment of the procedure.

In contrast, validation is a scientific analysis of results over time, including long-term results, and can be accomplished by well-controlled case series, particularly if the magnitude of the benefit is both frequent and significant and especially if no alternative therapy exists. Randomized clinical trials are the gold standard for appropriate interventions but are not always applicable.

A 1996 study by Majeed et al² provides a good example of validation-oriented surgical research. In this blinded trial, 200 patients scheduled for cholecystectomy were randomized to either laparoscopic or open (small-incision) procedures. The study found no differences between the groups in terms of hospital stay or postprocedure pain or recovery. In an accompanying commentary,³Lancet editor Richard Horton praised the design and conduct of the study, noting that it was very much the exception in surgical research, which he argued was preoccupied with case series. Horton offered the following speculation about this preoccupation:

Perhaps many surgeons do not see randomised trials as feasible strategy to resolve questions about surgical management. Cynics might even claim that the personal attributes that go to make a successful surgeon differ from those needed for collaborative multicentre research.³

IS THE ‘SURGICAL SCIENTIST’ AN OXYMORON?

Barnaby Reeves, writing in The Lancet 3 years later, offered a more diplomatic take on the difficulty of evaluating surgical procedures:

What makes a surgical technique new is not always easy to define because surgical procedures generally evolve in small steps, which makes it difficult to decide when a procedure has changed sufficiently to justify formal evaluation.⁴

Reeves went on to argue that doing an evaluation too early may preclude acceptance, since the technique may not have evolved sufficiently and surgeons may not have mastered it; conversely, doing an evaluation too late may make the evaluation moot, since the technique may have already become established and withholding it may be deemed unethical. Additionally, he noted that the quality of surgical evaluation is complicated by the possibility that some surgeons have better mastery of—and therefore better outcomes with—one procedure while other surgeons have better mastery and outcomes with an alternative procedure.⁴

These concerns were well captured by the late Dr. Judah Folkman, whom I once heard say, “When a basic scientist is informed that another investigator cannot reproduce his work, it has a chilling effect; for the surgeon, however, it is a source of pride.”

Even as we recognize these challenges specific to surgical evaluation, we are still left with the task of determining when a randomized controlled trial is appropriate and when a case-control series may suffice.

There are three broad sets of circumstances in which a randomized trial is essential:

• For preventive procedures, ie, when the operation is done to reduce the potential for a future adverse event. An example would be evaluating carotid endarterectomy to reduce the potential for stroke in asymptomatic patients with 60% or greater stenosis. Only a randomized trial could have shown a difference in favor of endarterectomy over aspirin plus best medical therapy.
• To compare a procedure with alternative medical or surgical interventions. I would argue that laparoscopic surgery should have been introduced with randomized trials, as it begs one to suspend judgment and accept that small incisions are invariably and de facto better than a large incision.
• For trials in oncology, where the outcome depends on long-term results, such as survival or time to recurrence. Examples would include comparisons of surgery alone versus surgery plus chemotherapy for prevention of cancer recurrence.

Similarly, there are several scenarios in which a case-control series is appropriate and adequate:

• When no alternative therapy exists. Falling into this category, in my view, are lung transplant, which we introduced successfully at the University of Toronto in 1983, and lung volume reduction surgery, which we introduced in 1993.
• When the natural history of the condition is well documented and the impact of the intervention is obvious.
• When the magnitude of the procedure’s effect is measurable, significant, and expected.

RANDOMIZED TRIALS IN SURGERY

Advantages of randomized trials

Randomized clinical trials confer a number of advantages. They eliminate bias. They ensure a balance between treatment groups in terms of known or unknown prognostic factors. And, importantly, they have a major impact on payors.

A tale of two Medicare payment decisions

The impact of clinical trials on payors is exemplified by the contrasting stories of two procedures: transmyocardial laser revascularization and lung volume reduction surgery.

Transmyocardial laser revascularization (TMR) involves the creation of channels in the myocardium with a laser to relieve angina. Although TMR is a dubious intervention with no physiologic rationale (similar to internal mammary artery ligation for angina5) and no proven improvement in life expectancy (only a reduction in pain), it was approved for reimbursement by Medicare because it was investigated in a randomized trial.⁶ However, the “randomized trial” was not truly a randomized investigation because the control patients received only medical therapy and did not go to the operating room to receive a sham operation.⁶ Despite this flaw, the perceived authority of the trial was sufficient to influence Medicare.

In contrast, Medicare refused to pay for lung volume reduction surgery until it was subjected to a randomized trial, despite the fact that the procedure had produced tremendous benefit in hundreds of patients at multiple centers who otherwise could not have achieved such benefit. Only after $50 million was spent on a randomized controlled trial, the National Emphysema Treatment Trial (NETT),^7–9 did Medicare agree to pay for lung volume reduction surgery. The trial showed that over 5 years, the procedure was associated with significant improvements in life expectancy, exercise tolerance, and quality of life, but the study took 8 years to conduct and by then it was a bit too late, as detailed in the following section.

NETT: A case study in how a trial can be counterproductive

Lung volume reduction surgery is an operation based on the recognition that the crippling effects of emphysema are hyperinflation of the chest, flattening of the diaphragm, and inability to move air in and out of the chest. The notion that the chest can be reconfigured in the patient with emphysema by removing the distending overinflated emphysema led us to develop the volume reduction operation.

The NETT was initiated by Medicare, and the protocol denied compassionate crossover of patients.⁷ In an attempt to establish clinical equipoise, surgeons who participated were not allowed to perform any volume reduction operations on non-Medicare patients or on Medicare patients not enrolled in the trial. After 2 years of slow patient enrollment, the clinical trial committee, in an effort to increase enrollment, eliminated the original entrance criteria specifying certain degrees of hyperinflation and diffusing capacity. An excess of mortality was discovered 2 years later in a subgroup randomized to volume reduction surgery;⁸ not surprisingly, further analysis showed that the excess mortality was largely confined to patients who would have been excluded based on the original entrance criteria. This is a matter of public record but was never acknowledged in published reports of the trial. Final 5-year NETT results showed that in patients with upper lobe emphysema, lung volume reduction surgery improved survival, increased exercise capacity, and improved quality of life.⁹ By the trial’s completion, however, the procedure’s reputation had been tarnished irreparably by bad publicity from the deaths attributable to the misguided changes to the original eligibility criteria.

Disadvantages of randomized trials

The NETT exemplifies many of the drawbacks of randomized trials in surgery, particularly the need to wait long periods while they are being conducted. During the 8 years in which the NETT was ongoing, the number of lung volume reduction operations declined, with the typical center performing fewer than 6 cases per year, on average. That limitation is certainly not conducive to the development of a new procedure for a disabling condition in patients with no ready alternative.

Other disadvantages of randomized trials in surgery are their considerable expense and the fact that they often are not generalizable and often are not appropriate. Moreover, when they are flawed, randomized trials propagate, sometimes for decades, misleading information that is nonetheless considered “authoritative.” For instance, lung cancer kills more men and women in the United States than the next three cancers combined, yet, on the basis of a flawed randomized trial,¹⁰ the American Cancer Society advises smokers to wait for symptoms before undergoing chest radiography, instead of recommending annual screening chest radiography. This is a major reason why two-thirds of lung cancer cases are discovered too late to save the patient.

‘Better to know nothing than to know what ain’t so’

Indeed, this potential for randomized clinical trials, when flawed, to propagate misleading information makes the perceived authoritativeness of randomized trials both an advantage and a disadvantage. As Berger and colleagues noted a few years ago, overuse of randomized trials for evaluating emerging operations could have led to the demise of heart transplantation, mechanical circulatory assist devices, cardiac valve procedures, coronary bypass grafting, and repair of congenital lesions.¹¹

For this reason, one of our responsibilities when reading the literature and conducting studies is not just to answer unanswered questions but to question unquestioned answers. As 19th-century humorist Josh Billings put it, “It’s better to know nothing than to know what ain’t so.”

A PERSONAL PERSPECTIVE

In my view, health care providers should restrict the application of new procedures to a limited number of centers of excellence that have appropriate resources and experience. Those centers should be required to document and report specified information regarding morbidity, mortality, and objective measures of outcome; if they do not comply, they should lose the privilege of doing such research. The data should be reviewed by an independent, nongovernmental scientific panel. In this way, the procedure can be offered to appropriate patients, insurers and patients can be protected against abuse, and the necessary data can be collected for objective analysis.

By Ralph V. Clayman, MD

Change in the surgical world involves three aspects, which I refer to as the three Ds: discovery, development, and dissemination. Change requires proof that the new method is superior to the old. When we, as innovators, develop something “new,” I believe that our immediate subsequent task is to do everything we can to prove that this “new” finding is of no value whatsoever before we determine that it is worth advancing.

Getting to Malcolm Gladwell’s tipping point—the act or event after which nothing is ever the same— requires a team of people, usually from different disciplines, coming together to concentrate on a problem, or an individual whose experiences in different fields provides the ability to “see” the next level. In my opinion, one person working in one discipline rarely leads to breakthrough progress in medicine.

These observations about surgical innovation stem largely from my experience in the development of laparoscopic nephrectomy, in which I was privileged to play a role while at Washington University in St. Louis, which I will outline here.

THE HISTORY BEHIND LAPAROSCOPIC NEPHRECTOMY

After doing preliminary work in dogs, the German surgeon Gustav Simon performed the first human nephrectomy in 1869, in a woman with a ureteral vaginal fistula. The operation was a success: it took him 50 minutes to complete the procedure, and 6 months later the patient went home.

From that point in 1869 until 1990, progress in nephrectomy was minimal, with open surgery remaining the gold standard. While the surgeon’s tools remained largely unchanged, the advances that did occur were in anesthesia, analgesia, and antibiotics, which allowed patients to better survive the onslaught of the operation.

In an unrelated arena, laparoscopy was developed in 1901 by another German surgeon, Georg Kelling, who pumped air into the peritoneal cavity of a dog in a successful effort to stop bleeding from the stomach. Within the pneumoperitoneum, Kelling was able to examine the canine organs with a cystoscope at pressures as high as 140 mm Hg. This discovery was not applied clinically, however, until 9 years later when the Swedish gastroenterologist H.C. Jacobeus used Kelling’s pneumoperitoneum concept and a cystoscope to visualize the peritoneal cavity to search for cancer. The technique advanced little in the subsequent decades —apart from Semm’s seminal laparoscopic removal of the appendix in the 1960s—until 1985, when the first laparoscopic gallbladder removal ignited the era of laparoscopic cholecystectomy.

Three technological developments spurred this recent surge in laparoscopy: (1) the ability to affix a camera to the endoscope, (2) the ability to display the camera’s images on a video screen, and (3) the development of self-feeding clip appliers to allow occlusion of vascular or ductal structures.

THE EVOLUTION OF LAPAROSCOPIC NEPHRECTOMY

Discovery

I became interested in the possibility of laparoscopic nephrectomy during the laparoscopic cholecystectomy craze in the late 1980s. At that time, I was working with Dr. Nat Soper, performing laparoscopic cholecystectomies in pigs to show that the procedure could be done safely with electrocautery rather than a laser. As it turns out, the anatomy of the porcine kidney is such that the colonic reflection lies medial rather than lateral to the organ. As such, the kidney is quite visible as soon as one enters the abdomen. Indeed, the kidney seemed to be saying to us, “Hey, what about me? I could come out through that hole too.” That is basically how the idea arose.

So, along with Dr. Lou Kavoussi and many others in our research team, we attempted laparoscopic nephrectomy in the pig and succeeded: the kidney could be removed through a small hole by entrapping it in a sack, breaking it up in the sack, and pulling it out.¹² The team involved in this discovery were specialists in urology and general surgery as well as biomedical engineers from industry, specifically a team from Cook Urological led by Mr. Fred Roemer.

After performing this technique numerous times in the laboratory, we reduced the operation’s duration to 90 minutes, at which point we believed the procedure had advanced sufficiently to be considered for clinical use.

Development

The patient we selected for the initial clinical case was an 85-year-old woman with a 3-cm mass in her kidney. She was deemed to be “too sick to operate on,” so she was presented to me as a candidate for the new laparoscopic procedure.

Amazing as it may seem in our current medical climate, at that time (1990) we were faced with the question of whether or not to seek institutional review board (IRB) approval. The argument could be made that since radical nephrectomy had been practiced for 120 years and laparoscopy had been around for nearly 100 years, the combination of these two well-accepted procedures might require nothing more than physician-patient informed consent. However, the concept of “informed consent” in this context was problematic: what could we tell the patient about a procedure that had never been done before except that if it was not working out we would convert to the standard open procedure?

A senior colleague—actually my boss at that time, Dr. Bill Catalona—sagely advised me to get IRB approval, noting, “If the operation works out well, you’ll be fine, but if it doesn’t work out well, they’ll kill you if you don’t have approval.” So we fortunately ended up seeking (and receiving) IRB approval, as well as providing, as best we could, informed consent to the patient and her best friend.

Our next consideration was designating a team member to determine if and when conversion to open surgery would be necessary. We needed a “referee” to aid in objectively determining a point at which we should convert. For our team, that person was Dr. Teri Monk, our anesthesiologist, who had no previous experience with our laboratory work but understood what we were attempting.

So we proceeded with the first clinical laparoscopic nephrectomy on June 25, 1990. The kidney was embolized the morning of the procedure. Five laparoscopic ports were placed. The clip appliers proved too small for renal vein occlusion, so the main renal vein had to be traced to its branches; in total we clipped five separate sets of renal vascular branches. The kidney was ensnared and morcellated, which took 7 minutes. Total operative time was 6.8 hours. The complications that arose were not anticipated:

• Intraoperative oliguria due to the prolonged pneumoperitoneum
• Fluid overload (postoperative congestive heart failure) due to providing fluids to the patient as though this were an open procedure
• Dilutional anemia, again due to providing excessive fluids for a closed procedure.

Postoperative pain medications consisted of one dose of morphine sulfate. The patient was discharged on postoperative day 6 and resumed normal activities by postoperative day 10.¹³

Dissemination

Before a new procedure is disseminated, evidence of the four Es—efficiency, effectiveness, equanimity, and economy—must be obtained. In retrospective reviews, laparoscopic removal was associated with a slightly longer operating time but much less blood loss, a shorter hospital stay, and fewer complications. The immediate cancer cure rate was the same for open and laparoscopic nephrectomy, and over time the laparoscopic procedure has been shown to be just as good as open surgery at 5 and now 10 years. Also, with time, laparoscopic nephrectomy was shown to reduce institutional costs.

The next question was the proper way to disseminate this knowledge. At Washington University we took the traditional route of providing courses, offering 17 courses on laparoscopic surgery to nearly 1,000 urologists from 1985 to 2002. But as Winfield and associates later showed, only 54% of urologists who completed a 2.5-day hands-on, laboratory-based laparoscopic course actually ended up introducing laparoscopy into their practice.¹⁴

The challenge of dissemination is still with us, and we need to find better methods of transferring new skills to our surgical colleagues. In this regard, longer experiences, such as weeklong mini-fellowships and the development of procedure-specific surgical simulators, hold great promise.

UNANSWERED CHALLENGES, UNMET NEEDS

With the advent of any technology comes a cornucopia of unanswered questions and challenges. In the areas of discovery and development, a key question is whether every procedure performed using a new Food and Drug Administration (FDA)-approved technology requires a separate approval by the IRB and ethics committee. For instance, if robotic prostatectomy is approved and performed, are separate approvals needed for robotic nephrectomy, robotic pyeloplasty, and robotic vasectomy? Where would or should the approvals end?

With respect to dissemination, many questions remain: How is a new technology taught effectively? How is surgical competency tested? How is clinical performance or proficiency evaluated?

One problem specific to dissemination is a lack of funding. While ample funding is available for discovery and development, as they bring prestige and profit, dollars are scarce for dissemination, or the teaching and testing of competency and proficiency with new procedures. 

Evidence of our failure to educate the postgraduate surgeon abounds in terms of poor outcomes and malpractice suits. The response of government all too often is the knee-jerk reaction to protect (ie, regulate), not educate. To be sure, we can do better, but only if our society commits to the process—not with words, but with funded educational action.

With regard to the last, I believe there is an unmet need for the development of accurate, validated surgical simulators. As a society, we need to find a way to fund the development of simulators for each surgical subspecialty and then use these devices to objectively test an individual surgeon’s manipulative skill as well as cognitive ability when he or she seeks certification or recertification—and perhaps, albeit in an abbreviated 5-minute format, before beginning each operative day. We owe this to ourselves, but most of all to our patients, who in all confidence place their lives in our hands.

By Thomas M. Krummel, MD

If we surgeons take a step back and consider for a moment what has changed in the operating room (OR) in the past 50 to 60 years, the clear answer is, “Just about everything.” The monitors, pumps, transport devices, and OR tables and lights have all changed dramatically, as have the tools, catheters, sutures, energy sources, scopes, staplers, ports, valves, and joints. If we consider technologies outside the OR that guide what we do inside the OR, the changes are just as striking. Circulatory assist devices for the failing heart and widespread use of dialysis for the failing kidney postdate 1950, as does all of our modern imaging capability—ultrasonography, computed tomography, magnetic resonance imaging, positron emission tomography, functional imaging. As for pharmacotherapy in 1950, there were three antibiotics, no antivirals, one antifungal, and three chemotherapeutic agents. Open drop ether was the anesthetic of choice. Not only have the tools and technologies changed, but virtually every procedure has been changed. Both our profession and the industry that has developed these devices and tools can be rightfully proud.

It is likewise necessary to recognize that our patients have been partners in this innovation. Many of them have given informed consent to participate in research and experimental procedures with the expectation that the benefits might accrue only to future patients and not to themselves. That is a hell of a contribution, and we can be proud of our patients’ partnership.

THE GOOD, THE BAD, AND THE UGLY OF INNOVATION

The history of progress in surgical care is always about innovation, and such progress almost always begins with an unsolved patient problem, regardless of the solution that is developed, be it a tool, a device, a technology, or a surgical procedure. At the same time, any discussion of the ethics of surgical innovation should recognize that while efforts to solve patient problems over the years have had many good results, they have also had some bad results and even the occasional ugly result.

This conference has already focused on much of the good that has come from surgical innovation, including transplantation, remarkable advances in cardiac and gastrointestinal surgery, a host of devices, and too many other benefits to list. Yet missteps have been made along the way, such as bloodletting, gastric freezing as a therapy for ulcer, and carotid denervation for treatment of asthma in children.

Then there are the ugly incidents, and these notably include a number of cases involving children, an issue of special interest to me as a pediatric surgeon. Consider the following examples:

• Edward Jenner’s notorious cowpox experiment in the late 18th century was conducted in an 8-year-old boy.
• A well-documented literature shows that orphans were used as subjects for tuberculosis and syphilis inoculations.
• The more recent case of Jesse Gelsinger involved a teenager with a nonlethal condition who died in a clinical trial of gene therapy, after which an undisclosed financial interest on the part of one of the treating physicians was revealed.

It should give us pause to note that many of these practices that look foolish in hindsight probably seemed more rational at the time they were undertaken.

CHILDREN: THE ORPHANS OF INNOVATION

Children have been the orphans of innovation, as technology development specifically for children has traditionally been a low priority. There are several reasons for this:

• FDA standards for approving therapies in children are high. For instance, the vast majority of chemotherapeutic drugs are not approved for use in children because conducting a trial specifically in children is deemed too expensive.
• Pediatric markets for therapies are small.
• The payor mix is poor.

The benefts of duality

Nevertheless, children have benefited enormously from the duality of technology development, in which a technology developed for one population—either adult or pediatric—ends up benefiting both populations. For instance, no one would have invented the pulse oximeter to care for a child, yet now it is the only device with which infants and children are monitored in the operating room and during transport.

Likewise, in some cases the solutions to pediatric problems have had reciprocal benefits in adults. Ligation of the patent ductus arteriosus and the Blalock-Taussig shunt for tetralogy of Fallot opened the door to our understanding of surgery on the great vessels and ultimately enabled the development of cardiac surgery. Similarly, the early impetus for Thomas Starzl’s groundbreaking work in transplantation was focused on children with biliary atresia even though this work is now much more widely applied in adults.

ETHICAL PRINCIPLES APPLY EQUALLY TO ADULTS AND CHILDREN

The principles of medical ethics that began with Hammurabi in 1750 BC and progressed through Hippocrates’ work circa 400 BC, the 1946 Nuremberg medical trial, the 1964 Declaration of Helsinki,¹⁵ Henry Beecher’s classic exposé in 1966,¹⁶ and the 1979 Belmont Report¹⁷ are just as valid for children as they are for adults.

Francis Moore, the great surgeon who created the environment and the team at Brigham and Women’s Hospital that facilitated the first twin-twin transplant, identified six important components of ethical surgical innovation:^18,19

• A solid scientific background (basic laboratory research)
• A skilled and experienced team (“field strength,” as Moore called it)
• An ethical climate within the institution
• An open display for ongoing discussion
• Public evaluation
• Public and professional discussion.

The principles behind these components remain as true today as they were 20 years ago when Moore outlined them.

SPECIAL CONSIDERATIONS IN PEDIATRIC SURGERY: A CASE STUDY IN MATERNAL-FETAL MEDICINE

The Belmont Report, mentioned above, was developed by the US government in 1979 to form the basis of regulations for federally funded research involving human subjects.¹⁷ The report identified three basic principles that must underlie such research:

• Respect for persons—protecting the autonomy of all subjects, treating them with courtesy, and allowing for informed consent
• Beneficence—maximizing benefits from the research initiative while minimizing risks to the subjects
• Justice—ensuring reasonable, nonexploitative, and well-considered procedures that are administered fairly.

In pediatric surgery, everyone agrees that the “best interests of the child” must be protected, but the issue of autonomy (a key element of the first Belmont principle) is more difficult to define, of course, when the patient is a child rather than an adult. The question of autonomy is especially tricky in the evolving field of maternal-fetal medicine: what if the patient is a fetus and the mother is an innocent bystander?

Over the past 20 years, tremendous progress has been made in our understanding of diseases of the fetus, particularly diseases that limit fetal viability and diseases that cause serious organ damage but which may be more responsive to postnatal therapy if they are treated prenatally. Michael Harrison, N. Scott Adzick, and a few of their disciples have laid the ethical groundwork for consideration of the fetus as a patient.

Considerations in maternal-fetal medicine

I will conclude with a case in maternal-fetal medicine for us to consider and perhaps debate in the panel discussion at the end of this session. As you consider this case, keep in mind several important observations relating to maternal-fetal medicine:

• The mother’s health interests cannot be underestimated.
• Most “fixable” fetal lesions (ie, those that interfere with development and cannot be fixed postnatally, but for which intervention in utero may result in normal development) are very rare. They include obstructive uropathy, lung lesions causing hydrops, congenital diaphragmatic hernia, sacrococcygeal teratoma, hydrocephalus, twin-twin transfusion syndrome, congenital high airway obstruction, hydrothorax, myelomeningocele, and congenital heart disease.
• The field is evolving, and the efficacy of therapy is supported by variable level I, II, and III evidence.
• The law has not kept (and perhaps cannot keep) pace with developments in this field.

Case study

A 24-year-old healthy woman has a fetus of 28 weeks’ gestational age with progressive lower urinary tract obstruction with megacystis, bilateral hydronephrosis, and oligohydramnios. In other words, there is diminished volume in the uterine cavity that causes compression of the fetal chest and subsequent respiratory compromise that will be fatal if not addressed. The karyotype is a normal 46,XY male. Serial urine sampling reveals electrolyte and protein profiles with a good prognosis.

Prenatal counseling with fetal therapy specialists suggests that this is the “perfect case” for a vesicoamniotic shunt. This is the least invasive, most successful fetal surgical intervention. It is done under local anesthesia and involves transabdominal transuterine percutaneous placement of a double-lumen pigtail catheter in the fetal bladder. There has never been a reported maternal death, and morbidities have been minimal. Renal and pulmonary function both are improved by approximately 80% in fetuses treated with this intervention, and survival is improved.

The father is eager to proceed. The mother is ambivalent. Should the mother be pressured to proceed, for the good of the child?

Questions to ponder

The following questions are intended to be provocative, with no clear-cut answers:

• Should (or does) the fetus have independent moral status? Is it full, graded, or none? Does it matter?
• What are the beneficence-based obligations to the fetus? At 28 weeks’ gestation, the fetus is viable outside the uterus. The fetus is otherwise well, without a lethal karyotype, and has currently good renal function.
• What are the beneficence-based and autonomy-based obligations to the mother? What are the mother’s obligations to the fetus?
• What if the mother ultimately decides to proceed and the insurance company denies coverage? What are the social responsibilities to care, cost, and research?

These questions lend themselves to discussion. As much as we surgeons like to be certain about what we do, we would do well to heed the quote from Voltaire that the great surgeon Norman Shumway hung on his office door: “Doubt is not a very agreeable state, but certainty is a ridiculous one.”

By Philip R. Schauer, MD

Obesity is a staggering problem: 100 million Americans are overweight, 85 million more are obese, and another 15 million are morbidly obese (ie, ≥ 100 lbs above ideal body weight). The incidence of obesity is rising rapidly and threatens to shorten the life spans of today’s young generations relative to their parents. Unlike other conditions, such as cardiovascular disease and cancer, obesity has seen no widespread progress in management in recent years.

Recognition of obesity as a medical problem is a challenge in itself. Many people consider obesity to be a character flaw or a behavioral issue and fail to recognize it as a disease entity. Yet obesity is the root cause of many metabolic conditions and diseases with metabolic components, including type 2 diabetes, heart disease, blood pressure, metabolic syndrome, acid reflux, gout, arthritis, and sleep apnea.

The approach to obesity treatment can be conceptualized as a pyramid, with the aggressiveness of the intervention based on the patient’s body mass index (BMI). At the base of the pyramid, for patients with lower BMIs, are minimally invasive (and minimally effective) interventions involving changes in diet, physical activity, and other lifestyle factors. As BMI increases, so does the intensity of treatment, to include pharmacotherapy and eventually bariatric surgery. Traditionally, surgery has been considered only at the very top of the pyramid, for morbidly obese patients, and is usually not offered as an option for the vast majority of people with this condition.

The sad reality is that the various combinations of these therapies are effective in fewer than 1% of the approximately 100 million Americans who are obese. Because surgery has been shown to be the most effective therapy for obesity, the remainder of my discussion will focus on surgery, with an eye toward potential new indications for bariatric procedures and the questions they raise.

SURGICAL APPROACHES TO OBESITY

Bariatric surgery has evolved over the past 50 years. Although there are about a dozen different permutations of bariatric procedures performed in the United States today, they fall into one of three major types of operations, as outlined below:

Gastric banding reduces appetite and satiety by adjusting and tightening the gastric band. This procedure has been in existence for 10 to 15 years and represents about 25% of operations for obesity in the United States.

The biliopancreatic diversion procedure diverts most of the small bowel and radically reduces absorption of calories. Patients undergoing this procedure lose weight because few calories are absorbed into the body. This approach, while quite effective, is somewhat radical and represents only about 2% of the operations for obesity in the United States.

The Roux-en-Y gastric bypass procedure has been the dominant procedure over the past 15 to 20 years. A combination of the above two procedures, it involves reducing the gastric reservoir and bypassing the stomach and upper intestine. The reduction in gastric volume reduces calorie intake by enhancing satiety, and the limited foregut bypass moderately reduces absorption.

No randomized trials, but much support from observational studies

Virtually none of these procedures evolved with randomized controlled trals. Instead, they evolved incrementally, primarily on the basis of knowledge gained from case procedures. Despite the lack of randomized trials, these operations have been shown to be effective, particularly in patients with multiple metabolic abnormalities associated with severe obesity. A large body of data from case-control and cohort studies demonstrates not only dramatic improvement in metabolic abnormalities with the use of various bariatric procedures, but also improvements in quality of life and survival.^20–26 The two most recent of these studies, published in 2007, found reductions in mortality of 29% (adjusted) and 40% among surgical patients compared with well-matched obese controls during mean follow-up of more than 7 years.^25,26 Reductions in the incidence of cardiovascular mortality and, secondly, cancer-related mortality were the two major contributors to the overall mortality reduction in these two studies. Consistent with this latter finding, obesity is starting to be thought of as a disease that may lead to cancer.

NEW FRONTIERS FOR BARIATRIC PROCEDURES

The current indications for bariatric surgery have existed intact for about 25 years, and were based on limited evidence available at the time. They are basically as follows, assuming acceptable operative risk and appropriate patient expectations:

• BMI greater than 40 kg/m²
• BMI greater than 35 kg/m² with significant obesity-related comorbidities.

Payors adhere strictly to these indications, such that they will not pay for bariatric surgery in a patient with a BMI less than 35 kg/m². This raises questions about the appropriateness of such a firm threshold and whether expansion of these strict indications may be reasonable.

Even without broadened indications, the volume of bariatric procedures in the United States has grown dramatically in recent years. Whereas only 10,000 to 20,000 of these operations were performed annually in the 1990s, approximately 200,000 such procedures were performed in 2007, and this number is expected to double over the next 5 years or so.

This growth in volume has been paralleled by burgeoning media interest in bariatric procedures, particularly in the last few years. More attention can be expected as we increasingly recognize the potential of bariatric procedures for indications beyond strictly the treatment of morbid obesity. At least two new frontiers loom: metabolic surgery and endoscopic surgery.

Metabolic surgery

Procedures that incorporate a bypass—the Roux-en-Y gastric bypass and the biliopancreatic diversion —have been associated with a reversal of metabolic diseases such as type 2 diabetes.^27–32  Many patients with type 2 diabetes who have undergone these procedures have been able to be weaned off insulin and insulin-sensitizing medications while maintaining normal blood glucose levels. The effect has been profound and immediate, occurring even before the patient loses weight. In one series of patients with type 2 diabetes who had undergone a bypass operation, 30% left the hospital in a euglycemic state.²⁹

These observations have been made primarily in the morbidly obese population, who are the primary candidates for bariatric bypass procedures. However, because of the rapid improvement in metabolic abnormalities that has been observed, interest has arisen in applying these procedures to populations that are not morbidly obese. Bypassing of the foregut appears to be critical, perhaps because it tempers the release of hormonally active peptides from the gastrointestinal tract.³³ In any case, the gut is regaining recognition as a major metabolic organ.

In light of these hypotheses, the duodenal-jejunal bypass is a bariatric procedure that may be beneficial for a patient with type 2 diabetes who is not morbidly obese. In this operation, the stomach volume is preserved but the foregut is bypassed. In a small experimental series from Brazil, patients with type 2 diabetes who were normal weight or only slightly overweight had resolution of their diabetes following this procedure, without any weight loss.³⁴

New applications for endoscopy

Another area of development is endoluminal and transgastric bariatric surgery. Endoluminal surgery is performed entirely within the lumen of the gastrointestinal tract using flexible endoscopy. Transgastric surgery is performed within the peritoneal cavity, which is accessed via a hollow viscus. Both approaches use natural orifices to gain surgical access, thereby avoiding access incisions and scars.³⁵

The benefits of such an approach are numerous:

(1) fewer complications and side effects; (2) less invasiveness, and thus the ability to perform in the outpatient setting; (3) reduced procedure costs; and (4) better access to treatment. The implication in terms of indications is the potential to use such procedures to prevent progression to morbid obesity.

Examples of these procedures are proliferating:

Gastrojejunostomy reduction is an endoscopic procedure that involves reducing the dilated opening of the gastric pouch after gastric bypass surgery. New endoscopic suturing or stapling devices enable the outlet reduction without requiring surgery. The result is enhancement of weight loss without a major operation.

Endoluminal suturing uses endoscopic instruments to suture the stomach to reduce its volume. When this procedure is perfected, the patient should be able to leave the endoscopy suite and return home within a few hours.

The duodenal sleeve is an avant garde concept in which an internal sleeve is threaded into the stomach and down the intestines.³⁶ The sleeve covers the absorptive surface of the small bowel, preventing absorption of nutrients to cause weight loss. This procedure has been shown to have a strong antidiabetic effect as well.

Clinical applications of these operations are emerging. An endoluminal sutured gastroplasty procedure to shrink stomach volume has been shown in a small clinical trial to cause loss of significant excess body weight; the operation leaves no scars and is associated with a low risk of bleeding or any type of surgical complication.³⁷ A similar procedure is in development that involves staples instead of sutures.

How best to validate innovations moving forward?

As we move into these new eras of metabolic surgery and endoluminal and transgastric bariatric surgery, interesting questions arise. We as innovators and caregivers are ethically obligated to demonstrate reasonable safety and efficacy before such new procedures are performed widely. Although some of these emerging procedures involve new devices that will go through the FDA review process, many are existing procedures for which indications may be expanded, while others are permutations of existing procedures for which no formal rules for validation exist. For new procedures that differ substantially from existing proven procedures but which do not require new devices, should we not be ethically bound to demonstrate safety and efficacy even though they do not require FDA review? These are the challenges that await as innovation takes bariatric surgery to new frontiers.

By Christopher Thompson, MD, MHES

Although the endoscope has changed very little since the first fiberscope was developed 50 years ago, the accessories and other instruments used in conjunction with the endoscope have changed remarkably. These include clips for hemostasis, ultrasonographic technology, and instruments for tissue dissection.

These advances in endoscopy, combined with advances in laparoscopic surgery, have led to the convergence of these two fields, culminating in the new field of natural orifice transluminal endoscopic surgery (NOTES). In NOTES, the surgeon enters a natural orifice and punctures through a viscus to perform surgery, removes the endoscope, and closes the area without leaving a scar.

HISTORY OF NOTES AT A GLANCE

NOTES was patented as a concept in 1992. Its first application was as an exploratory procedure in the pig in 2004.³⁸ Soon thereafter, therapeutic NOTES procedures in animals were reported, including tubal ligation, organ resection, cholecystectomy, and splenectomy.

Particularly notable in the development of NOTES is the extremely short interval between early animal experiments (2004) and the first human procedures, which took place as early as 2005 when surgeons in India used the technique to perform a human appendectomy. Since then, more than 300 NOTES procedures have been performed in humans throughout the United States, Europe, Latin America, and Asia, for applications ranging from percutaneous endoscopic gastrostomy rescue to transvaginal cholecystectomy.

This rapid adoption of NOTES in humans is concerning, as it raises clear questions about whether there has been time for adequate oversight and safety assessment. For instance, at a surgical conference in April 2008, questions and debate swirled around whether a large Brazilian registry of more than 200 NOTES cases did or did not include two deaths. Other ethical issues raised by NOTES are discussed further below.

DRIVING FORCES BEHIND NOTES

The medical rationale

Abdominal wounds can cause pain, are unaesthetic, and are prone to wound infections, ruptures, and hernias. They sometimes cause adhesions or may lead to abdominal wall syndromes with scar neuromas that cause pain later. They also require general anesthesia. Beyond these shortcomings of incision-based procedures, NOTES offers potential reductions in length of stay and therefore in cost. Moreover, certain patient populations may specifically stand to benefit from NOTES, such as obese patients, those with abdominal mesh in place, and those undergoing palliative procedures. This is the essence of the medical rationale for NOTES, which is somewhat thin.

Professional organizations and courses

In July 2005, leaders from the American Society of Gastrointestinal Endoscopy and the Society of American Gastrointestinal and Endoscopic Surgeons convened a working group to support and plan for the responsible development of NOTES.³⁹ The group formed the Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR), an organization that has since sponsored several conferences on NOTES and procured millions of dollars in grants for NOTES research in animals. (In the interest of full disclosure, I am one of the founding members of NOSCAR.)

Additionally, leading institutions in this field have held numerous hands-on courses on NOTES throughout the United States, Europe, Latin America, and Asia. These courses, including those held by my laboratory at Harvard University, are designed to teach colleagues at other institutions how to set up an appropriate animal laboratory and to promote and encourage proper research in NOTES. There have been unintended consequences, however, as we have learned that some course attendees have returned to their home countries and immediately started using the techniques in humans.

New technology

At the July 2005 working group meeting that launched NOSCAR, we determined that several technological advances were needed before NOTES could be safely applied to humans. These included development of multitasking platforms, better devices for tissue apposition and fixation, better imaging and spatial orientation, and improved means of retraction.³⁹ Industry responded with novel devices and end effectors such as guide tubes, direct drive systems, endoscopic suturing devices, magnetic retraction, devices for closing luminal defects, flexible staplers, and computerized robotics.

Other driving forces

Additional forces have undoubtedly contributed to the rapid development of NOTES:

• The slowdown in innovation in general surgery in recent years has left a vacuum to be filled.
• An abundance of venture capital has been available to rush into that vacuum.
• Perceived patient demand (owing to cosmetic advantages) has been a driver, especially in cities such as Rio de Janeiro, Milan, and New York.
• The fear of being left behind is a factor that cannot be underestimated. Surgeons who failed to convert to laparoscopic techniques from open techniques in the early 1990s for procedures such as cholecystectomy, fundoplication, and splenectomy were losing their patient bases. Many surgeons fear a similar phenomenon today if they do not adopt NOTES into their practices.

ETHICAL ISSUES RAISED BY NOTES

As NOTES moves toward further evaluation in humans, several ethical questions need to be grappled with:

• Must there be a significant potential for improvement in care before an innovation advances to human research?
• Is the cosmetic benefit of NOTES sufficient, considering the substantially increased risk? For instance, laparoscopic cholecystectomy is well established, whereas NOTES cholecystectomy carries an increased risk of bile duct injuries and other injuries. Is NOTES worth the risk?
• What about the corporate agenda behind new technologies and its associated influence on the media?
• Are hospital IRBs adequate to the task of evaluating and monitoring these questions, and will they be independent of the impact of hospitals’ larger agendas?

Finally, the problem of premature adoption of this technology is particularly concerning. I heard a surgeon explain at a course that he performed NOTES on a few pigs at a previous course and then returned home to Peru and immediately started performing it on patients at his ambulatory surgery center. There is also the temptation for well-respected surgeons to go to other countries to practice their NOTES skills before returning to the United States, in hopes that their experience will help them attain IRB approval. Practices like these raise questions about what ethical responsibilities lie with those of us who have pioneered the technology and are trying to develop and disseminate it responsibly. We can try to vigilantly watch course attendees from certain countries, but there is little we can do in the absence of regulation and enforcement in those countries. These are difficult ethical challenges.

Panel discussion

Moderated by Jonathan D. Moreno, PhD

Dr. Jonathan Moreno: I would like to begin with any questions that the panelists have for one another.

Dr. Philip Schauer: I would be curious to hear how my colleagues define incremental changes in a procedure. In other words, what constitutes a new procedure versus a modification of an existing one?

In bariatric surgery we are grappling with a procedure called the sleeve gastrectomy, which poses challenges comparable to lung volume reduction surgery as described by Dr. Cooper. Many of us believe that this procedure is just a slight modification of a gastroplasty, yet payors consider it an entirely different procedure, and some want 5 to 10 years of follow-up data before they will pay for the operation.

Dr. Joel Cooper: That is not an easy question, but I would approach it from the standpoint of what you would tell the patient. When we were first developing lung volume reduction, we performed it only in patients who had absolutely no other alternative. Only later in its development did we offer it as an alternative to transplantation. How do you approach the patient when you can already achieve a very good result with an existing procedure and you can tell the patient, with some assurance, what to expect with that procedure? In the case of NOTES, I do not think that the cosmetics are sufficient justification.

The second aspect is regulatory. I am not a supporter of the FDA’s practices for the introduction of new procedures, but I believe strongly that universities have been derelict in setting the standard for the introduction of new procedures, particularly minimally invasive procedures. They have been using these procedures as marketing tools to vie with private hospitals for dollars and patients. I cannot say whether the rapid promulgation of these procedures at too early a stage actually can be prevented, but I do not recall the chairmen of major surgery departments getting together to issue public statements about the proper protocol for introducing new techniques. As Pogo said, “We have met the enemy and he is us.”

This may not answer your question, but I believe there should be no payment for any new or novel procedure for a certain period after its introduction, and certainly the hospitals should not be able to profit from it, although the expenses of a new procedure may be recouped. That alone would perhaps put the brake on some of the marketing and the financial incentives, and it might separate, to some degree, the development of new procedures from economic interests.

WHO SHOULD OBTAIN INFORMED CONSENT?

Dr. Moreno: Should informed consent be obtained only by a knowledgeable third party rather than the surgeon-innovator?

Dr. Thomas Krummel: The question is whether there is a disinterested third party who truly is knowledgeable; in cases where there is such a person, I see no downside to having that person involved. However, the notion of having someone who is not associated with clinicians or surgeons obtaining informed consent makes me uncomfortable. Informed consent is not a piece of paper. It is a trust between physician and patient, and to ignore that could leave you in a heap of trouble.

Dr. Cooper: I agree, but another process is important as well. In proposing lung transplantation before there had been any successful transplants, we defined in advance the standards, indications, and contraindications that we thought should apply. We did this in the absence of any particular patient, and it relieved us of the difficulty of making arbitrary decisions that may have led to unfairly accommodating one patient over another. Once the standards have been set in this way, they can be applied—whether by the investigator or by a committee—in an objective way to the group of patients that is most appropriate in the early phases of development.

Dr. Ralph Clayman: It is difficult for the inventors of an operation to dampen their enthusiasm for their creation to a point where they are as objective as they should be. Joel is bringing up situations for which there are no alternatives. My realm is an area in which there were well-established alternatives for everything we have done laparoscopically or percutaneously, and it was difficult to decide the indications or contraindications early on. Often, the early indications only had to clear the threshold of not seeming ridiculous.

The early development of percutaneous stone removal at the University of Minnesota took place entirely outside the purview of an IRB. Percutaneous nephroscopy had been around since 1955, and we extended it to plucking out a stone. That is how that entire field developed. Early on, we were not going to go after a stone that was as big as a fist because we did not have a way to break it up. As time went by, however, it evolved to the point where there was no stone in the kidney—regardless of its size, location, or hardness— that could not be removed through a small hole in the back. But that entire evolution proceeded without IRB approval.

For laparoscopic nephrectomy, for which there were well-known alternatives, who should have obtained the informed consent? Should it have been me, bringing along the “white coat” factor and not being able to really explain the potential problems since nobody had yet gone there, despite my rapport with the patient? Or should it have been a third party with whom I had discussed the procedure and its possible problems? I do not know the answer, but it raises an interesting point, especially in this age of IRBs and ethics committees.

Dr. Krummel: It is not unlike what we have tried at Stanford when we are not sure of the boundary for IRB consultation. The surgical chairs are willing to convene and essentially police one another, so that when the neurosurgeon proposes a brain transplant, there probably will be a pretty interesting conversation before it gets the green light.

Dr. Cooper: My experiences with IRB involvement differed quite a bit between my work in lung transplantation and my work in volume reduction surgery, but the differences owe a lot to the countries where I was practicing at the time. I did my early work in transplantation in Canada, where I did ask for approval from my hospital’s ethics committee and other relevant committees. In Canada, the hospital had a global budget, and it made a decision that it was willing to use part of its budget for transplantation. We received no fees for years, until the operation was proven to be effective, but that did not stop us from developing the procedure.

I had returned to the United States when I began my work with lung volume reduction, and I did not ask the IRB for permission to do that procedure. My justification was that, theoretically, volume reduction was similar to accepted practices for removal of nonfunctioning lung to improve respiratory mechanics (bullectomy) and that we would simply be applying the concept to a different group of patients. However, unlike in Canada, I did not have institutional financial support for doing this new procedure, so how was I going to do it if the hospital could not receive payment for it? I went to the IRB, but instead of asking for permission to do the procedure I asked for permission to study the procedure and to collect data on it. In that way, I was notifying the IRB of my action and thus giving it an opportunity to act. If I had gone to the IRB to approve the procedure, however, the operation would have been labeled experimental by insurance companies, who would have then found a way to deny payment. At least that was how it was in those days.

Question from audience: What makes you think that in 10 years there won’t be 100 million obese Americans watching television ads for noninvasive bariatric surgery promising to rid them of their obesity problem? What will keep that from happening?

Dr. Krummel: Nothing. What makes you think it is not happening now? Just look at the ads for the Lap-Band in the lay press.

Dr. Clayman: We already have direct marketing of drugs and direct marketing of facilities. What Joel said is true: “the enemy is us.” When I was in training, the idea that a physician would advertise was considered unethical. I still consider it thus. But everybody is doing it, so should that make it acceptable? I think not.

The same thing is true of the huge amount of money spent marketing drugs on television. Why should a single nickel be spent to advertise health care beyond generically informing the public of important health care issues and initiatives? You cannot go to an airport without seeing a surgical robotics program being advertised or a hospital being advertised. You cannot turn on National Public Radio without hearing well-financed spots touting the achievements of a hospital. You cannot watch television without seeing ads for erectile dysfunction medications or other new drugs. It is a waste of dollars. If we took all of that money and redirected it, we could probably solve much of the indigent health care problem, but we as a society have chosen not to do that. 

SHOULD THE BAR BE RAISED FOR SURGICAL TRIALS?

Dr. Moreno: Let’s consider some additional questions. Why shouldn’t the government raise the bar on the level of evidence needed to gain regulatory approval for new devices? Why not require randomized trials, as is done for drugs?

Dr. Cooper: Procedures that lend themselves to a randomized trial should be studied at a limited number of centers with mandatory reporting and preset indications for promulgation and payment. I believe that universities have been derelict in their duty to require this level of evidence.

This question is always nuanced, however. Consider the case of laparoscopic procedures. They offer the advantage of smaller incisions, yet how many patients have had to die or suffer serious consequences for the sake of these smaller incisions? On the other hand, how many patients may have been saved from pulmonary embolism, wound infections, or a prolonged hospital stay as a result of laparoscopic techniques? Only a randomized trial could demonstrate whether or not there has been an overall payback from new procedures such as this, although even then the payback may be present for some types of patients but not others.

Dr. Schauer: The problem is expense. Perhaps it is all a matter of economics. Return on investment for the drug industry is something like 10 to 1, but return on investment for the medical device industry is generally much lower. Therefore, conducting large randomized controlled trials is extremely expensive and much more complicated for a device or procedure. This may explain why the standard for trials is different for the two industries.

Dr. Krummel: Virtually all fetal surgical procedures have been subjected to a trial, several of them randomized. The National Institutes of Health paid for many of these trials. One such study prevented rapid uptake of the congenital diaphragmatic hernia operation, which has never been proven in a randomized trial to be better than our current therapy. It is a good example of a randomized trial making a difference.

Dr. Clayman: As Joel pointed out, surgery is constantly evolving, whereas a drug remains unchanged throughout its lifespan. If we had started a prospective randomized trial after we had done our first laparoscopic nephrectomy, the procedure would have died because we were not nearly as facile with our first 10 as we were after our first 100. The technology continues to develop, and the surgeon continues to develop his or her skills, which makes a study of this nature overly dynamic. Perhaps the best you can do is a retrospective, matched, controlled study with the same surgeon, comparing his or her results after 40 or 50 laparoscopic procedures with results after his or her 50 most recent open procedures.

Dr. Cooper: How do you put a brake on the system? Would some sort of limited trial perhaps put a brake on the too-rapid promulgation that we often see?

Dr. Clayman: In the general surgery realm, laparoscopic cholecystectomy came out of private practice. It did not come out of the university with its faculty and laboratories dedicated to exploration and investigation. It never was properly vetted in the scientific realm but rather came to the light of day as an “economic” edge.

Dr. Krummel: I would not underestimate the talent and creativity of those that we train who go out into private practice. Much innovation has come from very active practitioners.

Dr. Clayman: Right, but they do not have the infrastructure that we are blessed with at universities both to create and to validate.

Dr. Schauer: I agree that academia does not have a monopoly on creative ideas. But perhaps academia should play a major role in defining validation-type studies. That is one area where we may be especially well suited to meet an important need.

THE INNOVATION-TRAINING INTERFACE

Question from audience: I have a dilemma as a residency program director. Our residents want to learn the new technology—laparoscopic surgery, robotic surgery, etc—but we have them in our program for such a limited time. How do you justify teaching them new technology and at the same time still teach them basic, traditional surgical procedures, especially with the reduction in residents’ hours? It is fine to be able to do a nephrectomy laparoscopically, but if you get in trouble, you still have to know how to do a good open nephrectomy. How do you address this?

Dr. Schauer: I think the answer largely is fellowship training. Emerging procedures probably should be introduced in fellowship programs until they reach the point where they are so standardized that they become a major part of practice. For example, cholecystectomy quickly became part of general surgery practice, but laparoscopic colectomy took several years to evolve and was taught primarily in fellowship or advanced training, after which it gradually filtered down to residency programs.

Dr. Krummel: All of us who are responsible for training are wrestling with this problem. Residents are expected to learn more yet do so in less time. One approach would be early specialization, so that instead of 5 years of general surgery, you would have 3 years of general surgery and then 3 years of, for instance, thoracic surgery. Also, Ralph mentioned earlier the advantage of skills labs. We increasingly see that type of approach as a backbone for providing broad training without putting patients at harm.

As for teaching the use of new technology, first you have to teach the existing base of practicing surgeons. Here again there is much to be said for skills labs, and I give credit to the American College of Surgeons for its drive to establish and accredit centers around the country as a way to teach this base of surgeons.

Dr. Schauer: If I may expand this question beyond residency and fellowship training, how do we balance the desire to share new innovations with our colleagues against the need to temper their desire to prematurely jump into an area where they do not yet really belong? Chris, I know this applies to your challenges in disseminating knowledge about NOTES.

Dr. Christopher Thompson: Yes, courses on NOTES are also being held in conjunction with all the major society meetings, and we are seeing many enthusiastic trainees at these hands-on courses. The original intent was to give attendees instruction on setting up their own animal labs, yet some trainees took it beyond this limited purpose. As a result, some in our field believe that we should not allow foreign physicians to come here to be trained in NOTES, for fear they will go back to their home countries and use it on humans. I am not certain that that approach is the best way to go, but there has been much discussion about how to handle this. It is a real conundrum. Certainly there are a number of surgical residents and gastroenterology fellows who are clamoring to get into the lab right now and learn these techniques.

Dr. Clayman: This goes back to our earlier discussion about from where new technologies should emerge. What frightens me are the consequences of creative activity occurring outside the university, where there are no laboratories or animal or cadaver models for refining or testing a technique. To me, it was frightening to see laparoscopic cholecystectomy suddenly emerge as a craze without the proper animal and clinical studies having been done. That is not the way I believe clinical research should go forward. I once heard a prominent urologic surgeon say at a major surgical meeting, after a presentation on the impact of percutaneous stone surgery on the canine kidney, “Now that I’ve done a thousand of these in humans, it’s reassuring to know that it’s safe to do in dogs.” That is not the way it should happen, and every time it does happen that way, we pay a large price, some of us as individuals and all of us as a society.

Dr. Cooper: The answer therefore is to use our academic facilities to facilitate the training of those in community practice. We should continue to offer training because we have the resources to make it available.

Dr. Clayman: Yes, and this is why I emphasized earlier that support for surgical training centers is so essential. I see all the dollars spent on health care advertising and wonder why these dollars are not instead poured into surgical training, or research facilities, or training simulators.

The way we should train surgeons in new technologies is to train them on simulators equipped with a properly vetted curriculum. This is the future for training, because once you put instruments through small ports, everything becomes measurable—economy of motion, past pointing, and efficiency; simulators with a curriculum will also be able to assess the trainee’s cognitive abilities. When an individual performs well on the simulator, he or she can then come into the operating room and work with surgeons experienced in the procedure. The use of simulators in this manner should ultimately improve the overall quality and safety of each surgical specialty.

Question from audience: I am curious how the panel members interpret early randomized trial data showing an increased cost without an improvement in care with the use of surgical robots in certain procedures. Should we persist or consider an investment in the future as robotic technology improves and surgeons further adapt to it?

Dr. Cooper: I think the robot should be used only for those procedures for which it has unique capability and can perform a task better than we can. It appears that the robot performs better than the ear, nose, and throat surgeon for operations on the base of the tongue. The same may be true of prostate surgery, but I am not certain. But to do a laparoscopic Nissen repair with a robot…as Dr. Nat Soper of Northwestern University has said, “If I needed a robot, I shouldn’t be doing laparoscopic Nissens.”

The robot provides light, it gives you magnification, and it reduces tremor. We should concentrate on its use for operations where these attributes are particularly valuable. But we should be wary of its use as an expensive marketing tool.

Dr. Clayman: The robot provides you with superhuman capabilities: 10 to 30X magnification, no tremor, a 540-degree wrist, instrumentation with 6 degrees of freedom, and motion scaling. It allows you to be a better surgeon than you are without it. I agree that it is expensive. It is woefully overpriced at this point, but I believe the expense will come down with time. It is no different than the first computers, which were terribly expensive. The robot enables surgeons to do a better job than they would without it if we are talking about reconstructive-type surgery.

Ergonomically, the robot is very positive for the surgeon. For the first time, the surgeon is actually allowed to sit down in a comfortable environment and can work for 4 hours straight, get up at the end of the surgery, and feel fine. If you are older than 50 and you operate standing at the table staring at a television screen on the other side for 4 to 6 hours, you are going to ache afterwards. I believe surgeons work better if they are comfortable.

Dr. Schauer: At least within my field of general surgery, there has been no evidence that this superhuman ability has translated into superhuman results, in terms of reduced operating time, fewer complications, or better efficacy. We should probably develop the metrics to measure progress. How do the theoretical benefits translate into clinical benefit?

Dr. Clayman: It is not theoretical in radical prostatectomy if you look at the data. The potency rates for patients who undergo robotic surgery for these procedures are now almost 90%, which is something that no surgeon performing open prostatectomy has ever achieved. Fortunately, the continence mechanism is so strong in most adults that it does not matter whether prostatectomy is done with a robot or open surgery—patients are probably going to be all right. But the bottom line is that robotic surgery is a bit better. Most surgeons would use it if it were free. The problem is that it is so expensive right now and it is breaking the backs of many hospitals.

Dr. Schauer: You make a good point. Demonstrating metrics is important, and prostatectomy is a good example. But I am not aware of any other procedures for which benefit from robotic surgery has been documented.

Dr. Krummel: The history of robotic surgery is so interesting because the killer application was supposed to be coronary work—percutaneous bypass surgery. But then the heart port went to pot and patients with anterior wall lesions ended up not being a big enough group. It turns out that it is still difficult to do and there is not a lot of room. So prostatectomy has ended up as the initial killer application.

Keep in mind that the current robot is not an end device. We will see more. There are now robotic steerable catheters that I think will be adopted into NOTES procedures. This theme of immediate benefit versus follow-on iterations is the story of device development in this country.

Conflict-of-interest statement
I am seriously conflicted. You may assume that
I have a financial interest and conflicts with any
emerging med-tech company you choose. In addition,
I actually take royalties when possible and encourage
innovation and entrepreneurship in others.

As an inventor, my perspective on financial relationships with medical technology companies is quite different from the one presented by Dr. Arnold Relman in his earlier keynote address. Although I agree with him that the state of medicine is indeed a mess, the mechanism by which that mess can be cleaned up is debatable. I believe strongly that the mechanism advocated by Dr. Relman— prohibiting financial rewards (outside of salaries) to physicians involved in innovation—will do nothing to benefit patients.

My assessment of the topic I am charged with addressing—will the United States maintain its preeminence in medical technology?—is that it will not. I will use this talk to present the reasons for that assessment in the hope that you will understand that we are going the wrong way in American medicine today.

THE NATURE OF INNOVATION

True innovation requires broad acceptance

Innovation, invention, and technology development are not simple or single occurrences. They represent an iterative process requiring reduction to practice and, most important, acceptability by others. An inventor does not determine the worth of his invention; his peers do. Self-proclaimed inventors are numerous and multiple, and the technologies that they put forward rarely receive broad acceptance. Everybody wants to be an inventor, recognizing that it brings attention and reward, but it also brings a lot of baggage, which I will discuss shortly.

What’s wrong with a medical-industrial complex?

Dr. Relman and others may object to the term “medical-industrial complex,” but to do so is to deny reality, because health care in the United States simply is a medical-industrial complex, but one devoted to optimal patient care.

The process by which optimal patient care is delivered involves relationships among a whole host of people. In my view, the key players are the engineers and physicians coming together to develop a technology intended to benefit patients—this relationship is a critical element of invention and innovation. At the same time, patients are the most important individuals involved in any process of innovation. Without patients, we simply could not innovate. Of course, other players have roles as well: institutions, the government, industry, entrepreneurs, lawyers, payors, investors. And in the middle of this mix we have chief executive officers of industry, whose job is to make sure all these players are talking to one another and collaborating for the benefit of patients.

CHALLENGES TO INNOVATION

Challenges to innovation are abundant, and some of them have been with us for decades. I have outlined some major challenges below.

Technology evaluation

There are many ways that technology can be evaluated. We hear a lot about evidence-based medicine, which is ideal if used appropriately, yet too many people demand it in a knee-jerk way. In the field of surgery, level I evidence is often impractical, extremely costly, and sometimes not even possible, and attempts to use it may lead to inaccurate conclusions. If applied too broadly, the demand for level I evidence can impede innovation, so it is important to recognize that evidence-based medicine is only one way to get answers about a technology, especially in the surgical specialties.

Teaching and training

Teaching and training of new technologies is another challenge. The shelf life of a new surgical technology is approximately 5 years. Failure to recognize a new technology can lead to a loss of business, as in the case of cardiac surgeons who initially ignored catheter-mediated therapy. Other specialties are rarely willing to help surgeons adapt to new technology, for fear of losing business. So the issues at play can be pretty complex.

Who is to do the training? Because academic medical centers cannot afford to teach new technology, industry must take on this role. We need to recognize that industry offers a very valuable service in the process of teaching and training. As for potential downsides, surgeons should be smart and savvy enough to be able to evaluate whether a sales representative’s presentation is solid or nothing more than marketing. If we cannot do that, our medical schools have egregiously failed in their mission.

Cost is one of the most significant deterrents to innovation. The accelerating cost of innovation is difficult to imagine. For example, the first embolectomy catheter cost about $3,000 to develop back in the early 1960s. As its developer, I can tell you that it cost so little because I stole or borrowed—on a permanent basis—most of the equipment needed to make the catheter systems, which I sterilized in a preparation of glutaraldehyde (Cidex) and reused. Compare that cost to the cost of developing the drug-coated stent. If the costs of the drug, the device, and the clinical trials are all included, Johnson & Johnson’s total cost of developing its drug-coated stent was more than $1 billion.

What is often not acknowledged, however, is that technology may be a solution to accelerating costs. Many startup companies fail to obtain funding simply because venture capitalists do not believe they will be able to make money based on the cost of product development and dissemination. Therefore, many potentially valuable technologies that could address large patient populations may never see the light of day. This is a very significant problem that must be addressed. Overregulation, when analyzed, is extremely expensive.

‘Committeeism’

Another obstacle to innovation is likely to be familiar to all: what I call “committeeism,” or the expansion or growth of multiple committees for multiple purposes. It is rampant not only among universities but within industry as well.

There is an overabundance of committees involved in technology evaluation and acceptance at hospitals in the United States, including the institutional review board (IRB), the conflict-of-interest committee, and committees in charge of everything from ethics to contracts to adjudication. The IRB is clearly the most valuable, but it is only as effective as its members. Through the Federal Register, the federal government has outlined what the functions of IRBs should be.¹ However, I have personally polled IRB members and found that very few are aware of these Federal Register guidelines for IRBs. As a result, individual IRBs come up with their own concepts for what they are supposed to do, and often they do not correlate with the Federal Register’s concepts, which obviously creates problems.

Of course, committees are necessary to some extent and they can bring value. In my experience, however, committees usually consist of a group of the unwilling picked from the unfit to do the unnecessary. Too often we come out of committee meetings with little more than the date and time of the next committee meeting—or perhaps with a newly created subcommittee, whose members are typically culled from those absent from the committee meeting. If we honestly reflect on the effectiveness of most committees, we will usually conclude that it is fairly marginal.

From the standpoint of the inventor or innovator, committees and consensus can constitute a significant deterrent. Invention is not done by committee. Patients are not treated by committee. Many committee members have never been involved in patient care, yet physicians are encumbered by committees and a point is often reached where the patient is not being served in the best way. Of course, oversight is needed, and we still need some committees, but the overall number and value of committees needs to be reevaluated throughout the health care system. My experience suggests that fewer committees and smaller committees would serve us all better.

Confict of interest

Conflict of interest represents yet another challenge to innovation. The dictionary definition of conflict of interest is “to be at odds.” My practical definition is that it involves trying to serve more than one master.

Who has got conflict of interest? We all do. If you do not have conflict of interest, you are not doing very much. Should we get rid of our conflicts? We cannot—it is impossible to get rid of conflict of interest if you are going to be a productive human being.

Conflict of interest exists in practice. When a surgeon operates on a patient, is he or she doing it to benefit the patient or to make money? The honest answer is that it is probably for both reasons.

Likewise, conflict exists when physicians are involved in research, either basic or clinical. Why do we do research, and why do universities encourage it? In the case of basic research, is it done for discovery, or to pay for direct and indirect overhead? The reality is that it is done for both reasons. Similarly, clinical research is conducted for many reasons. One is to benefit patients. Another is to gain notoriety as someone who has benefited patients through innovation. A third reason is financial. In most cases, clinical research is probably done for all three reasons, and the particular emphasis will differ according to the individual.

The concept of making money while benefiting patients is egregious to many academic medical centers today. But the reality is that if you develop useful technology, you will make money. That is just the American way. Should medical innovators start out with the motivation of making money? No, although some do. However, if their innovation provides a real service to humanity, there is nothing wrong with that approach, although financial rewards should come only as a byproduct of benefiting patients.

Institutional conflicts are present as well. Historically, institutions have had significant conflicts of interest, but only recently have these conflicts been scrutinized. Advertising of services is an example of an institutional conflict, with the goal being to attract patients to increase revenue. Whether or not this is bad depends on whether there is an overriding benefit to patients in the big picture, as well as on how the advertising is done.

Finally, there are personal conflicts as well. How much time do you spend at the institution? How much time do you spend seeing a patient? Doing clinical research? Spending time with your family? All of these things are technically in conflict with one another, and occasionally they can represent serious conflicts. Conflicts are inescapable, so to say that you do not have any is simply not consistent with reality.

Academia

The way that some major academic centers have responded to concerns about conflicts of interest has actually turned some of these academic centers— which are supposed to promote exploration and innovation—into deterrents to innovation. To innovate at these institutions has become extremely cumbersome, costly, and inefficient. I do not believe that these institutions—which include prestigious teaching centers such as my institution, Stanford University, and Harvard Medical School—really understand the effects that some of their policies are having. Nevertheless, these policies are taking a toll as these institutions do less and less in the way of medical innovation. In the process, the institutions are failing to fully serve their missions. An example of the mentality behind such policies is laid out in the following section.

AAMC’s ‘rebuttable presumption’ policy does not serve patients

The Association of American Medical Colleges (AAMC) is a group of academic institutions that helps to define policy for the conduct of research in academic medicine. A few years ago an AAMC task force came out with a policy for the oversight of financial interests in clinical research, which states the following: “Institutional policies should establish the rebuttable presumption that an individual who holds a significant financial interest in research involving human subjects may not conduct such research.”²

This “rebuttable presumption” policy, which establishes the premise of guilt until innocence can be proven, is decidedly un-American. Although patient harm or other abuses can occur when a physician performs clinical research using devices, procedures, or drugs in which he has a financial stake, such abuses are quite rare in my experience. This AAMC policy is not in the best interest of patients because it insists that innovators recuse themselves from research that involves the very technology in which they are the ones who are most expert and knowledgeable. As a result, patients who are candidates for a new procedure or a procedure that uses a new device will not be able to undergo the operation at the hands of the most capable person but must be sent to another surgeon. This is the case even if the patients are referred to the innovator by their own personal physician and even if another independent surgeon agrees that the proposed procedure makes sense.

The only party whose interest is served by this ridiculous policy is the institution, as the goal is to prevent potential adverse publicity. In this, too, the policy is misguided, since bad publicity for an institution can come from cases involving new procedures and old procedures alike.

Conflicts must be accepted and managed

The AAMC has come out with a related policy maintaining that conflicts of interest among researchers are to be avoided at all costs. I take that to mean that researchers are supposed to just die, since conflicts of interest are inherent in our existence and represent a critical element in all relationships. It is true that most routine daily conflicts are not serious, but to deny conflicts when they exist serves no useful purpose. We have conflicts and we have to learn how to manage them, consistent with protecting the interests of individuals. In the case of physicians, these individuals are our patients.

THE NECESSARY WORK OF DEFYING CONSENSUS

Much of what is done in health care—developing rules and regulations; issuing recommendations, standards, and guidelines; working to increase compliance—is aimed at creating order and consensus. While a certain degree of order and consensus is necessary, of course, these are not the factors needed to spur improvements and advances. Improvement requires people who are willing to challenge, who will defy consensus and tell us what we are doing that is not so good.

This is the natural tendency of the inventor and the innovator—to go against the grain, to go outside the standard of care and do something that is new, that is not in compliance, and that may or may not be accepted. This is why, in my view, it takes more courage than brains to be an innovator. No one likes to be ridiculed or to be told that they are not in compliance and are perhaps endangering patients’ lives. Of course, inventors and innovators often do not help themselves in this regard, as they tend to be odd ducks by nature and do not always express themselves well. Still, their function of defying consensus is necessary to virtually all medical progress.

A WAKE-UP CALL FOR INNOVATION IN AMERICA

I will conclude by returning to my broad topic of whether the United States will maintain its preeminence in medical technology. As I said at the outset, I cannot answer that question in the affirmative, largely because of the breakdown in cooperation and collaboration among practitioners, academia, and industry for the reasons I have outlined above.

The signs of our waning preeminence cannot be missed. The manufacturing of medical technologies is going offshore, with significant economic implications. More importantly, clinical studies are now increasingly moving offshore. I was recently involved in 9 months of offshore clinical studies to collect the necessary data to submit a device for US approval, because the studies were prohibited from being performed in the United States. Despite this prohibition, it is these offshore studies that reveal any deficiencies in the technologies being assessed and that allow those deficiencies to be corrected for the benefit of US patients. And US patients themselves are increasingly going offshore for medical care—either to obtain medications or to undergo procedures that involve a device that cannot be used in the United States.

As a result of the above developments, significant investment is going offshore, taking with it a great deal of interest in innovation. Meanwhile, that interest in innovation is decreasing in the United States because it is being deterred, delayed, and encumbered by overregulation. This practice is not in the best interest of our economy and certainly not in the best interest of patients in this country, and not enough people are aware of this considerable problem.

I will be happy to take questions from the audience.

Question from audience: Is it possible that changing some laws could allow us to increase innovation and enable more clinical research?

Dr. Fogarty: I think it is possible, but laws cannot be changed unless people become aware of the issues. I want to spend the rest of my life making people aware of issues that deter innovation. That is the reason I started the Institute for Innovation: to create an environment in which innovation can take place efficiently, honestly, effectively, and with proper oversight to ensure consistency with the relevant rules and regulations. Many of the rules and regulations are self-imposed. Most of them are misunderstood by the people to whom they apply.

The rapidity of technologic change clearly outpaces the ability of the Food and Drug Administration (FDA) to keep up. The FDA has a difficult time attracting people who have the background and experience to assess the value of clinical investigation. My approach to the FDA is to be as collaborative as possible. I will approach the FDA and simply ask what they want me to do to support a submission for product approval and then assure them that I will do it if it is possible. That is a good way to make clear that your intent is to be collaborative for the benefit of the patient.

Another problem is that regulatory and reimbursement approvals should be simultaneous and take parallel paths, but that is not the case. While the FDA covers the regulatory piece, the Centers for Medicare and Medicaid Services (CMS) covers the reimbursement piece, and it has a different charter and operates on a separate timetable. What happens is that old technologies are being rewarded by being reimbursed but new technologies are not being rewarded because they are not being cleared for reimbursement quickly enough. Ultimately CMS will pay for these new technologies, but if a product is a 510(k) submission (a premarket submission to the FDA to demonstrate that a new device is at least as safe and effective as an existing device),³ the interval from the time of concept to implementation is usually 7 years. This delay cannot be tolerated, since it means that many patients are being deprived of the potential of effective technology as a result of regulation.

Question from audience: I agree with many of your criticisms and your concern about bureaucracy getting in the way of innovation. However, I really object to your use of the term “the American way,” which implies that there is an “un-American way,” which I guess is the way that is different from your way. Also, you seem to imply that the medical-industrial complex has as its primary purpose good patient care. But this complex does not have any fiduciary responsibility to patients, so what do you base your implication on?

Dr. Fogarty: Industry does not want a bad outcome, just as a physician does not want a bad outcome. If you have related to industry throughout your career, you will come to see that this is absolutely the case. Now, are there bad occurrences within the framework of industry? You bet there are, but they are not common and they are not intended.

Question from audience: Let me reframe the previous questioner’s question. Companies have a fiduciary duty to stockholders to make a profit. The best way to do that is to develop good products that benefit patients. But when you have a product that is just as good as someone else’s but you can find a way to sell more of it, you have a fiduciary duty to do that as well. Your duty is to make money, and if there are times when your product does not really benefit patients or is to the detriment of patients, your duty is still to make money. So to say, by definition, that all that people care about is maximizing patient care just doesn’t make sense.

Dr. Fogarty: Let me ask you: how often have you related to and worked with industry?

Questioner: I don’t think that is relevant.

Dr. Fogarty: It is very relevant. You have to know how other parties think and why they think that way. When responsible people in industry can identify a consistent occurrence of adverse events related to their technology, they do something about it. Now, some don’t, and may hide it…

Questioner: And there have been multiple cases of that.

Dr. Fogarty: I am not denying that, because it is certainly true, and they have done so for bad reasons. But that does not mean all of industry functions that way, because it doesn’t. It is the frequency that you have to look at. I would suggest that it is relatively infrequent, although sometimes it is very egregious. It is the same way with physicians.

Question from audience: Perhaps regulation is actually beneficial to industry, in that it creates a barrier  to entry. For example, when Johnson & Johnson has to spend a billion dollars to develop a drug-eluting stent, it can be highly confident that there are very few other entities capable of reproducing that feat. As a result, it will have a lot of market presence for many years to allow it to recoup its investment. How would you respond to that?

Dr. Fogarty: You are right—I have seen companies take products that obviously warrant a 510(k) submission and try to submit them as PMA (premarket approval) candidates for precisely the reason you suggest. That type of thinking does go on, but those who really understand economics recognize that that is not a good way to go. From my perspective, competition is good, and to eliminate it by any mechanism is not good. If you are going to have competition, you want to have good competition because you can learn from it. Overregulation that creates barriers to entry is not in the interest of patient care and it encumbers competitive companies, certainly from a time standpoint.

Comment from audience: I enjoyed Dr. Fogarty’s talk, but I would like to add one comment: we should not confuse duty with ethics. One’s duty is to make money, but one’s ethics are to be honest, and we each have to decide what we are going to follow. That is true in industry, and it is true in medicine. I have worked with a lot of companies, and most of them are ethical and have the patient’s best interest at heart. I have seen companies spend millions of dollars on products that never came into clinical use because clinical trials showed them not to have value. Most companies cannot sustain that because they will disappear. The bottom line is that I have seen very high ethics within industry, as I have in medicine. The problem is that when ethics are violated, it hits the news and then unfortunately gets generalized to the entire profession or industry.

Conflict-of-interest statement
I am seriously conflicted. You may assume that
I have a financial interest and conflicts with any
emerging med-tech company you choose. In addition,
I actually take royalties when possible and encourage
innovation and entrepreneurship in others.

As an inventor, my perspective on financial relationships with medical technology companies is quite different from the one presented by Dr. Arnold Relman in his earlier keynote address. Although I agree with him that the state of medicine is indeed a mess, the mechanism by which that mess can be cleaned up is debatable. I believe strongly that the mechanism advocated by Dr. Relman— prohibiting financial rewards (outside of salaries) to physicians involved in innovation—will do nothing to benefit patients.

My assessment of the topic I am charged with addressing—will the United States maintain its preeminence in medical technology?—is that it will not. I will use this talk to present the reasons for that assessment in the hope that you will understand that we are going the wrong way in American medicine today.

THE NATURE OF INNOVATION

True innovation requires broad acceptance

Innovation, invention, and technology development are not simple or single occurrences. They represent an iterative process requiring reduction to practice and, most important, acceptability by others. An inventor does not determine the worth of his invention; his peers do. Self-proclaimed inventors are numerous and multiple, and the technologies that they put forward rarely receive broad acceptance. Everybody wants to be an inventor, recognizing that it brings attention and reward, but it also brings a lot of baggage, which I will discuss shortly.

What’s wrong with a medical-industrial complex?

Dr. Relman and others may object to the term “medical-industrial complex,” but to do so is to deny reality, because health care in the United States simply is a medical-industrial complex, but one devoted to optimal patient care.

The process by which optimal patient care is delivered involves relationships among a whole host of people. In my view, the key players are the engineers and physicians coming together to develop a technology intended to benefit patients—this relationship is a critical element of invention and innovation. At the same time, patients are the most important individuals involved in any process of innovation. Without patients, we simply could not innovate. Of course, other players have roles as well: institutions, the government, industry, entrepreneurs, lawyers, payors, investors. And in the middle of this mix we have chief executive officers of industry, whose job is to make sure all these players are talking to one another and collaborating for the benefit of patients.

CHALLENGES TO INNOVATION

Challenges to innovation are abundant, and some of them have been with us for decades. I have outlined some major challenges below.

Technology evaluation

There are many ways that technology can be evaluated. We hear a lot about evidence-based medicine, which is ideal if used appropriately, yet too many people demand it in a knee-jerk way. In the field of surgery, level I evidence is often impractical, extremely costly, and sometimes not even possible, and attempts to use it may lead to inaccurate conclusions. If applied too broadly, the demand for level I evidence can impede innovation, so it is important to recognize that evidence-based medicine is only one way to get answers about a technology, especially in the surgical specialties.

Teaching and training

Teaching and training of new technologies is another challenge. The shelf life of a new surgical technology is approximately 5 years. Failure to recognize a new technology can lead to a loss of business, as in the case of cardiac surgeons who initially ignored catheter-mediated therapy. Other specialties are rarely willing to help surgeons adapt to new technology, for fear of losing business. So the issues at play can be pretty complex.

Who is to do the training? Because academic medical centers cannot afford to teach new technology, industry must take on this role. We need to recognize that industry offers a very valuable service in the process of teaching and training. As for potential downsides, surgeons should be smart and savvy enough to be able to evaluate whether a sales representative’s presentation is solid or nothing more than marketing. If we cannot do that, our medical schools have egregiously failed in their mission.

Cost is one of the most significant deterrents to innovation. The accelerating cost of innovation is difficult to imagine. For example, the first embolectomy catheter cost about $3,000 to develop back in the early 1960s. As its developer, I can tell you that it cost so little because I stole or borrowed—on a permanent basis—most of the equipment needed to make the catheter systems, which I sterilized in a preparation of glutaraldehyde (Cidex) and reused. Compare that cost to the cost of developing the drug-coated stent. If the costs of the drug, the device, and the clinical trials are all included, Johnson & Johnson’s total cost of developing its drug-coated stent was more than $1 billion.

What is often not acknowledged, however, is that technology may be a solution to accelerating costs. Many startup companies fail to obtain funding simply because venture capitalists do not believe they will be able to make money based on the cost of product development and dissemination. Therefore, many potentially valuable technologies that could address large patient populations may never see the light of day. This is a very significant problem that must be addressed. Overregulation, when analyzed, is extremely expensive.

‘Committeeism’

Another obstacle to innovation is likely to be familiar to all: what I call “committeeism,” or the expansion or growth of multiple committees for multiple purposes. It is rampant not only among universities but within industry as well.

There is an overabundance of committees involved in technology evaluation and acceptance at hospitals in the United States, including the institutional review board (IRB), the conflict-of-interest committee, and committees in charge of everything from ethics to contracts to adjudication. The IRB is clearly the most valuable, but it is only as effective as its members. Through the Federal Register, the federal government has outlined what the functions of IRBs should be.¹ However, I have personally polled IRB members and found that very few are aware of these Federal Register guidelines for IRBs. As a result, individual IRBs come up with their own concepts for what they are supposed to do, and often they do not correlate with the Federal Register’s concepts, which obviously creates problems.

Of course, committees are necessary to some extent and they can bring value. In my experience, however, committees usually consist of a group of the unwilling picked from the unfit to do the unnecessary. Too often we come out of committee meetings with little more than the date and time of the next committee meeting—or perhaps with a newly created subcommittee, whose members are typically culled from those absent from the committee meeting. If we honestly reflect on the effectiveness of most committees, we will usually conclude that it is fairly marginal.

From the standpoint of the inventor or innovator, committees and consensus can constitute a significant deterrent. Invention is not done by committee. Patients are not treated by committee. Many committee members have never been involved in patient care, yet physicians are encumbered by committees and a point is often reached where the patient is not being served in the best way. Of course, oversight is needed, and we still need some committees, but the overall number and value of committees needs to be reevaluated throughout the health care system. My experience suggests that fewer committees and smaller committees would serve us all better.

Confict of interest

Conflict of interest represents yet another challenge to innovation. The dictionary definition of conflict of interest is “to be at odds.” My practical definition is that it involves trying to serve more than one master.

Who has got conflict of interest? We all do. If you do not have conflict of interest, you are not doing very much. Should we get rid of our conflicts? We cannot—it is impossible to get rid of conflict of interest if you are going to be a productive human being.

Conflict of interest exists in practice. When a surgeon operates on a patient, is he or she doing it to benefit the patient or to make money? The honest answer is that it is probably for both reasons.

Likewise, conflict exists when physicians are involved in research, either basic or clinical. Why do we do research, and why do universities encourage it? In the case of basic research, is it done for discovery, or to pay for direct and indirect overhead? The reality is that it is done for both reasons. Similarly, clinical research is conducted for many reasons. One is to benefit patients. Another is to gain notoriety as someone who has benefited patients through innovation. A third reason is financial. In most cases, clinical research is probably done for all three reasons, and the particular emphasis will differ according to the individual.

The concept of making money while benefiting patients is egregious to many academic medical centers today. But the reality is that if you develop useful technology, you will make money. That is just the American way. Should medical innovators start out with the motivation of making money? No, although some do. However, if their innovation provides a real service to humanity, there is nothing wrong with that approach, although financial rewards should come only as a byproduct of benefiting patients.

Institutional conflicts are present as well. Historically, institutions have had significant conflicts of interest, but only recently have these conflicts been scrutinized. Advertising of services is an example of an institutional conflict, with the goal being to attract patients to increase revenue. Whether or not this is bad depends on whether there is an overriding benefit to patients in the big picture, as well as on how the advertising is done.

Finally, there are personal conflicts as well. How much time do you spend at the institution? How much time do you spend seeing a patient? Doing clinical research? Spending time with your family? All of these things are technically in conflict with one another, and occasionally they can represent serious conflicts. Conflicts are inescapable, so to say that you do not have any is simply not consistent with reality.

Academia

The way that some major academic centers have responded to concerns about conflicts of interest has actually turned some of these academic centers— which are supposed to promote exploration and innovation—into deterrents to innovation. To innovate at these institutions has become extremely cumbersome, costly, and inefficient. I do not believe that these institutions—which include prestigious teaching centers such as my institution, Stanford University, and Harvard Medical School—really understand the effects that some of their policies are having. Nevertheless, these policies are taking a toll as these institutions do less and less in the way of medical innovation. In the process, the institutions are failing to fully serve their missions. An example of the mentality behind such policies is laid out in the following section.

AAMC’s ‘rebuttable presumption’ policy does not serve patients

The Association of American Medical Colleges (AAMC) is a group of academic institutions that helps to define policy for the conduct of research in academic medicine. A few years ago an AAMC task force came out with a policy for the oversight of financial interests in clinical research, which states the following: “Institutional policies should establish the rebuttable presumption that an individual who holds a significant financial interest in research involving human subjects may not conduct such research.”²

This “rebuttable presumption” policy, which establishes the premise of guilt until innocence can be proven, is decidedly un-American. Although patient harm or other abuses can occur when a physician performs clinical research using devices, procedures, or drugs in which he has a financial stake, such abuses are quite rare in my experience. This AAMC policy is not in the best interest of patients because it insists that innovators recuse themselves from research that involves the very technology in which they are the ones who are most expert and knowledgeable. As a result, patients who are candidates for a new procedure or a procedure that uses a new device will not be able to undergo the operation at the hands of the most capable person but must be sent to another surgeon. This is the case even if the patients are referred to the innovator by their own personal physician and even if another independent surgeon agrees that the proposed procedure makes sense.

The only party whose interest is served by this ridiculous policy is the institution, as the goal is to prevent potential adverse publicity. In this, too, the policy is misguided, since bad publicity for an institution can come from cases involving new procedures and old procedures alike.

Conflicts must be accepted and managed

The AAMC has come out with a related policy maintaining that conflicts of interest among researchers are to be avoided at all costs. I take that to mean that researchers are supposed to just die, since conflicts of interest are inherent in our existence and represent a critical element in all relationships. It is true that most routine daily conflicts are not serious, but to deny conflicts when they exist serves no useful purpose. We have conflicts and we have to learn how to manage them, consistent with protecting the interests of individuals. In the case of physicians, these individuals are our patients.

THE NECESSARY WORK OF DEFYING CONSENSUS

Much of what is done in health care—developing rules and regulations; issuing recommendations, standards, and guidelines; working to increase compliance—is aimed at creating order and consensus. While a certain degree of order and consensus is necessary, of course, these are not the factors needed to spur improvements and advances. Improvement requires people who are willing to challenge, who will defy consensus and tell us what we are doing that is not so good.

This is the natural tendency of the inventor and the innovator—to go against the grain, to go outside the standard of care and do something that is new, that is not in compliance, and that may or may not be accepted. This is why, in my view, it takes more courage than brains to be an innovator. No one likes to be ridiculed or to be told that they are not in compliance and are perhaps endangering patients’ lives. Of course, inventors and innovators often do not help themselves in this regard, as they tend to be odd ducks by nature and do not always express themselves well. Still, their function of defying consensus is necessary to virtually all medical progress.

A WAKE-UP CALL FOR INNOVATION IN AMERICA

I will conclude by returning to my broad topic of whether the United States will maintain its preeminence in medical technology. As I said at the outset, I cannot answer that question in the affirmative, largely because of the breakdown in cooperation and collaboration among practitioners, academia, and industry for the reasons I have outlined above.

The signs of our waning preeminence cannot be missed. The manufacturing of medical technologies is going offshore, with significant economic implications. More importantly, clinical studies are now increasingly moving offshore. I was recently involved in 9 months of offshore clinical studies to collect the necessary data to submit a device for US approval, because the studies were prohibited from being performed in the United States. Despite this prohibition, it is these offshore studies that reveal any deficiencies in the technologies being assessed and that allow those deficiencies to be corrected for the benefit of US patients. And US patients themselves are increasingly going offshore for medical care—either to obtain medications or to undergo procedures that involve a device that cannot be used in the United States.

As a result of the above developments, significant investment is going offshore, taking with it a great deal of interest in innovation. Meanwhile, that interest in innovation is decreasing in the United States because it is being deterred, delayed, and encumbered by overregulation. This practice is not in the best interest of our economy and certainly not in the best interest of patients in this country, and not enough people are aware of this considerable problem.

I will be happy to take questions from the audience.

Question from audience: Is it possible that changing some laws could allow us to increase innovation and enable more clinical research?

Dr. Fogarty: I think it is possible, but laws cannot be changed unless people become aware of the issues. I want to spend the rest of my life making people aware of issues that deter innovation. That is the reason I started the Institute for Innovation: to create an environment in which innovation can take place efficiently, honestly, effectively, and with proper oversight to ensure consistency with the relevant rules and regulations. Many of the rules and regulations are self-imposed. Most of them are misunderstood by the people to whom they apply.

The rapidity of technologic change clearly outpaces the ability of the Food and Drug Administration (FDA) to keep up. The FDA has a difficult time attracting people who have the background and experience to assess the value of clinical investigation. My approach to the FDA is to be as collaborative as possible. I will approach the FDA and simply ask what they want me to do to support a submission for product approval and then assure them that I will do it if it is possible. That is a good way to make clear that your intent is to be collaborative for the benefit of the patient.

Another problem is that regulatory and reimbursement approvals should be simultaneous and take parallel paths, but that is not the case. While the FDA covers the regulatory piece, the Centers for Medicare and Medicaid Services (CMS) covers the reimbursement piece, and it has a different charter and operates on a separate timetable. What happens is that old technologies are being rewarded by being reimbursed but new technologies are not being rewarded because they are not being cleared for reimbursement quickly enough. Ultimately CMS will pay for these new technologies, but if a product is a 510(k) submission (a premarket submission to the FDA to demonstrate that a new device is at least as safe and effective as an existing device),³ the interval from the time of concept to implementation is usually 7 years. This delay cannot be tolerated, since it means that many patients are being deprived of the potential of effective technology as a result of regulation.

Question from audience: I agree with many of your criticisms and your concern about bureaucracy getting in the way of innovation. However, I really object to your use of the term “the American way,” which implies that there is an “un-American way,” which I guess is the way that is different from your way. Also, you seem to imply that the medical-industrial complex has as its primary purpose good patient care. But this complex does not have any fiduciary responsibility to patients, so what do you base your implication on?

Dr. Fogarty: Industry does not want a bad outcome, just as a physician does not want a bad outcome. If you have related to industry throughout your career, you will come to see that this is absolutely the case. Now, are there bad occurrences within the framework of industry? You bet there are, but they are not common and they are not intended.

Question from audience: Let me reframe the previous questioner’s question. Companies have a fiduciary duty to stockholders to make a profit. The best way to do that is to develop good products that benefit patients. But when you have a product that is just as good as someone else’s but you can find a way to sell more of it, you have a fiduciary duty to do that as well. Your duty is to make money, and if there are times when your product does not really benefit patients or is to the detriment of patients, your duty is still to make money. So to say, by definition, that all that people care about is maximizing patient care just doesn’t make sense.

Dr. Fogarty: Let me ask you: how often have you related to and worked with industry?

Questioner: I don’t think that is relevant.

Dr. Fogarty: It is very relevant. You have to know how other parties think and why they think that way. When responsible people in industry can identify a consistent occurrence of adverse events related to their technology, they do something about it. Now, some don’t, and may hide it…

Questioner: And there have been multiple cases of that.

Dr. Fogarty: I am not denying that, because it is certainly true, and they have done so for bad reasons. But that does not mean all of industry functions that way, because it doesn’t. It is the frequency that you have to look at. I would suggest that it is relatively infrequent, although sometimes it is very egregious. It is the same way with physicians.

Question from audience: Perhaps regulation is actually beneficial to industry, in that it creates a barrier  to entry. For example, when Johnson & Johnson has to spend a billion dollars to develop a drug-eluting stent, it can be highly confident that there are very few other entities capable of reproducing that feat. As a result, it will have a lot of market presence for many years to allow it to recoup its investment. How would you respond to that?

Dr. Fogarty: You are right—I have seen companies take products that obviously warrant a 510(k) submission and try to submit them as PMA (premarket approval) candidates for precisely the reason you suggest. That type of thinking does go on, but those who really understand economics recognize that that is not a good way to go. From my perspective, competition is good, and to eliminate it by any mechanism is not good. If you are going to have competition, you want to have good competition because you can learn from it. Overregulation that creates barriers to entry is not in the interest of patient care and it encumbers competitive companies, certainly from a time standpoint.

Comment from audience: I enjoyed Dr. Fogarty’s talk, but I would like to add one comment: we should not confuse duty with ethics. One’s duty is to make money, but one’s ethics are to be honest, and we each have to decide what we are going to follow. That is true in industry, and it is true in medicine. I have worked with a lot of companies, and most of them are ethical and have the patient’s best interest at heart. I have seen companies spend millions of dollars on products that never came into clinical use because clinical trials showed them not to have value. Most companies cannot sustain that because they will disappear. The bottom line is that I have seen very high ethics within industry, as I have in medicine. The problem is that when ethics are violated, it hits the news and then unfortunately gets generalized to the entire profession or industry.

Conflict-of-interest statement
I am seriously conflicted. You may assume that
I have a financial interest and conflicts with any
emerging med-tech company you choose. In addition,
I actually take royalties when possible and encourage
innovation and entrepreneurship in others.

As an inventor, my perspective on financial relationships with medical technology companies is quite different from the one presented by Dr. Arnold Relman in his earlier keynote address. Although I agree with him that the state of medicine is indeed a mess, the mechanism by which that mess can be cleaned up is debatable. I believe strongly that the mechanism advocated by Dr. Relman— prohibiting financial rewards (outside of salaries) to physicians involved in innovation—will do nothing to benefit patients.

My assessment of the topic I am charged with addressing—will the United States maintain its preeminence in medical technology?—is that it will not. I will use this talk to present the reasons for that assessment in the hope that you will understand that we are going the wrong way in American medicine today.

THE NATURE OF INNOVATION

True innovation requires broad acceptance

Innovation, invention, and technology development are not simple or single occurrences. They represent an iterative process requiring reduction to practice and, most important, acceptability by others. An inventor does not determine the worth of his invention; his peers do. Self-proclaimed inventors are numerous and multiple, and the technologies that they put forward rarely receive broad acceptance. Everybody wants to be an inventor, recognizing that it brings attention and reward, but it also brings a lot of baggage, which I will discuss shortly.

What’s wrong with a medical-industrial complex?

Dr. Relman and others may object to the term “medical-industrial complex,” but to do so is to deny reality, because health care in the United States simply is a medical-industrial complex, but one devoted to optimal patient care.

The process by which optimal patient care is delivered involves relationships among a whole host of people. In my view, the key players are the engineers and physicians coming together to develop a technology intended to benefit patients—this relationship is a critical element of invention and innovation. At the same time, patients are the most important individuals involved in any process of innovation. Without patients, we simply could not innovate. Of course, other players have roles as well: institutions, the government, industry, entrepreneurs, lawyers, payors, investors. And in the middle of this mix we have chief executive officers of industry, whose job is to make sure all these players are talking to one another and collaborating for the benefit of patients.

CHALLENGES TO INNOVATION

Challenges to innovation are abundant, and some of them have been with us for decades. I have outlined some major challenges below.

Technology evaluation

There are many ways that technology can be evaluated. We hear a lot about evidence-based medicine, which is ideal if used appropriately, yet too many people demand it in a knee-jerk way. In the field of surgery, level I evidence is often impractical, extremely costly, and sometimes not even possible, and attempts to use it may lead to inaccurate conclusions. If applied too broadly, the demand for level I evidence can impede innovation, so it is important to recognize that evidence-based medicine is only one way to get answers about a technology, especially in the surgical specialties.

Teaching and training

Teaching and training of new technologies is another challenge. The shelf life of a new surgical technology is approximately 5 years. Failure to recognize a new technology can lead to a loss of business, as in the case of cardiac surgeons who initially ignored catheter-mediated therapy. Other specialties are rarely willing to help surgeons adapt to new technology, for fear of losing business. So the issues at play can be pretty complex.

Who is to do the training? Because academic medical centers cannot afford to teach new technology, industry must take on this role. We need to recognize that industry offers a very valuable service in the process of teaching and training. As for potential downsides, surgeons should be smart and savvy enough to be able to evaluate whether a sales representative’s presentation is solid or nothing more than marketing. If we cannot do that, our medical schools have egregiously failed in their mission.

Cost is one of the most significant deterrents to innovation. The accelerating cost of innovation is difficult to imagine. For example, the first embolectomy catheter cost about $3,000 to develop back in the early 1960s. As its developer, I can tell you that it cost so little because I stole or borrowed—on a permanent basis—most of the equipment needed to make the catheter systems, which I sterilized in a preparation of glutaraldehyde (Cidex) and reused. Compare that cost to the cost of developing the drug-coated stent. If the costs of the drug, the device, and the clinical trials are all included, Johnson & Johnson’s total cost of developing its drug-coated stent was more than $1 billion.

What is often not acknowledged, however, is that technology may be a solution to accelerating costs. Many startup companies fail to obtain funding simply because venture capitalists do not believe they will be able to make money based on the cost of product development and dissemination. Therefore, many potentially valuable technologies that could address large patient populations may never see the light of day. This is a very significant problem that must be addressed. Overregulation, when analyzed, is extremely expensive.

‘Committeeism’

Another obstacle to innovation is likely to be familiar to all: what I call “committeeism,” or the expansion or growth of multiple committees for multiple purposes. It is rampant not only among universities but within industry as well.

There is an overabundance of committees involved in technology evaluation and acceptance at hospitals in the United States, including the institutional review board (IRB), the conflict-of-interest committee, and committees in charge of everything from ethics to contracts to adjudication. The IRB is clearly the most valuable, but it is only as effective as its members. Through the Federal Register, the federal government has outlined what the functions of IRBs should be.¹ However, I have personally polled IRB members and found that very few are aware of these Federal Register guidelines for IRBs. As a result, individual IRBs come up with their own concepts for what they are supposed to do, and often they do not correlate with the Federal Register’s concepts, which obviously creates problems.

Of course, committees are necessary to some extent and they can bring value. In my experience, however, committees usually consist of a group of the unwilling picked from the unfit to do the unnecessary. Too often we come out of committee meetings with little more than the date and time of the next committee meeting—or perhaps with a newly created subcommittee, whose members are typically culled from those absent from the committee meeting. If we honestly reflect on the effectiveness of most committees, we will usually conclude that it is fairly marginal.

From the standpoint of the inventor or innovator, committees and consensus can constitute a significant deterrent. Invention is not done by committee. Patients are not treated by committee. Many committee members have never been involved in patient care, yet physicians are encumbered by committees and a point is often reached where the patient is not being served in the best way. Of course, oversight is needed, and we still need some committees, but the overall number and value of committees needs to be reevaluated throughout the health care system. My experience suggests that fewer committees and smaller committees would serve us all better.

Confict of interest

Conflict of interest represents yet another challenge to innovation. The dictionary definition of conflict of interest is “to be at odds.” My practical definition is that it involves trying to serve more than one master.

Who has got conflict of interest? We all do. If you do not have conflict of interest, you are not doing very much. Should we get rid of our conflicts? We cannot—it is impossible to get rid of conflict of interest if you are going to be a productive human being.

Conflict of interest exists in practice. When a surgeon operates on a patient, is he or she doing it to benefit the patient or to make money? The honest answer is that it is probably for both reasons.

Likewise, conflict exists when physicians are involved in research, either basic or clinical. Why do we do research, and why do universities encourage it? In the case of basic research, is it done for discovery, or to pay for direct and indirect overhead? The reality is that it is done for both reasons. Similarly, clinical research is conducted for many reasons. One is to benefit patients. Another is to gain notoriety as someone who has benefited patients through innovation. A third reason is financial. In most cases, clinical research is probably done for all three reasons, and the particular emphasis will differ according to the individual.

The concept of making money while benefiting patients is egregious to many academic medical centers today. But the reality is that if you develop useful technology, you will make money. That is just the American way. Should medical innovators start out with the motivation of making money? No, although some do. However, if their innovation provides a real service to humanity, there is nothing wrong with that approach, although financial rewards should come only as a byproduct of benefiting patients.

Institutional conflicts are present as well. Historically, institutions have had significant conflicts of interest, but only recently have these conflicts been scrutinized. Advertising of services is an example of an institutional conflict, with the goal being to attract patients to increase revenue. Whether or not this is bad depends on whether there is an overriding benefit to patients in the big picture, as well as on how the advertising is done.

Finally, there are personal conflicts as well. How much time do you spend at the institution? How much time do you spend seeing a patient? Doing clinical research? Spending time with your family? All of these things are technically in conflict with one another, and occasionally they can represent serious conflicts. Conflicts are inescapable, so to say that you do not have any is simply not consistent with reality.

Academia

The way that some major academic centers have responded to concerns about conflicts of interest has actually turned some of these academic centers— which are supposed to promote exploration and innovation—into deterrents to innovation. To innovate at these institutions has become extremely cumbersome, costly, and inefficient. I do not believe that these institutions—which include prestigious teaching centers such as my institution, Stanford University, and Harvard Medical School—really understand the effects that some of their policies are having. Nevertheless, these policies are taking a toll as these institutions do less and less in the way of medical innovation. In the process, the institutions are failing to fully serve their missions. An example of the mentality behind such policies is laid out in the following section.

AAMC’s ‘rebuttable presumption’ policy does not serve patients

The Association of American Medical Colleges (AAMC) is a group of academic institutions that helps to define policy for the conduct of research in academic medicine. A few years ago an AAMC task force came out with a policy for the oversight of financial interests in clinical research, which states the following: “Institutional policies should establish the rebuttable presumption that an individual who holds a significant financial interest in research involving human subjects may not conduct such research.”²

This “rebuttable presumption” policy, which establishes the premise of guilt until innocence can be proven, is decidedly un-American. Although patient harm or other abuses can occur when a physician performs clinical research using devices, procedures, or drugs in which he has a financial stake, such abuses are quite rare in my experience. This AAMC policy is not in the best interest of patients because it insists that innovators recuse themselves from research that involves the very technology in which they are the ones who are most expert and knowledgeable. As a result, patients who are candidates for a new procedure or a procedure that uses a new device will not be able to undergo the operation at the hands of the most capable person but must be sent to another surgeon. This is the case even if the patients are referred to the innovator by their own personal physician and even if another independent surgeon agrees that the proposed procedure makes sense.

The only party whose interest is served by this ridiculous policy is the institution, as the goal is to prevent potential adverse publicity. In this, too, the policy is misguided, since bad publicity for an institution can come from cases involving new procedures and old procedures alike.

Conflicts must be accepted and managed

The AAMC has come out with a related policy maintaining that conflicts of interest among researchers are to be avoided at all costs. I take that to mean that researchers are supposed to just die, since conflicts of interest are inherent in our existence and represent a critical element in all relationships. It is true that most routine daily conflicts are not serious, but to deny conflicts when they exist serves no useful purpose. We have conflicts and we have to learn how to manage them, consistent with protecting the interests of individuals. In the case of physicians, these individuals are our patients.

THE NECESSARY WORK OF DEFYING CONSENSUS

Much of what is done in health care—developing rules and regulations; issuing recommendations, standards, and guidelines; working to increase compliance—is aimed at creating order and consensus. While a certain degree of order and consensus is necessary, of course, these are not the factors needed to spur improvements and advances. Improvement requires people who are willing to challenge, who will defy consensus and tell us what we are doing that is not so good.

This is the natural tendency of the inventor and the innovator—to go against the grain, to go outside the standard of care and do something that is new, that is not in compliance, and that may or may not be accepted. This is why, in my view, it takes more courage than brains to be an innovator. No one likes to be ridiculed or to be told that they are not in compliance and are perhaps endangering patients’ lives. Of course, inventors and innovators often do not help themselves in this regard, as they tend to be odd ducks by nature and do not always express themselves well. Still, their function of defying consensus is necessary to virtually all medical progress.

A WAKE-UP CALL FOR INNOVATION IN AMERICA

I will conclude by returning to my broad topic of whether the United States will maintain its preeminence in medical technology. As I said at the outset, I cannot answer that question in the affirmative, largely because of the breakdown in cooperation and collaboration among practitioners, academia, and industry for the reasons I have outlined above.

The signs of our waning preeminence cannot be missed. The manufacturing of medical technologies is going offshore, with significant economic implications. More importantly, clinical studies are now increasingly moving offshore. I was recently involved in 9 months of offshore clinical studies to collect the necessary data to submit a device for US approval, because the studies were prohibited from being performed in the United States. Despite this prohibition, it is these offshore studies that reveal any deficiencies in the technologies being assessed and that allow those deficiencies to be corrected for the benefit of US patients. And US patients themselves are increasingly going offshore for medical care—either to obtain medications or to undergo procedures that involve a device that cannot be used in the United States.

As a result of the above developments, significant investment is going offshore, taking with it a great deal of interest in innovation. Meanwhile, that interest in innovation is decreasing in the United States because it is being deterred, delayed, and encumbered by overregulation. This practice is not in the best interest of our economy and certainly not in the best interest of patients in this country, and not enough people are aware of this considerable problem.

I will be happy to take questions from the audience.

Question from audience: Is it possible that changing some laws could allow us to increase innovation and enable more clinical research?

Dr. Fogarty: I think it is possible, but laws cannot be changed unless people become aware of the issues. I want to spend the rest of my life making people aware of issues that deter innovation. That is the reason I started the Institute for Innovation: to create an environment in which innovation can take place efficiently, honestly, effectively, and with proper oversight to ensure consistency with the relevant rules and regulations. Many of the rules and regulations are self-imposed. Most of them are misunderstood by the people to whom they apply.

The rapidity of technologic change clearly outpaces the ability of the Food and Drug Administration (FDA) to keep up. The FDA has a difficult time attracting people who have the background and experience to assess the value of clinical investigation. My approach to the FDA is to be as collaborative as possible. I will approach the FDA and simply ask what they want me to do to support a submission for product approval and then assure them that I will do it if it is possible. That is a good way to make clear that your intent is to be collaborative for the benefit of the patient.

Another problem is that regulatory and reimbursement approvals should be simultaneous and take parallel paths, but that is not the case. While the FDA covers the regulatory piece, the Centers for Medicare and Medicaid Services (CMS) covers the reimbursement piece, and it has a different charter and operates on a separate timetable. What happens is that old technologies are being rewarded by being reimbursed but new technologies are not being rewarded because they are not being cleared for reimbursement quickly enough. Ultimately CMS will pay for these new technologies, but if a product is a 510(k) submission (a premarket submission to the FDA to demonstrate that a new device is at least as safe and effective as an existing device),³ the interval from the time of concept to implementation is usually 7 years. This delay cannot be tolerated, since it means that many patients are being deprived of the potential of effective technology as a result of regulation.

Question from audience: I agree with many of your criticisms and your concern about bureaucracy getting in the way of innovation. However, I really object to your use of the term “the American way,” which implies that there is an “un-American way,” which I guess is the way that is different from your way. Also, you seem to imply that the medical-industrial complex has as its primary purpose good patient care. But this complex does not have any fiduciary responsibility to patients, so what do you base your implication on?

Dr. Fogarty: Industry does not want a bad outcome, just as a physician does not want a bad outcome. If you have related to industry throughout your career, you will come to see that this is absolutely the case. Now, are there bad occurrences within the framework of industry? You bet there are, but they are not common and they are not intended.

Question from audience: Let me reframe the previous questioner’s question. Companies have a fiduciary duty to stockholders to make a profit. The best way to do that is to develop good products that benefit patients. But when you have a product that is just as good as someone else’s but you can find a way to sell more of it, you have a fiduciary duty to do that as well. Your duty is to make money, and if there are times when your product does not really benefit patients or is to the detriment of patients, your duty is still to make money. So to say, by definition, that all that people care about is maximizing patient care just doesn’t make sense.

Dr. Fogarty: Let me ask you: how often have you related to and worked with industry?

Questioner: I don’t think that is relevant.

Dr. Fogarty: It is very relevant. You have to know how other parties think and why they think that way. When responsible people in industry can identify a consistent occurrence of adverse events related to their technology, they do something about it. Now, some don’t, and may hide it…

Questioner: And there have been multiple cases of that.

Dr. Fogarty: I am not denying that, because it is certainly true, and they have done so for bad reasons. But that does not mean all of industry functions that way, because it doesn’t. It is the frequency that you have to look at. I would suggest that it is relatively infrequent, although sometimes it is very egregious. It is the same way with physicians.

Question from audience: Perhaps regulation is actually beneficial to industry, in that it creates a barrier  to entry. For example, when Johnson & Johnson has to spend a billion dollars to develop a drug-eluting stent, it can be highly confident that there are very few other entities capable of reproducing that feat. As a result, it will have a lot of market presence for many years to allow it to recoup its investment. How would you respond to that?

Dr. Fogarty: You are right—I have seen companies take products that obviously warrant a 510(k) submission and try to submit them as PMA (premarket approval) candidates for precisely the reason you suggest. That type of thinking does go on, but those who really understand economics recognize that that is not a good way to go. From my perspective, competition is good, and to eliminate it by any mechanism is not good. If you are going to have competition, you want to have good competition because you can learn from it. Overregulation that creates barriers to entry is not in the interest of patient care and it encumbers competitive companies, certainly from a time standpoint.

Comment from audience: I enjoyed Dr. Fogarty’s talk, but I would like to add one comment: we should not confuse duty with ethics. One’s duty is to make money, but one’s ethics are to be honest, and we each have to decide what we are going to follow. That is true in industry, and it is true in medicine. I have worked with a lot of companies, and most of them are ethical and have the patient’s best interest at heart. I have seen companies spend millions of dollars on products that never came into clinical use because clinical trials showed them not to have value. Most companies cannot sustain that because they will disappear. The bottom line is that I have seen very high ethics within industry, as I have in medicine. The problem is that when ethics are violated, it hits the news and then unfortunately gets generalized to the entire profession or industry.

Preface

By Lawrence K. Altman, MD (Moderator)

Early in the history of the United States, physicians commonly discussed medical issues in newspapers and other public forums. But a remark attributed to Osler, “Never trust anything you read in a newspaper…and if you do, immediately doubt it at once,” was used by the medical profession for decades to justify avoiding public discussion of medical issues. This retreat by physicians from the public discourse was particularly harmful in that it overlapped with the period when the public began paying for most medical research via federal research funding. Recently the medical profession has again started to discuss medical matters openly with the public, but this step has been taken reluctantly, in response to public pressure.

This resurgence in physicians’ engagement with the public has come not a moment too soon, as factors and players outside the operating room—economic forces, regulators, legislators, lawyers, and others—today may have as much influence on what goes on in US operating rooms as do the surgeons, nurses, and technicians who work there. Our panel will address some of these influences on surgical innovation from outside the operating room, touching on historical and current examples of attempts to regulate innovation as well as the points of view of device companies, investors, lawyers, government, and health economists.

By Michael A. Mussallem

I am honored to be here to represent industry. Although medical technology companies compete fiercely with one another in the marketplace, we also have a broad common interest: we want to develop innovations to help patients.

DEVICE AND DRUG DEVELOPMENT DIFFER

Discussing ethical challenges involving industry is easier in the context of pharmaceutical development, for a number of reasons. The pharmaceutical industry is so large that it tends to dominate the discussion. But medical devices, which are primarily what is involved when we speak of surgical innovation, differ from pharmaceuticals in key ways.

The physician-company relationship is central

First, medical devices are not used directly by patients but are tools for physicians, which makes the relationship between industry and physicians more closely intertwined when devices are involved.

An iterative process by nature

Second, it takes years of development and enormous sums of money before a drug is finally approved. The final product then has a market life of 10 or 20 years. In contrast, device development is an inherently iterative process. After Thomas Edison developed the light bulb, attempts to improve the product were immediate and constant: “Can the light be made softer? The bulb smaller? Can it be turned off?” The same type of continuous improvement process happens with medical devices, which typically are refined every 12 to 18 months. Occasional breakthroughs occur and open up a whole new way of thinking, but far more often device innovation is about incremental modifications and improvements.

SUCCESS BREEDS CONFLICTS…AND REGULATION

The development of medical devices is an American success story; we tend to be better at it than any other country. Our system works well and rewards risks and innovation. When technology is racing forward to address an unmet patient need, a tremendous amount of value is created in the form of patients living longer and healthier lives. People pay for that value, which can create substantial payoffs for successful innovators and companies. I believe that six of the companies in the Fortune 500 are medical device companies, and the medical device industry has a $450 billion market capitalization in total.

The medical device business is like an ecosystem with many interacting components. Someone with a bright idea puts a physician and an engineer together, starts a company, attracts some capital, and develops a product. Because they need startup money for production, they might offer physicians a share of the company and some stock options, and immediately an opportunity for conflict of interest arises.

As a result of these many interacting components and the conflicts they can create, medical device companies today are highly regulated by a long list of entities, including the Securities and Exchange Commission, the Food and Drug Administration (FDA), the Department of Justice, the Internal Revenue Service, the Environmental Protection Agency, the New York and NASDAQ stock exchanges, the Office of the Inspector General, and the Foreign Practices Act. This degree of regulation makes every part of the medical device development process more time-consuming and expensive.

LONG-TERM SUCCESS REQUIRES THAT COMPANIES SERVE PATIENTS

The motivation of medical technology companies is often called into question. Medical device companies are certainly motivated to make money, and they certainly have obligations to shareholders. But for a company to be successful for many years, it cannot be single-minded about the constituencies that it serves. Great medical device companies have employees who want to work for them, physicians who want to buy products from them, communities that welcome them, and shareholders who want to own their stock, but the primary goal is always to serve patients: if that is done really well over the long term, the company can count on those other success factors being present. To have a sustainable competitive advantage, one must think beyond the next quarter and run a highly respectable business on an ongoing basis.

It is true that there are outlier medical device companies who do not always operate with full integrity, as there are in any industry. The challenge, both for the medical technology industry and for the broader health care community, is to raise the standards and encourage everyone to operate at a highly ethical level. I refuse to believe that doing so requires pulling apart companies, engineers, scientists, and physicians. Instead, we need to find ways for these various players to engage together.

A good start may be the revised Physician Payments Sunshine Act, proposed by US Senator Charles Grassley. This legislation, which is supported by the Advanced Medical Technology Association (AdvaMed), would establish a national registry of payments made to physicians by medical device, medical supply, and pharmaceutical companies, and seems to make a lot of sense. As we move forward on this and other efforts to raise the ethical bar in health care innovation, it is important that there be a place at the table for everyone involved.

By Rebecca Dresser, JD

My comments will focus on off-label use of medical devices, which is a topic rife with ethical questions. I will begin by reviewing recent experience with drug-eluting coronary stents, which are regulated by the FDA as Class III devices, as this experience touches on many of the challenges that arise from off-label product use.

CASE STUDY: DRUG-ELUTING STENTS

The earliest coronary stents were made of bare metal. Over time, arteries treated with these stents tend to become blocked again, requiring patients to return for repeat revascularization. Drug-eluting stents were developed to extend the time that the artery stays open.

Earlier this decade, a couple of device manufacturers sought FDA approval to market their drug-eluting stents. Each manufacturer submitted data from randomized clinical trials in otherwise healthy patients with small, newly diagnosed heart blockages. The trials showed that patients who had received drug-eluting stents had reduced reclogging rates after 9 months compared with those who had received bare metal stents. Risks appeared to be similar between the two types of stents. On the basis of this evidence, the FDA approved the initial drug-eluting stents for marketing in 2003 and 2004.¹

Soon after they were approved, drug-eluting stents were being used in about 80% of patients who received coronary stents. However, although these new stents had been tested and approved for use in otherwise healthy patients with small, newly diagnosed heart blockages, about 60% of their real-world use was off label—specifically, in patients with large blockages or additional health problems such as diabetes.

Reports of adverse events with drug-eluting stents began to emerge, so the FDA issued a statement of concern in September 2006 and subsequently convened an advisory panel of outside experts to review the data and make recommendations. In January 2007, that advisory panel concluded that off-label use of drug-eluting stents is associated with an increased risk of thrombosis, death, or myocardial infarction compared with on-label use. The panel noted, however, that data on off-label use were limited and that additional studies were needed to determine optimal treatments for more complex patients.²

So research on the safety of off-label use of drug-eluting stents continues. Recent data—including studies published in the New England Journal of Medicine and JAMA earlier this year^3,4—suggest that some off-label uses are safe and effective, but much uncertainty remains.

PHYSICIANS SHOULDER THE ETHICAL BURDEN

The story of drug-eluting stents illustrates some of the issues that can arise with off-label use of devices. Currently, the FDA gives physicians discretion to prescribe approved products for uses that deviate from the products’ FDA-approved package inserts. Although the FDA is imperfect, it provides the most thorough and systematic review we have of medical product safety and efficacy. However, an FDA review typically addresses the risks and benefits of a product in only one context or patient population, which might not apply to another context or population. For instance, children and the elderly are generally not well studied in clinical trials, so off-label use of therapies is particularly common in these populations. Of course, patients can be harmed if off-label use presents unappreciated risks or does not provide an adequate benefit. Even if no adverse effects result from off-label therapy, other harms are possible: an alternative therapy might have been superior or the treatment may simply be a waste of money.

In this absence of regulation, the questions of whether and when to prescribe off label—and what the guiding ethical standards should be—fall to physicians. A few professional groups provide some guidance. The American Medical Association states that off-label use is justified when “based upon sound scientific evidence and sound medical opinion.”⁵ The American Academy of Pediatrics (AAP) has issued what is perhaps the best statement6 (although it focuses on drugs, its principles can be applied to devices as well). The AAP maintains that off-label use should be based on “sound scientific evidence, expert medical judgment, or published literature” and notes that physicians who prescribe off label have “a public and professional responsibility to assist in the systematic development of the information” about a particular off-label use. The AAP also advocates that prescribers consider discussing with patients (or their parents) the off-label status of a therapy and the degree of the therapy’s acceptance among physicians for the proposed off-label use.

SPECIFIC ETHICAL ISSUES

How to evaluate evidence about off-label use?

The justification for off-label use is not to advance knowledge but to best meet the needs of an individual patient. But how can a physician know that a therapy is best for a proposed use when it has not been through the FDA approval process for that use or for the particular type of patient at hand? Some off-label uses are supported by strong data while others are not. Physicians have the responsibility to evaluate the available evidence with integrity and to promote rigorous research when the available evidence is inadequate.

Healthy skepticism of industry promotion warranted

One problem is that the pharmaceutical and device industries are heavily involved in communicating about off-label uses of products. Since 1997, the FDA has permitted drug and device companies to engage in limited promotion of off-label product uses through distribution of “enduring materials”

such as textbook chapters and peer-reviewed articles. Industry has also been allowed to sponsor education sessions about off-label uses so long as an independent continuing medical education provider is involved in planning the sessions. The authorization for such off-label promotion expired recently, however, and was not renewed in the FDA reauthorization law passed in the fall of 2007. The FDA has since proposed a similar rule regarding off-label promotion,⁷ but it has been criticized for being a bit more lenient toward such promotion.

Concerns about off-label promotion and communication remain. Manufacturers sometimes violate the spirit of the rules that require independence, for example, through compensating physicians who speak favorably about off-label uses. Similarly, manufacturers sometimes design studies of off-label uses of therapies so that the results are especially likely to turn out favorably.

Data collection: Easier said than done

The aim of promoting information gathering and systematic research on off-label uses may be viewed as a professional duty,⁶ but in practice this duty is complicated by the question of who will pay for it. Often product manufacturers are already making plenty of money from an off-label use and therefore have little financial incentive to conduct trials to obtain FDA approval to add a new indication or population to the label. At the same time, there is very little money available in the public sector for such studies.

No consensus on patient consent

The principle of informing patients about off-label use is also controversial. Not much litigation has been brought on this issue. The few courts that have addressed it have ruled that no obligation exists to specifically inform patients of off-label status and that physicians are obliged only to inform patients about risks, anticipated benefits, and alternatives to an off-label treatment. Some writers think that most patients do not understand the concept of off-label use and that informing patients will only confuse them. Others argue that off-label uses ought to be disclosed, especially in situations involving very innovative off-label applications or when insurers may not provide coverage. Interestingly, a recent Harris Interactive poll found that about half of the US public feels that doctors should only be allowed to prescribe drugs for diseases for which they are FDA-approved.⁸

WHAT SHOULD BE DONE?

Some people argue that the regulatory approach to off-label use already works well. Others want more government oversight. Probably no one would argue that every variation from the label should be subjected to the FDA approval process. There is debate over exactly how to define an off-label use—ie, how different it must be from the approved use to legitimately warrant the “off label” title. This is similar to the question of how to define when a change in surgical technique is innovative enough to require formal evaluation.

Some argue that better postmarketing surveillance is needed to assess the effects of off-label device use in patients. Additional help could come from a 2007 amendment to federal law that strengthens requirements to make clinical trial information publicly available through clinical trial registries. This will make it difficult for sponsors to conceal unfavorable data from trials involving off-label uses. More information exchange and independent assessments of off-label uses are also needed to promote better and safer off-label use of medical devices.

By Paul A. Lombardo, PhD, JD

As a historian and a lawyer, I tend to look back to established precedents, a tendency that often leads to a conservative and cautious perspective. This kind of temperament is slow to reach sweeping conclusions, slow to push for change, and slow to believe that anything is really very new. This temperament is in stark contrast to that of the successful surgeon, who tends—again, speaking in stereotypes—to be aggressive, bold, courageous, pathbreaking, and, at the best moments, even heroic.

This contrast in temperaments may bring a different and perhaps helpful perspective to the task I have at hand—to look to the past for examples of ethical challenges in surgical innovation. In gathering these examples I was struck by how many of the foundational ethical issues that surgeons have faced over the years remain with us today.

CASE 1, 1649: ‘STANDARD OF CARE’ CONCEPT ARTICULATED

In 1649, an ordinance passed by the Massachusetts Bay Colony made it a crime to operate on a person without consent. It also stated that no person employed as a surgeon may perform any act contrary to “the known approved rules of the art” as laid out by one’s medical peers. The ordinance pointed out that this rule was meant not to discourage “the legal use of the skills of healers” but rather to inhibit those who might not be restrained from “the presumptuous arrogance of their own skill.”

This law mandated three things that are a foundation of what we think of as surgical ethics today:

• The notion of a standard of care (“the known approved rules of the art”)
• Peer review (the need to consult preoperatively with peers regarding that standard)
• Patient consent.

Interestingly, this ordinance was adopted at a time when most surgery was performed on visible pathologies or deformities, and elective surgery was all but unknown. Only about 150 years later did surgeons open a body cavity on a regular basis.

CASE 2, 1809: INNOVATION IN THE FACE OF CONDEMNATION

In 1809, Ephraim McDowell, a Kentucky surgeon, described the desperation of his patients as a motive for attempting a new procedure to fix a problem that was otherwise incurable. In his most famous case, McDowell reported visiting a woman some 60 miles from his home who thought she was pregnant but who actually had a large ovarian tumor. McDowell told her that there was no cure but invited her to come to his home if she were willing to undergo an experiment. He thought she would not make the trip, but, to his surprise, she arrived on Christmas Day in 1809.

As McDowell prepared for surgery, his nephew, who was a physician and his partner, argued that the procedure was a terrible thing to try. McDowell was also condemned from the pulpit by a preacher, who declared that the surgery was tantamount to murder if it failed.

While his patient recited psalms from the Bible, McDowell removed a 22-pound lump of tissue without anesthetic or antisepsis. The patient returned home about a month later and lived for more than 30 more years.

After having performed this oophorectomy procedure three times, McDowell deemed it less perilous than any other mode of treatment and the only certain cure for diseased ovaries. Later, surgeons in England who read about his work criticized McDowell for not explaining the operation sufficiently for others to replicate it, although he denied this charge.

In pioneering oophorectomy, McDowell did something quite innovative in the face of considerable professional and community opposition. Moreover, he took care to obtain patient consent and to include his patient in decision making.

CASE 3, MID-1800s: J.MARION SIMS AND ‘THERAPEUTIC MISCONCEPTION’

J. Marion Sims, considered the father of American gynecologic surgery, is famous not only for his technique as a surgeon but also for inventing several instruments, including the speculum. Yet he is criticized by historians and ethicists, primarily because he often performed experimental procedures on slaves, who probably were not in a position to give true consent. He kept patients as boarders for many months, doing a variety of experiments on them, and described in his writings how much pain his patients endured from his mistakes or from the prolonged operations.

Sims’ work is an example of “therapeutic misconception”: while he told his patients that he was going to cure them, he often had no idea whether he could. Thus, his patients believed that the operations were primarily for their benefit although he seems, as critical colleagues came to believe over time, to have sometimes been simply experimenting on patients who were uniquely vulnerable.

CASE 4, 1903: EARLY EXAMPLE OF MODERN INFORMED CONSENT

In contrast to the record of Sims, some 50 years later Dr. Franklin Martin described the painstaking approach he took to advising a patient who would undergo one of the first ovarian transplants, performed around 1903. Martin wrote:

I carefully explained to her the difficulties which we had to surmount…. I also clearly informed her that the operation must be looked upon entirely in the light of an experiment, and that she must be prepared to assume all responsibility with regard to failure in the outcome. Being a woman of unusual intelligence and one who was thoroughly in earnest in her efforts to regain her normal condition, these preliminaries were very easily settled.⁹

Without being required to do so, 100 years ago Martin went through a process equal to any informed consent disclosure that one might encounter today.

CASE 5, EARLY 1900s: A CALL FOR RESTRAINT IN EXPERIMENTATION

Around the same time, at the beginning of the 20th century, a surgeon writing in the Boston Medical and Surgical Journal condemned “over-confidence in the benefits to be derived from mechanical interference and an unrestrained enthusiasm for doing something tangible and heroic.”¹⁰ He urged his colleagues to “be brave enough to refrain from the mutilation and suffering caused by too late and hopeless operations.”¹⁰ He noted the habit of experimentation with new methods, arguing that advances in surgery led to a disproportionate focus on surgery as an art and too little attention to surgery as a science.

These arguments from a century ago make clear that today’s debates about the evidence required to move forward with innovative procedures are certainly not new.

CASE 6, 1913: COMPLEX INSTITUTIONAL MOTIVATIONS

In his 1913 book, The Modern Hospital: Its Inspiration, Its Architecture, Its Equipment, Its Operation, Dr. John Allen Hornsby wrote:

Benefactors of institutions, before giving their money, will want to know just what care the poor…are actually receiving at the hands of the institutions asking for their aid….Yet there must be a difference between the service given to a millionaire and a pauper, but that service should be wholly of the luxuries. The pauper need not have broiled quail and asparagus tips for dinner, and he need not have a private room with adjoining bath, with roses on every stand and the odor of perfumes scenting the room; but these extras should be the only ones that the man of millions should have that the pauper should not have; and patrons of wealth and refinement and of humanitarian instincts will give thousands annually to the institution where they know the poor are getting everything a rich man can get that is needful, where they will give begrudgingly a few paltry dollars to the institution that they know is neglecting the wants and welfare of the poor.¹¹

While this excerpt is notable for Hornsby’s eloquence in arguing for meeting a standard of care for the poor, it is just as notable for demonstrating how complex Hornsby’s motivations were. Not only should we care for the poor, but we have to do it right or the institution will not get money from the rich. In other words, “give the donors what they want.” Then, as now, it took large sums of money to run institutions, as well as to put new innovations in place. And then, as now, institutions had to grapple with complicated motives.

SAME ISSUES, NEW CONTEXTS

This historical review makes clear that the ethical issues we face today are not new. The foundational questions about the ethics of biomedical research as applied to surgery consistently revolve around consent, how thoroughly to inform patients, the use of vulnerable populations as research subjects, distinguishing between experimentation and therapy, and, of course, money and the best use of resources. Variations on these questions continue to loom for surgeons and other physicians.

By Peter A. Ubel, MD

I am a fan of innovation: my patients benefit from it every day. But I am also concerned about the cost of health care. In the Veterans Affairs health system, I see patients who cannot afford their medications and who cannot afford to get private insurance; such problems are largely due to the high cost of health care.

As an example, consider a new pharmaceutical innovation, bevacizumab (Avastin), which costs approximately $106,000 per year when used to treat lung cancer.¹² On average, the treatment leads to a 2-month increase in survival, making the cost of this intervention more than $600,000 per quality-adjusted life-year. Or consider the use of a left ventricular assist device rather than medical management for patients with congestive heart failure who are not eligible for transplantation. The estimated cost is approximately $900,000 per quality-adjusted life-year.

These examples illustrate that some benefits to patients can come at a very high cost. For this reason, I believe that we need to set limits in (ie, ration) health care. I will outline here why we need to do so and why third-party payors—both government and private insurance companies—need to consider the cost-effectiveness of health care interventions in deciding whether to pay for them. In the process, I will discuss common thresholds for defining the price of life and explore whether special moral considerations are required for life-saving treatments—ie, whether the price of life should be higher for severely ill patients.

WHY IS IT TIME TO RATION MEDICAL CARE?

Spending on health care in the United States has risen steadily in the last few decades both in real dollars and as a percentage of the gross domestic product. One important reason for setting limits on health care spending is that we have other things to spend our money on. Medicare budgets compete with tax cuts, education, military spending, homeland security, and many other national interests. Economics teaches us that we have to make difficult choices: when we spend more on health care, we have less money to spend on other things.

Cost-effectiveness analysis provides insight on why it is important to set limits. When I trained at the Mayo Clinic, we used to send patients home with six fecal occult blood test cards to screen for colon cancer. (Patients smear stool on a card and mail it to the laboratory, where it is tested for blood; if blood is present, the patient needs a colonoscopy. The six card samples are taken and mailed at periodic intervals to maximize sensitivity.) What is the cost-effectiveness of the sixth card? The answer is surprising: although the cards cost only a couple of dollars, the cost per life saved is an estimated $26 million, which most would agree is more than we can afford to spend to save a life from cancer.

Why is the sixth card so expensive? If any of the first five cards shows blood, the sixth card is worthless, as it provides no new information. On the other hand, if none of the first five cards shows blood, the chance is minuscule that the sixth card will show blood that actually comes from a precancerous lesion that can be removed and save a person’s life.

This example illustrates that cost-effectiveness does not apply only to expensive new therapies like Avastin; it also applies to really inexpensive items like fecal occult blood test cards.

WHAT IS A YEAR OF LIFE WORTH?

If our own child were sick, we would say that a year’s life is worth an infinite amount of money; we would do anything we could to save our child’s life. But the job of the cost-effectiveness community is to address this question from a societal perspective, and they have a different answer. The most commonly cited view among experts in cost-effectiveness analysis is about $50,000 per quality-adjusted life-year, although it typically ranges up to $100,000.¹³

This figure has not risen with inflation, and it probably should not. If enough new technologies were developed at the threshold of $50,000 per quality-adjusted life-year, the entire budget of the country would quickly be used up.¹⁴ Making payment decisions based on a certain cost-effectiveness threshold sets no real limit on health care spending. The threshold is not meant to be a realistic number but should illustrate the kind of thinking required about how much we want to spend on health care relative to other things. The aim is to help us decide how much “bang for the buck” we should expect from our dollars spent on health care.

WHAT DO PEOPLE VALUE WHEN SETTING LIMITS?

In light of the above, how do we set limits when trying to decide what the price of life is? Might our limit-setting be changed if we are facing a desperately ill patient? Examination of questions like these reveals that people value other factors beyond just economic efficiency, as can be illustrated with a couple of theoretical policy dilemmas.

Dilemma 1: Cost-effectiveness vs fairness

Imagine that the Medicaid program decides to screen for colon cancer. They have enough money either to offer an inexpensive test (“Test 1”) to everyone and save 1,000 lives or to offer a more expensive test (“Test 2”) to half the population (selected randomly) and save 1,100 lives.

If the decision were made according to rational cost-effectiveness principles, the choice would be to go with Test 2 in half the population, as it saves 10% more lives and thus maximizes the average health of the population. However, a survey found that the option of offering Test 1 to everyone was favored by 55% of the general US public, as well as by 55% of medical ethicists and even by 45% of cost-effectiveness experts, all of whom were willing to give up some cost-effectiveness for fairness.¹⁵

This tendency to favor fairness suggests that moral considerations affect health policy decisions in important ways. Yet further analysis raises questions about the extent to which these considerations are based truly on moral values as opposed to psychological quirks.

For instance, my colleagues and I presented this same choice of colon cancer testing scenarios to a separate survey sample, and again a highly similar rate of respondents—56%—favored offering Test 1 to the full population as opposed to offering Test 2 to half the population. However, to test whether this preference for equity over efficiency persists when neither test can be offered to the entire population, we changed the scenarios for a separate group of randomly selected participants. In one version of the scenario, we told participants that only 90% of the population could receive Test 1 and only 40% could receive Test 2. (As in the original scenario, we indicated that Test 1 saves 1,000 lives, whereas Test 2 saves 1,100 lives.) With just this small variation in test availability, the proportion of respondents favoring Test 1 plummeted to 27%. Similarly, we randomly selected another group of participants to receive a third version of the scenario, in which 50% of the population could receive Test 1 and 25% could receive Test 2, saving 1,000 and 1,100 lives, respectively. Once again, the proportion of the respondents favoring Test 1 remained low (28%).¹⁶

These results suggest that people’s preference for equity versus efficiency depends, in large part, on whether the more equitable option can be offered to everyone in a population. But people’s preferences are actually not nearly that coherent. Consider a follow-up study in which we repeated the scenario again for each respondent, but with a twist.

In one group, we began with our original scenario: 100% of the population can receive Test 1, saving 1,000 lives, or 50% can receive Test 2, saving 1,100 lives. As expected, 60% of participants chose Test

1. But then we told this same group of participants that the number of people qualifying for Medicaid had doubled, so that the tests could be offered to only 50% and 25% of the population, respectively (still saving 1,000 and 1,100 lives, of course, since the population was now twice as large). Remember that when people were initially presented with this 50% versus 25% option (without any other scenario being presented first), the preference for Test 1 plummeted. In this case, however, almost no one changed their mind: the majority (60%) still favored Test 1.¹⁷

People’s preferences for how to allocate scarce health care resources—the moral values that they believe should guide our health system choices—are often disturbingly arbitrary.¹⁸

Dilemma 2: Targeting severe vs moderate illness

Now imagine a new scenario. A treatment is available that will help patients with an illness that causes severe health problems, but it provides only modest benefit. Another treatment helps patients with an illness that causes moderate health problems, and it provides considerable benefit. The cost of the two treatments is the same. How should funding be allocated?

Although a majority (60%) of survey respondents say that most funding should go toward treating the moderate illness where considerable benefit is expected, a sizeable share of people (40%) favor devoting most funding to the severe illness despite the more modest benefit.¹⁹ This is another instance where moral values seem to come into play, as a large minority will favor helping the severely ill even at the expense of efficiency.

A variation of this dilemma illustrates another salient point—that people like “easy outs.” When we present people with an additional option—“How about spending money equally between the two treatments?”—the vast majority (75%) choose that “compromise” option over the option of devoting most funds to either of the individual illnesses.¹⁹ The lesson is that we hate making difficult decisions, both as individuals and as a society.

COST-EFFECTIVENESS IS THE MOST RATIONAL AND ETHICAL WAY TO SET LIMITS

These surveys make clear that many of the moral values that people express are fragile at best or even psychological quirks. I have heard no compelling moral arguments to support treatments that cost more than $500,000 per quality-adjusted life-year, which leads me to conclude that many new medical interventions are unaffordable. The resistance to limiting such treatments is psychological and political, but it is not ethical.

The appropriate response is for third-party payors, such as Medicare and insurance companies, to let industry know that cost-effectiveness matters. If a treatment is not cost-effective, it should be limited to people who pay out of pocket or for experimental purposes. To make this happen, we need cost-effectiveness analyses of new technologies. Because such studies are expensive and time-consuming, we should develop new incentives to motivate companies to conduct such studies of their products, perhaps by extending patent protection for products that are shown to be cost-effective. We need to work with industry on how to implement such a plan. But continuing to ignore the cost-effectiveness of interventions when they come to market is harming patients who can no longer afford insurance, which has real consequences on people’s health and well-being.

By Christopher L. White, Esq

I serve as general counsel of the Advanced Medical Technology Association (AdvaMed), a Washington (DC)-based trade association that advocates on behalf of the medical device innovation community. Most of the approximately 1,600 companies we represent are small, having fewer than 100 employees. All of our member companies have a great interest in creating an environment that will sustain innovation to fuel additional benefits in patient care.

PHYSICIANS AND THE DEVICE INDUSTRY: INTERACTIONS ARE MANY, VARIED, ESSENTIAL

As noted earlier in this session by Mike Mussallem, who serves as chairman of AdvaMed’s board of directors, the medical device industry is very different from the pharmaceutical industry. Device innovation requires a great deal of collaboration with physicians in the field. Moreover, devices are not simply prescribed—they are used. That is, many of the inventions are an extension of the surgeon’s hand, such that technique influences how devices are deployed and used. As a result, with each incremental innovation, there is often a need for retraining.

Physicians wear many hats in their relationships with the medical device industry. Not only are they purchasers of products but they are collaborators, inventors, trainers, and trainees. They are also recipients of charitable contributions and of research grants. We recognize that these multiple relationships can become intertwined and, from a distance, can arouse confusion or suspicion. But simply because these relationships exist does not mean that there is a conflict of interest—there may be dualities of interest. In most cases we have a common interest and are working toward a common objective: to provide care in the best interest of the patient.

THE ADVAMED CODE OF ETHICS

The key question from industry’s perspective is how best to manage these relationships with physicians and any potential conflicts of interest. To that end, AdvaMed has developed a code of ethics to provide guidance relevant to the most common interactions between device manufacturers and health care professionals.²⁰ The AdvaMed code has been adopted by international device trade associations and embraced or cross-referenced by physician specialty societies.

Although the AdvaMed code has become a “gold standard,” it is a living document, and we are in the process of reviewing and revising it in an effort to address challenging new issues such as royalty payments, among others, which have become the focus of public questions and scrutiny.

MOVING FORWARD AFTER THE JUSTICE DEPARTMENT DEFERRED PROSECUTION AGREEMENTS

Recently, five orthopedic hip and knee implant manufacturers entered into novel deferred prosecution and non-prosecution agreements with the US Department of Justice following a Justice Department investigation into financial relationships and consulting agreements between these companies and orthopedic surgeons. The agreements include the appointment of federal monitors to review virtually every transaction that these companies have with physicians. These agreements impose a level of governmental review over the device industry that has never been seen before.

The agreements also require the five companies to disclose on their public Web sites all payments made to physicians. The disclosures must follow a specified format listing each physician’s name and location, the amount of the payments, and limited information regarding the purpose of the payments (eg, for consulting, royalties, charitable contributions, research grants). This requirement has created much interest as well as a good deal of confusion.

These developments have also spurred AdvaMed to work aggressively on federal and state legislative efforts. We are taking a proactive position on the disclosure of financial arrangements between industry and physicians in the context of the proposed Physician Payments Sunshine Act mentioned earlier by Mike Mussallem. If passed, this legislation would change the landscape by requiring that all pharmaceutical and device companies report to a single federal database all transfers of value or other payments, subject to certain exceptions, from industry to physicians. Similar to the federal agreements with the orthopedic implant manufacturers, the bill would require that the name and location of the physicians receiving payments be disclosed, along with the payment amount, but with greater context regarding the purpose of the payment. AdvaMed has been advocating for providing detailed explanations of this context so that everyone, including the public, can understand why such payments are made and how they can be beneficial.

Moderated by Lawrence K. Altman, MD

Dr. Lawrence Altman: Let us start by opening the discussion to the audience.

Comment from audience: Considerable discussion has focused on the conflict between regulation and innovation, but I find very little evidence that such a conflict actually exists. It was pointed out that the United States is by far the biggest producer and user of medical devices and has been since World War II. Economists estimate that 50% of the growth of the US economy since then has resulted directly from innovations in science and technology. During that same period, the regulatory apparatus—including the FDA—has vastly expanded. Apparently, innovation has not been stifled by regulation but actually seems to thrive in a regulated environment.

I speak often with venture capitalists who finance science technology. They know this history, and they know that regulation is inevitable. Rather than opposing it, they want clarity about regulation. For instance, many of them avoid financing human embryonic stem cell research because the rules around it are not clear, owing to the stigma and political controversy surrounding it.

Michael Mussallem: You make great points. People who invest in medical innovation would like an idea of the rules before they make investment decisions. And good, solid regulation—such as when the FDA pushes companies for the kind of science and evidence needed to clear a hurdle—is absolutely appropriate. But as regulation increases, the time and costs to bring an innovation to market increase. At the moment, the innovation equation is fragile. When too many obstacles are put in the way, the risk of failure becomes too high.

Keep in mind that the success rate in innovation is low. Although I have been in this field my entire career, it would be much easier for me to hit a major league fastball than it is to successfully innovate in medical technology. We are wrong many more times than we are right. For every success, there may be 9 failures, or 19 failures, or even 99 failures.

Rebecca Dresser: I agree that regulation sometimes does not effectively advance its goal. When that is the case, I think we need to be willing to negotiate rather than condemn; we need to show where regulation is not meeting agreed-upon goals (such as protecting patients) and figure out how to reach those goals more efficiently.

We also should keep in mind the cliché, “If professions do not adequately self-regulate, external regulation will come in.” Perhaps that is what has happened. Professionals need to self-examine and organizations need to develop voluntary standards to help avoid stupid regulation.

Christopher White: We need to be mindful of the unique relationships that we have within this niche sector of the health care industry. Issues that might not appear to threaten us directly may have unanticipated implications. Some of the barriers that regulation can impose may not be immediately perceptible and can be masked by otherwise beneficial public policies. For example, we now have a patent reform debate on Capitol Hill promoted by the information technology industry as pro-innovation, but in the context of the life sciences industry, many of the proposed patent reforms threaten innovation by devaluing device improvements.

Also, much of the regulation the device industry confronts is responsive to dynamics in the pharmaceutical industry. For example, one house of the Massachusetts legislature recently passed a bill that would ban gifts to health care professionals and require licensure of pharmaceutical and device sales representatives who work in the state. The term “gift” is defined very broadly and could include not only meals and the other things that we read about regularly but also rebates, educational grants, and training. [Editor’s note: A modified version of this legislation was signed by Massachusetts’ governor in August 2008 and will take effect January 1, 2009.]

Question from audience: As a practicing surgeon, I think the major problem lies in the area of off-label use. If one accepts that the device manufacturer is well-intentioned and living up to the AdvaMed code of ethics, the system falls apart once the device has cleared the hurdle of FDA approval for a labeled indication. The product then reaches the broad market, where it is subject to commission-based sales. Whether or not to use the device in innovative ways is generally at the discretion of the physician, until it reaches the threshold of research and institutional review board approval. We have virtually no post-market surveillance by the manufacturer. At what point is the manufacturer culpable for the off-label use of its product when patients are harmed and no surveillance exists until enough casualties occur that the problem becomes obvious?

Mr. Mussallem: Put yourself in the shoes of a physician who is facing a difficult situation that has not been studied and is outside the realm of any approved, “on-label” therapies. A classic case is for children with congenital heart defects. Since no one advances a medical device for such small patient populations, physicians treating such cases are forced to be creative. They take devices that were intended and tested for adults and apply them to a child. Do you punish those physicians? Do you punish the company that created the devices?

When you look at the question down at this level, where it becomes quite practical and quite personal, the issue of off-label use takes on a different color. In many ways, it comes down to how much we trust physicians and to what extent we think they should be regulated. I would want to give physicians the freedom to try to do what is best for their patients and to use their judgment to apply a device in a different way—one that they understand has not been tested or approved for that use. But I would also want transparency: I would want them to explain to the patient (or the parents) what is known and unknown about the situation. It is in the absence of that transparency that you enter dangerous ground.

Paul Lombardo: When a new law is passed or a new regulation comes down, it is usually in response to a scandal: something bad enough happened to scare everyone to death. If I were advising industry, I would tell them to go to any length to avoid the kind of scandals that we have seen that challenge the trust of the public. So I agree that transparency is critical. It is one thing to say, “I am trying to do what is best for my patients and trying new things because I do not have access to tools especially designed for children.” But when we find out that a doctor or a manufacturer has hidden data about a method of using equipment that has never been approved, and is covertly pushing that use, the predictable result is that somebody will want to regulate it.

Ms. Dresser: Of course, malpractice suits are an option, but they will cover only a few cases, generally the most extreme ones. I think the greatest need is for information gathering. The medical profession should think about how to encourage data collection for off-label use so that problems can be detected earlier than they are now. This type of data collection is also in device manufacturers’ best interest, as it helps to avoid scandal.

Another approach is to extend the patent exclusivity of products whose manufacturers conduct trials in underserved patient populations, thus providing a financial incentive to do such studies. This approach has in fact been adopted in the case of pediatric trials and for orphan diseases. Interestingly, some pediatric trials prompted by this patent extension incentive have shown that certain medications or dosages previously accepted as standard medical practice turned out to be harmful in children once they were formally studied.

Dr. Altman: What about proposals to use published literature—which also is subject to abuse—as a criterion for off-label use?

Ms. Dresser: Peer-reviewed journals do not have access to raw data, which can be manipulated in a lot of ways, so they cannot completely substitute for FDA review. Recent articles in JAMA addressed these concerns.^21,22

Comment from audience: There seems to be a misguided desire to look to our regulatory agencies to tell us how we should manage a patient. As a practicing surgeon who does minimally invasive procedures, I never look to regulatory agencies to tell me what the optimal therapy is for a patient; rather, I look to them to tell me whether a product is a therapeutic option for a patient, and then I use my judgment to decide whether it is the best option for this particular patient.

Consider how Britain’s National Institute for Clinical Excellence (NICE) has approached drug-eluting stents. They looked specifically at off-label uses of these stents and determined that the stents confer a benefit in these off-label areas, based on subgroup analysis. But then they did a cost-effectiveness analysis and determined that the benefit was not great enough to offset the cost to society based on the quality-adjusted life-years gained. Well, that may be a fine theoretical discussion, but when I am sitting in front of a 75-year-old who I think will do better with a particular device, it is hard to be concerned about whether it is on label or off label, or does or does not meet cost-effectiveness criteria.

Mr. Mussallem: This comes back to the trust that we have in our physicians. Should product manufacturers be allowed to hand out peer-reviewed journal articles? If physicians are provided with those articles, does that provide too much information for them and steer them inappropriately? Well, if physicians single-mindedly made such articles the sole basis for a treatment pattern, then it absolutely would be inappropriate, but we should give physicians a little bit of credit. Their job is to take a tremendous amount of data—everything that they have learned through their own experiences, plus journal articles and other sources—and apply it to design the best course of treatment they can for a specific patient.

If we try to overprescribe how a physician behaves, we will find it is too complex to regulate or legislate from the top. We should have a lighter hand and design incentives appropriately so that physicians are first and foremost motivated to take care of the patient. We should not try to tell them too much about exactly how to practice; after all, a large study that finds that one treatment has a 62% chance of being superior does not prove that it is the best treatment for a specific patient. You always want to preserve physician judgment.

Dr. Peter Ubel: I agree, but if we are to avoid overmanaging the day-to­day decisions that doctors make, we doctors also have to think more broadly about our responsibilities. If our duty is only to the patient in front of us, we can ignore being told that a treatment offers only a very small benefit for the cost. If we doctors say that it is not our job to be mindful of costs, then somebody is eventually going to have the job of telling us when we can and cannot use those stents, as a way to rein in costs because no one can afford insurance anymore.

For physicians to maintain more room for our judgment in influencing clinical practice, we have to remember that we are stewards not just of individual patients but of the general health care system. The cost of technology plays a huge role in driving up the cost of medical care.

Preface

By Lawrence K. Altman, MD (Moderator)

Early in the history of the United States, physicians commonly discussed medical issues in newspapers and other public forums. But a remark attributed to Osler, “Never trust anything you read in a newspaper…and if you do, immediately doubt it at once,” was used by the medical profession for decades to justify avoiding public discussion of medical issues. This retreat by physicians from the public discourse was particularly harmful in that it overlapped with the period when the public began paying for most medical research via federal research funding. Recently the medical profession has again started to discuss medical matters openly with the public, but this step has been taken reluctantly, in response to public pressure.

This resurgence in physicians’ engagement with the public has come not a moment too soon, as factors and players outside the operating room—economic forces, regulators, legislators, lawyers, and others—today may have as much influence on what goes on in US operating rooms as do the surgeons, nurses, and technicians who work there. Our panel will address some of these influences on surgical innovation from outside the operating room, touching on historical and current examples of attempts to regulate innovation as well as the points of view of device companies, investors, lawyers, government, and health economists.

By Michael A. Mussallem

I am honored to be here to represent industry. Although medical technology companies compete fiercely with one another in the marketplace, we also have a broad common interest: we want to develop innovations to help patients.

DEVICE AND DRUG DEVELOPMENT DIFFER

Discussing ethical challenges involving industry is easier in the context of pharmaceutical development, for a number of reasons. The pharmaceutical industry is so large that it tends to dominate the discussion. But medical devices, which are primarily what is involved when we speak of surgical innovation, differ from pharmaceuticals in key ways.

The physician-company relationship is central

First, medical devices are not used directly by patients but are tools for physicians, which makes the relationship between industry and physicians more closely intertwined when devices are involved.

An iterative process by nature

Second, it takes years of development and enormous sums of money before a drug is finally approved. The final product then has a market life of 10 or 20 years. In contrast, device development is an inherently iterative process. After Thomas Edison developed the light bulb, attempts to improve the product were immediate and constant: “Can the light be made softer? The bulb smaller? Can it be turned off?” The same type of continuous improvement process happens with medical devices, which typically are refined every 12 to 18 months. Occasional breakthroughs occur and open up a whole new way of thinking, but far more often device innovation is about incremental modifications and improvements.

SUCCESS BREEDS CONFLICTS…AND REGULATION

The development of medical devices is an American success story; we tend to be better at it than any other country. Our system works well and rewards risks and innovation. When technology is racing forward to address an unmet patient need, a tremendous amount of value is created in the form of patients living longer and healthier lives. People pay for that value, which can create substantial payoffs for successful innovators and companies. I believe that six of the companies in the Fortune 500 are medical device companies, and the medical device industry has a $450 billion market capitalization in total.

The medical device business is like an ecosystem with many interacting components. Someone with a bright idea puts a physician and an engineer together, starts a company, attracts some capital, and develops a product. Because they need startup money for production, they might offer physicians a share of the company and some stock options, and immediately an opportunity for conflict of interest arises.

As a result of these many interacting components and the conflicts they can create, medical device companies today are highly regulated by a long list of entities, including the Securities and Exchange Commission, the Food and Drug Administration (FDA), the Department of Justice, the Internal Revenue Service, the Environmental Protection Agency, the New York and NASDAQ stock exchanges, the Office of the Inspector General, and the Foreign Practices Act. This degree of regulation makes every part of the medical device development process more time-consuming and expensive.

LONG-TERM SUCCESS REQUIRES THAT COMPANIES SERVE PATIENTS

The motivation of medical technology companies is often called into question. Medical device companies are certainly motivated to make money, and they certainly have obligations to shareholders. But for a company to be successful for many years, it cannot be single-minded about the constituencies that it serves. Great medical device companies have employees who want to work for them, physicians who want to buy products from them, communities that welcome them, and shareholders who want to own their stock, but the primary goal is always to serve patients: if that is done really well over the long term, the company can count on those other success factors being present. To have a sustainable competitive advantage, one must think beyond the next quarter and run a highly respectable business on an ongoing basis.

It is true that there are outlier medical device companies who do not always operate with full integrity, as there are in any industry. The challenge, both for the medical technology industry and for the broader health care community, is to raise the standards and encourage everyone to operate at a highly ethical level. I refuse to believe that doing so requires pulling apart companies, engineers, scientists, and physicians. Instead, we need to find ways for these various players to engage together.

A good start may be the revised Physician Payments Sunshine Act, proposed by US Senator Charles Grassley. This legislation, which is supported by the Advanced Medical Technology Association (AdvaMed), would establish a national registry of payments made to physicians by medical device, medical supply, and pharmaceutical companies, and seems to make a lot of sense. As we move forward on this and other efforts to raise the ethical bar in health care innovation, it is important that there be a place at the table for everyone involved.

By Rebecca Dresser, JD

My comments will focus on off-label use of medical devices, which is a topic rife with ethical questions. I will begin by reviewing recent experience with drug-eluting coronary stents, which are regulated by the FDA as Class III devices, as this experience touches on many of the challenges that arise from off-label product use.

CASE STUDY: DRUG-ELUTING STENTS

The earliest coronary stents were made of bare metal. Over time, arteries treated with these stents tend to become blocked again, requiring patients to return for repeat revascularization. Drug-eluting stents were developed to extend the time that the artery stays open.

Earlier this decade, a couple of device manufacturers sought FDA approval to market their drug-eluting stents. Each manufacturer submitted data from randomized clinical trials in otherwise healthy patients with small, newly diagnosed heart blockages. The trials showed that patients who had received drug-eluting stents had reduced reclogging rates after 9 months compared with those who had received bare metal stents. Risks appeared to be similar between the two types of stents. On the basis of this evidence, the FDA approved the initial drug-eluting stents for marketing in 2003 and 2004.¹

Soon after they were approved, drug-eluting stents were being used in about 80% of patients who received coronary stents. However, although these new stents had been tested and approved for use in otherwise healthy patients with small, newly diagnosed heart blockages, about 60% of their real-world use was off label—specifically, in patients with large blockages or additional health problems such as diabetes.

Reports of adverse events with drug-eluting stents began to emerge, so the FDA issued a statement of concern in September 2006 and subsequently convened an advisory panel of outside experts to review the data and make recommendations. In January 2007, that advisory panel concluded that off-label use of drug-eluting stents is associated with an increased risk of thrombosis, death, or myocardial infarction compared with on-label use. The panel noted, however, that data on off-label use were limited and that additional studies were needed to determine optimal treatments for more complex patients.²

So research on the safety of off-label use of drug-eluting stents continues. Recent data—including studies published in the New England Journal of Medicine and JAMA earlier this year^3,4—suggest that some off-label uses are safe and effective, but much uncertainty remains.

PHYSICIANS SHOULDER THE ETHICAL BURDEN

The story of drug-eluting stents illustrates some of the issues that can arise with off-label use of devices. Currently, the FDA gives physicians discretion to prescribe approved products for uses that deviate from the products’ FDA-approved package inserts. Although the FDA is imperfect, it provides the most thorough and systematic review we have of medical product safety and efficacy. However, an FDA review typically addresses the risks and benefits of a product in only one context or patient population, which might not apply to another context or population. For instance, children and the elderly are generally not well studied in clinical trials, so off-label use of therapies is particularly common in these populations. Of course, patients can be harmed if off-label use presents unappreciated risks or does not provide an adequate benefit. Even if no adverse effects result from off-label therapy, other harms are possible: an alternative therapy might have been superior or the treatment may simply be a waste of money.

In this absence of regulation, the questions of whether and when to prescribe off label—and what the guiding ethical standards should be—fall to physicians. A few professional groups provide some guidance. The American Medical Association states that off-label use is justified when “based upon sound scientific evidence and sound medical opinion.”⁵ The American Academy of Pediatrics (AAP) has issued what is perhaps the best statement6 (although it focuses on drugs, its principles can be applied to devices as well). The AAP maintains that off-label use should be based on “sound scientific evidence, expert medical judgment, or published literature” and notes that physicians who prescribe off label have “a public and professional responsibility to assist in the systematic development of the information” about a particular off-label use. The AAP also advocates that prescribers consider discussing with patients (or their parents) the off-label status of a therapy and the degree of the therapy’s acceptance among physicians for the proposed off-label use.

SPECIFIC ETHICAL ISSUES

How to evaluate evidence about off-label use?

The justification for off-label use is not to advance knowledge but to best meet the needs of an individual patient. But how can a physician know that a therapy is best for a proposed use when it has not been through the FDA approval process for that use or for the particular type of patient at hand? Some off-label uses are supported by strong data while others are not. Physicians have the responsibility to evaluate the available evidence with integrity and to promote rigorous research when the available evidence is inadequate.

Healthy skepticism of industry promotion warranted

One problem is that the pharmaceutical and device industries are heavily involved in communicating about off-label uses of products. Since 1997, the FDA has permitted drug and device companies to engage in limited promotion of off-label product uses through distribution of “enduring materials”

such as textbook chapters and peer-reviewed articles. Industry has also been allowed to sponsor education sessions about off-label uses so long as an independent continuing medical education provider is involved in planning the sessions. The authorization for such off-label promotion expired recently, however, and was not renewed in the FDA reauthorization law passed in the fall of 2007. The FDA has since proposed a similar rule regarding off-label promotion,⁷ but it has been criticized for being a bit more lenient toward such promotion.

Concerns about off-label promotion and communication remain. Manufacturers sometimes violate the spirit of the rules that require independence, for example, through compensating physicians who speak favorably about off-label uses. Similarly, manufacturers sometimes design studies of off-label uses of therapies so that the results are especially likely to turn out favorably.

Data collection: Easier said than done

The aim of promoting information gathering and systematic research on off-label uses may be viewed as a professional duty,⁶ but in practice this duty is complicated by the question of who will pay for it. Often product manufacturers are already making plenty of money from an off-label use and therefore have little financial incentive to conduct trials to obtain FDA approval to add a new indication or population to the label. At the same time, there is very little money available in the public sector for such studies.

No consensus on patient consent

The principle of informing patients about off-label use is also controversial. Not much litigation has been brought on this issue. The few courts that have addressed it have ruled that no obligation exists to specifically inform patients of off-label status and that physicians are obliged only to inform patients about risks, anticipated benefits, and alternatives to an off-label treatment. Some writers think that most patients do not understand the concept of off-label use and that informing patients will only confuse them. Others argue that off-label uses ought to be disclosed, especially in situations involving very innovative off-label applications or when insurers may not provide coverage. Interestingly, a recent Harris Interactive poll found that about half of the US public feels that doctors should only be allowed to prescribe drugs for diseases for which they are FDA-approved.⁸

WHAT SHOULD BE DONE?

Some people argue that the regulatory approach to off-label use already works well. Others want more government oversight. Probably no one would argue that every variation from the label should be subjected to the FDA approval process. There is debate over exactly how to define an off-label use—ie, how different it must be from the approved use to legitimately warrant the “off label” title. This is similar to the question of how to define when a change in surgical technique is innovative enough to require formal evaluation.

Some argue that better postmarketing surveillance is needed to assess the effects of off-label device use in patients. Additional help could come from a 2007 amendment to federal law that strengthens requirements to make clinical trial information publicly available through clinical trial registries. This will make it difficult for sponsors to conceal unfavorable data from trials involving off-label uses. More information exchange and independent assessments of off-label uses are also needed to promote better and safer off-label use of medical devices.

By Paul A. Lombardo, PhD, JD

As a historian and a lawyer, I tend to look back to established precedents, a tendency that often leads to a conservative and cautious perspective. This kind of temperament is slow to reach sweeping conclusions, slow to push for change, and slow to believe that anything is really very new. This temperament is in stark contrast to that of the successful surgeon, who tends—again, speaking in stereotypes—to be aggressive, bold, courageous, pathbreaking, and, at the best moments, even heroic.

This contrast in temperaments may bring a different and perhaps helpful perspective to the task I have at hand—to look to the past for examples of ethical challenges in surgical innovation. In gathering these examples I was struck by how many of the foundational ethical issues that surgeons have faced over the years remain with us today.

CASE 1, 1649: ‘STANDARD OF CARE’ CONCEPT ARTICULATED

In 1649, an ordinance passed by the Massachusetts Bay Colony made it a crime to operate on a person without consent. It also stated that no person employed as a surgeon may perform any act contrary to “the known approved rules of the art” as laid out by one’s medical peers. The ordinance pointed out that this rule was meant not to discourage “the legal use of the skills of healers” but rather to inhibit those who might not be restrained from “the presumptuous arrogance of their own skill.”

This law mandated three things that are a foundation of what we think of as surgical ethics today:

• The notion of a standard of care (“the known approved rules of the art”)
• Peer review (the need to consult preoperatively with peers regarding that standard)
• Patient consent.

Interestingly, this ordinance was adopted at a time when most surgery was performed on visible pathologies or deformities, and elective surgery was all but unknown. Only about 150 years later did surgeons open a body cavity on a regular basis.

CASE 2, 1809: INNOVATION IN THE FACE OF CONDEMNATION

In 1809, Ephraim McDowell, a Kentucky surgeon, described the desperation of his patients as a motive for attempting a new procedure to fix a problem that was otherwise incurable. In his most famous case, McDowell reported visiting a woman some 60 miles from his home who thought she was pregnant but who actually had a large ovarian tumor. McDowell told her that there was no cure but invited her to come to his home if she were willing to undergo an experiment. He thought she would not make the trip, but, to his surprise, she arrived on Christmas Day in 1809.

As McDowell prepared for surgery, his nephew, who was a physician and his partner, argued that the procedure was a terrible thing to try. McDowell was also condemned from the pulpit by a preacher, who declared that the surgery was tantamount to murder if it failed.

While his patient recited psalms from the Bible, McDowell removed a 22-pound lump of tissue without anesthetic or antisepsis. The patient returned home about a month later and lived for more than 30 more years.

After having performed this oophorectomy procedure three times, McDowell deemed it less perilous than any other mode of treatment and the only certain cure for diseased ovaries. Later, surgeons in England who read about his work criticized McDowell for not explaining the operation sufficiently for others to replicate it, although he denied this charge.

In pioneering oophorectomy, McDowell did something quite innovative in the face of considerable professional and community opposition. Moreover, he took care to obtain patient consent and to include his patient in decision making.

CASE 3, MID-1800s: J.MARION SIMS AND ‘THERAPEUTIC MISCONCEPTION’

J. Marion Sims, considered the father of American gynecologic surgery, is famous not only for his technique as a surgeon but also for inventing several instruments, including the speculum. Yet he is criticized by historians and ethicists, primarily because he often performed experimental procedures on slaves, who probably were not in a position to give true consent. He kept patients as boarders for many months, doing a variety of experiments on them, and described in his writings how much pain his patients endured from his mistakes or from the prolonged operations.

Sims’ work is an example of “therapeutic misconception”: while he told his patients that he was going to cure them, he often had no idea whether he could. Thus, his patients believed that the operations were primarily for their benefit although he seems, as critical colleagues came to believe over time, to have sometimes been simply experimenting on patients who were uniquely vulnerable.

CASE 4, 1903: EARLY EXAMPLE OF MODERN INFORMED CONSENT

In contrast to the record of Sims, some 50 years later Dr. Franklin Martin described the painstaking approach he took to advising a patient who would undergo one of the first ovarian transplants, performed around 1903. Martin wrote:

I carefully explained to her the difficulties which we had to surmount…. I also clearly informed her that the operation must be looked upon entirely in the light of an experiment, and that she must be prepared to assume all responsibility with regard to failure in the outcome. Being a woman of unusual intelligence and one who was thoroughly in earnest in her efforts to regain her normal condition, these preliminaries were very easily settled.⁹

Without being required to do so, 100 years ago Martin went through a process equal to any informed consent disclosure that one might encounter today.

CASE 5, EARLY 1900s: A CALL FOR RESTRAINT IN EXPERIMENTATION

Around the same time, at the beginning of the 20th century, a surgeon writing in the Boston Medical and Surgical Journal condemned “over-confidence in the benefits to be derived from mechanical interference and an unrestrained enthusiasm for doing something tangible and heroic.”¹⁰ He urged his colleagues to “be brave enough to refrain from the mutilation and suffering caused by too late and hopeless operations.”¹⁰ He noted the habit of experimentation with new methods, arguing that advances in surgery led to a disproportionate focus on surgery as an art and too little attention to surgery as a science.

These arguments from a century ago make clear that today’s debates about the evidence required to move forward with innovative procedures are certainly not new.

CASE 6, 1913: COMPLEX INSTITUTIONAL MOTIVATIONS

In his 1913 book, The Modern Hospital: Its Inspiration, Its Architecture, Its Equipment, Its Operation, Dr. John Allen Hornsby wrote:

Benefactors of institutions, before giving their money, will want to know just what care the poor…are actually receiving at the hands of the institutions asking for their aid….Yet there must be a difference between the service given to a millionaire and a pauper, but that service should be wholly of the luxuries. The pauper need not have broiled quail and asparagus tips for dinner, and he need not have a private room with adjoining bath, with roses on every stand and the odor of perfumes scenting the room; but these extras should be the only ones that the man of millions should have that the pauper should not have; and patrons of wealth and refinement and of humanitarian instincts will give thousands annually to the institution where they know the poor are getting everything a rich man can get that is needful, where they will give begrudgingly a few paltry dollars to the institution that they know is neglecting the wants and welfare of the poor.¹¹

While this excerpt is notable for Hornsby’s eloquence in arguing for meeting a standard of care for the poor, it is just as notable for demonstrating how complex Hornsby’s motivations were. Not only should we care for the poor, but we have to do it right or the institution will not get money from the rich. In other words, “give the donors what they want.” Then, as now, it took large sums of money to run institutions, as well as to put new innovations in place. And then, as now, institutions had to grapple with complicated motives.

SAME ISSUES, NEW CONTEXTS

This historical review makes clear that the ethical issues we face today are not new. The foundational questions about the ethics of biomedical research as applied to surgery consistently revolve around consent, how thoroughly to inform patients, the use of vulnerable populations as research subjects, distinguishing between experimentation and therapy, and, of course, money and the best use of resources. Variations on these questions continue to loom for surgeons and other physicians.

By Peter A. Ubel, MD

I am a fan of innovation: my patients benefit from it every day. But I am also concerned about the cost of health care. In the Veterans Affairs health system, I see patients who cannot afford their medications and who cannot afford to get private insurance; such problems are largely due to the high cost of health care.

As an example, consider a new pharmaceutical innovation, bevacizumab (Avastin), which costs approximately $106,000 per year when used to treat lung cancer.¹² On average, the treatment leads to a 2-month increase in survival, making the cost of this intervention more than $600,000 per quality-adjusted life-year. Or consider the use of a left ventricular assist device rather than medical management for patients with congestive heart failure who are not eligible for transplantation. The estimated cost is approximately $900,000 per quality-adjusted life-year.

These examples illustrate that some benefits to patients can come at a very high cost. For this reason, I believe that we need to set limits in (ie, ration) health care. I will outline here why we need to do so and why third-party payors—both government and private insurance companies—need to consider the cost-effectiveness of health care interventions in deciding whether to pay for them. In the process, I will discuss common thresholds for defining the price of life and explore whether special moral considerations are required for life-saving treatments—ie, whether the price of life should be higher for severely ill patients.

WHY IS IT TIME TO RATION MEDICAL CARE?

Spending on health care in the United States has risen steadily in the last few decades both in real dollars and as a percentage of the gross domestic product. One important reason for setting limits on health care spending is that we have other things to spend our money on. Medicare budgets compete with tax cuts, education, military spending, homeland security, and many other national interests. Economics teaches us that we have to make difficult choices: when we spend more on health care, we have less money to spend on other things.

Cost-effectiveness analysis provides insight on why it is important to set limits. When I trained at the Mayo Clinic, we used to send patients home with six fecal occult blood test cards to screen for colon cancer. (Patients smear stool on a card and mail it to the laboratory, where it is tested for blood; if blood is present, the patient needs a colonoscopy. The six card samples are taken and mailed at periodic intervals to maximize sensitivity.) What is the cost-effectiveness of the sixth card? The answer is surprising: although the cards cost only a couple of dollars, the cost per life saved is an estimated $26 million, which most would agree is more than we can afford to spend to save a life from cancer.

Why is the sixth card so expensive? If any of the first five cards shows blood, the sixth card is worthless, as it provides no new information. On the other hand, if none of the first five cards shows blood, the chance is minuscule that the sixth card will show blood that actually comes from a precancerous lesion that can be removed and save a person’s life.

This example illustrates that cost-effectiveness does not apply only to expensive new therapies like Avastin; it also applies to really inexpensive items like fecal occult blood test cards.

WHAT IS A YEAR OF LIFE WORTH?

If our own child were sick, we would say that a year’s life is worth an infinite amount of money; we would do anything we could to save our child’s life. But the job of the cost-effectiveness community is to address this question from a societal perspective, and they have a different answer. The most commonly cited view among experts in cost-effectiveness analysis is about $50,000 per quality-adjusted life-year, although it typically ranges up to $100,000.¹³

This figure has not risen with inflation, and it probably should not. If enough new technologies were developed at the threshold of $50,000 per quality-adjusted life-year, the entire budget of the country would quickly be used up.¹⁴ Making payment decisions based on a certain cost-effectiveness threshold sets no real limit on health care spending. The threshold is not meant to be a realistic number but should illustrate the kind of thinking required about how much we want to spend on health care relative to other things. The aim is to help us decide how much “bang for the buck” we should expect from our dollars spent on health care.

WHAT DO PEOPLE VALUE WHEN SETTING LIMITS?

In light of the above, how do we set limits when trying to decide what the price of life is? Might our limit-setting be changed if we are facing a desperately ill patient? Examination of questions like these reveals that people value other factors beyond just economic efficiency, as can be illustrated with a couple of theoretical policy dilemmas.

Dilemma 1: Cost-effectiveness vs fairness

Imagine that the Medicaid program decides to screen for colon cancer. They have enough money either to offer an inexpensive test (“Test 1”) to everyone and save 1,000 lives or to offer a more expensive test (“Test 2”) to half the population (selected randomly) and save 1,100 lives.

If the decision were made according to rational cost-effectiveness principles, the choice would be to go with Test 2 in half the population, as it saves 10% more lives and thus maximizes the average health of the population. However, a survey found that the option of offering Test 1 to everyone was favored by 55% of the general US public, as well as by 55% of medical ethicists and even by 45% of cost-effectiveness experts, all of whom were willing to give up some cost-effectiveness for fairness.¹⁵

This tendency to favor fairness suggests that moral considerations affect health policy decisions in important ways. Yet further analysis raises questions about the extent to which these considerations are based truly on moral values as opposed to psychological quirks.

For instance, my colleagues and I presented this same choice of colon cancer testing scenarios to a separate survey sample, and again a highly similar rate of respondents—56%—favored offering Test 1 to the full population as opposed to offering Test 2 to half the population. However, to test whether this preference for equity over efficiency persists when neither test can be offered to the entire population, we changed the scenarios for a separate group of randomly selected participants. In one version of the scenario, we told participants that only 90% of the population could receive Test 1 and only 40% could receive Test 2. (As in the original scenario, we indicated that Test 1 saves 1,000 lives, whereas Test 2 saves 1,100 lives.) With just this small variation in test availability, the proportion of respondents favoring Test 1 plummeted to 27%. Similarly, we randomly selected another group of participants to receive a third version of the scenario, in which 50% of the population could receive Test 1 and 25% could receive Test 2, saving 1,000 and 1,100 lives, respectively. Once again, the proportion of the respondents favoring Test 1 remained low (28%).¹⁶

These results suggest that people’s preference for equity versus efficiency depends, in large part, on whether the more equitable option can be offered to everyone in a population. But people’s preferences are actually not nearly that coherent. Consider a follow-up study in which we repeated the scenario again for each respondent, but with a twist.

In one group, we began with our original scenario: 100% of the population can receive Test 1, saving 1,000 lives, or 50% can receive Test 2, saving 1,100 lives. As expected, 60% of participants chose Test

1. But then we told this same group of participants that the number of people qualifying for Medicaid had doubled, so that the tests could be offered to only 50% and 25% of the population, respectively (still saving 1,000 and 1,100 lives, of course, since the population was now twice as large). Remember that when people were initially presented with this 50% versus 25% option (without any other scenario being presented first), the preference for Test 1 plummeted. In this case, however, almost no one changed their mind: the majority (60%) still favored Test 1.¹⁷

People’s preferences for how to allocate scarce health care resources—the moral values that they believe should guide our health system choices—are often disturbingly arbitrary.¹⁸

Dilemma 2: Targeting severe vs moderate illness

Now imagine a new scenario. A treatment is available that will help patients with an illness that causes severe health problems, but it provides only modest benefit. Another treatment helps patients with an illness that causes moderate health problems, and it provides considerable benefit. The cost of the two treatments is the same. How should funding be allocated?

Although a majority (60%) of survey respondents say that most funding should go toward treating the moderate illness where considerable benefit is expected, a sizeable share of people (40%) favor devoting most funding to the severe illness despite the more modest benefit.¹⁹ This is another instance where moral values seem to come into play, as a large minority will favor helping the severely ill even at the expense of efficiency.

A variation of this dilemma illustrates another salient point—that people like “easy outs.” When we present people with an additional option—“How about spending money equally between the two treatments?”—the vast majority (75%) choose that “compromise” option over the option of devoting most funds to either of the individual illnesses.¹⁹ The lesson is that we hate making difficult decisions, both as individuals and as a society.

COST-EFFECTIVENESS IS THE MOST RATIONAL AND ETHICAL WAY TO SET LIMITS

These surveys make clear that many of the moral values that people express are fragile at best or even psychological quirks. I have heard no compelling moral arguments to support treatments that cost more than $500,000 per quality-adjusted life-year, which leads me to conclude that many new medical interventions are unaffordable. The resistance to limiting such treatments is psychological and political, but it is not ethical.

The appropriate response is for third-party payors, such as Medicare and insurance companies, to let industry know that cost-effectiveness matters. If a treatment is not cost-effective, it should be limited to people who pay out of pocket or for experimental purposes. To make this happen, we need cost-effectiveness analyses of new technologies. Because such studies are expensive and time-consuming, we should develop new incentives to motivate companies to conduct such studies of their products, perhaps by extending patent protection for products that are shown to be cost-effective. We need to work with industry on how to implement such a plan. But continuing to ignore the cost-effectiveness of interventions when they come to market is harming patients who can no longer afford insurance, which has real consequences on people’s health and well-being.

By Christopher L. White, Esq

I serve as general counsel of the Advanced Medical Technology Association (AdvaMed), a Washington (DC)-based trade association that advocates on behalf of the medical device innovation community. Most of the approximately 1,600 companies we represent are small, having fewer than 100 employees. All of our member companies have a great interest in creating an environment that will sustain innovation to fuel additional benefits in patient care.

PHYSICIANS AND THE DEVICE INDUSTRY: INTERACTIONS ARE MANY, VARIED, ESSENTIAL

As noted earlier in this session by Mike Mussallem, who serves as chairman of AdvaMed’s board of directors, the medical device industry is very different from the pharmaceutical industry. Device innovation requires a great deal of collaboration with physicians in the field. Moreover, devices are not simply prescribed—they are used. That is, many of the inventions are an extension of the surgeon’s hand, such that technique influences how devices are deployed and used. As a result, with each incremental innovation, there is often a need for retraining.

Physicians wear many hats in their relationships with the medical device industry. Not only are they purchasers of products but they are collaborators, inventors, trainers, and trainees. They are also recipients of charitable contributions and of research grants. We recognize that these multiple relationships can become intertwined and, from a distance, can arouse confusion or suspicion. But simply because these relationships exist does not mean that there is a conflict of interest—there may be dualities of interest. In most cases we have a common interest and are working toward a common objective: to provide care in the best interest of the patient.

THE ADVAMED CODE OF ETHICS

The key question from industry’s perspective is how best to manage these relationships with physicians and any potential conflicts of interest. To that end, AdvaMed has developed a code of ethics to provide guidance relevant to the most common interactions between device manufacturers and health care professionals.²⁰ The AdvaMed code has been adopted by international device trade associations and embraced or cross-referenced by physician specialty societies.

Although the AdvaMed code has become a “gold standard,” it is a living document, and we are in the process of reviewing and revising it in an effort to address challenging new issues such as royalty payments, among others, which have become the focus of public questions and scrutiny.

MOVING FORWARD AFTER THE JUSTICE DEPARTMENT DEFERRED PROSECUTION AGREEMENTS

Recently, five orthopedic hip and knee implant manufacturers entered into novel deferred prosecution and non-prosecution agreements with the US Department of Justice following a Justice Department investigation into financial relationships and consulting agreements between these companies and orthopedic surgeons. The agreements include the appointment of federal monitors to review virtually every transaction that these companies have with physicians. These agreements impose a level of governmental review over the device industry that has never been seen before.

The agreements also require the five companies to disclose on their public Web sites all payments made to physicians. The disclosures must follow a specified format listing each physician’s name and location, the amount of the payments, and limited information regarding the purpose of the payments (eg, for consulting, royalties, charitable contributions, research grants). This requirement has created much interest as well as a good deal of confusion.

These developments have also spurred AdvaMed to work aggressively on federal and state legislative efforts. We are taking a proactive position on the disclosure of financial arrangements between industry and physicians in the context of the proposed Physician Payments Sunshine Act mentioned earlier by Mike Mussallem. If passed, this legislation would change the landscape by requiring that all pharmaceutical and device companies report to a single federal database all transfers of value or other payments, subject to certain exceptions, from industry to physicians. Similar to the federal agreements with the orthopedic implant manufacturers, the bill would require that the name and location of the physicians receiving payments be disclosed, along with the payment amount, but with greater context regarding the purpose of the payment. AdvaMed has been advocating for providing detailed explanations of this context so that everyone, including the public, can understand why such payments are made and how they can be beneficial.

Moderated by Lawrence K. Altman, MD

Dr. Lawrence Altman: Let us start by opening the discussion to the audience.

Comment from audience: Considerable discussion has focused on the conflict between regulation and innovation, but I find very little evidence that such a conflict actually exists. It was pointed out that the United States is by far the biggest producer and user of medical devices and has been since World War II. Economists estimate that 50% of the growth of the US economy since then has resulted directly from innovations in science and technology. During that same period, the regulatory apparatus—including the FDA—has vastly expanded. Apparently, innovation has not been stifled by regulation but actually seems to thrive in a regulated environment.

I speak often with venture capitalists who finance science technology. They know this history, and they know that regulation is inevitable. Rather than opposing it, they want clarity about regulation. For instance, many of them avoid financing human embryonic stem cell research because the rules around it are not clear, owing to the stigma and political controversy surrounding it.

Michael Mussallem: You make great points. People who invest in medical innovation would like an idea of the rules before they make investment decisions. And good, solid regulation—such as when the FDA pushes companies for the kind of science and evidence needed to clear a hurdle—is absolutely appropriate. But as regulation increases, the time and costs to bring an innovation to market increase. At the moment, the innovation equation is fragile. When too many obstacles are put in the way, the risk of failure becomes too high.

Keep in mind that the success rate in innovation is low. Although I have been in this field my entire career, it would be much easier for me to hit a major league fastball than it is to successfully innovate in medical technology. We are wrong many more times than we are right. For every success, there may be 9 failures, or 19 failures, or even 99 failures.

Rebecca Dresser: I agree that regulation sometimes does not effectively advance its goal. When that is the case, I think we need to be willing to negotiate rather than condemn; we need to show where regulation is not meeting agreed-upon goals (such as protecting patients) and figure out how to reach those goals more efficiently.

We also should keep in mind the cliché, “If professions do not adequately self-regulate, external regulation will come in.” Perhaps that is what has happened. Professionals need to self-examine and organizations need to develop voluntary standards to help avoid stupid regulation.

Christopher White: We need to be mindful of the unique relationships that we have within this niche sector of the health care industry. Issues that might not appear to threaten us directly may have unanticipated implications. Some of the barriers that regulation can impose may not be immediately perceptible and can be masked by otherwise beneficial public policies. For example, we now have a patent reform debate on Capitol Hill promoted by the information technology industry as pro-innovation, but in the context of the life sciences industry, many of the proposed patent reforms threaten innovation by devaluing device improvements.

Also, much of the regulation the device industry confronts is responsive to dynamics in the pharmaceutical industry. For example, one house of the Massachusetts legislature recently passed a bill that would ban gifts to health care professionals and require licensure of pharmaceutical and device sales representatives who work in the state. The term “gift” is defined very broadly and could include not only meals and the other things that we read about regularly but also rebates, educational grants, and training. [Editor’s note: A modified version of this legislation was signed by Massachusetts’ governor in August 2008 and will take effect January 1, 2009.]

Question from audience: As a practicing surgeon, I think the major problem lies in the area of off-label use. If one accepts that the device manufacturer is well-intentioned and living up to the AdvaMed code of ethics, the system falls apart once the device has cleared the hurdle of FDA approval for a labeled indication. The product then reaches the broad market, where it is subject to commission-based sales. Whether or not to use the device in innovative ways is generally at the discretion of the physician, until it reaches the threshold of research and institutional review board approval. We have virtually no post-market surveillance by the manufacturer. At what point is the manufacturer culpable for the off-label use of its product when patients are harmed and no surveillance exists until enough casualties occur that the problem becomes obvious?

Mr. Mussallem: Put yourself in the shoes of a physician who is facing a difficult situation that has not been studied and is outside the realm of any approved, “on-label” therapies. A classic case is for children with congenital heart defects. Since no one advances a medical device for such small patient populations, physicians treating such cases are forced to be creative. They take devices that were intended and tested for adults and apply them to a child. Do you punish those physicians? Do you punish the company that created the devices?

When you look at the question down at this level, where it becomes quite practical and quite personal, the issue of off-label use takes on a different color. In many ways, it comes down to how much we trust physicians and to what extent we think they should be regulated. I would want to give physicians the freedom to try to do what is best for their patients and to use their judgment to apply a device in a different way—one that they understand has not been tested or approved for that use. But I would also want transparency: I would want them to explain to the patient (or the parents) what is known and unknown about the situation. It is in the absence of that transparency that you enter dangerous ground.

Paul Lombardo: When a new law is passed or a new regulation comes down, it is usually in response to a scandal: something bad enough happened to scare everyone to death. If I were advising industry, I would tell them to go to any length to avoid the kind of scandals that we have seen that challenge the trust of the public. So I agree that transparency is critical. It is one thing to say, “I am trying to do what is best for my patients and trying new things because I do not have access to tools especially designed for children.” But when we find out that a doctor or a manufacturer has hidden data about a method of using equipment that has never been approved, and is covertly pushing that use, the predictable result is that somebody will want to regulate it.

Ms. Dresser: Of course, malpractice suits are an option, but they will cover only a few cases, generally the most extreme ones. I think the greatest need is for information gathering. The medical profession should think about how to encourage data collection for off-label use so that problems can be detected earlier than they are now. This type of data collection is also in device manufacturers’ best interest, as it helps to avoid scandal.

Another approach is to extend the patent exclusivity of products whose manufacturers conduct trials in underserved patient populations, thus providing a financial incentive to do such studies. This approach has in fact been adopted in the case of pediatric trials and for orphan diseases. Interestingly, some pediatric trials prompted by this patent extension incentive have shown that certain medications or dosages previously accepted as standard medical practice turned out to be harmful in children once they were formally studied.

Dr. Altman: What about proposals to use published literature—which also is subject to abuse—as a criterion for off-label use?

Ms. Dresser: Peer-reviewed journals do not have access to raw data, which can be manipulated in a lot of ways, so they cannot completely substitute for FDA review. Recent articles in JAMA addressed these concerns.^21,22

Comment from audience: There seems to be a misguided desire to look to our regulatory agencies to tell us how we should manage a patient. As a practicing surgeon who does minimally invasive procedures, I never look to regulatory agencies to tell me what the optimal therapy is for a patient; rather, I look to them to tell me whether a product is a therapeutic option for a patient, and then I use my judgment to decide whether it is the best option for this particular patient.

Consider how Britain’s National Institute for Clinical Excellence (NICE) has approached drug-eluting stents. They looked specifically at off-label uses of these stents and determined that the stents confer a benefit in these off-label areas, based on subgroup analysis. But then they did a cost-effectiveness analysis and determined that the benefit was not great enough to offset the cost to society based on the quality-adjusted life-years gained. Well, that may be a fine theoretical discussion, but when I am sitting in front of a 75-year-old who I think will do better with a particular device, it is hard to be concerned about whether it is on label or off label, or does or does not meet cost-effectiveness criteria.

Mr. Mussallem: This comes back to the trust that we have in our physicians. Should product manufacturers be allowed to hand out peer-reviewed journal articles? If physicians are provided with those articles, does that provide too much information for them and steer them inappropriately? Well, if physicians single-mindedly made such articles the sole basis for a treatment pattern, then it absolutely would be inappropriate, but we should give physicians a little bit of credit. Their job is to take a tremendous amount of data—everything that they have learned through their own experiences, plus journal articles and other sources—and apply it to design the best course of treatment they can for a specific patient.

If we try to overprescribe how a physician behaves, we will find it is too complex to regulate or legislate from the top. We should have a lighter hand and design incentives appropriately so that physicians are first and foremost motivated to take care of the patient. We should not try to tell them too much about exactly how to practice; after all, a large study that finds that one treatment has a 62% chance of being superior does not prove that it is the best treatment for a specific patient. You always want to preserve physician judgment.

Dr. Peter Ubel: I agree, but if we are to avoid overmanaging the day-to­day decisions that doctors make, we doctors also have to think more broadly about our responsibilities. If our duty is only to the patient in front of us, we can ignore being told that a treatment offers only a very small benefit for the cost. If we doctors say that it is not our job to be mindful of costs, then somebody is eventually going to have the job of telling us when we can and cannot use those stents, as a way to rein in costs because no one can afford insurance anymore.

For physicians to maintain more room for our judgment in influencing clinical practice, we have to remember that we are stewards not just of individual patients but of the general health care system. The cost of technology plays a huge role in driving up the cost of medical care.

Preface

By Lawrence K. Altman, MD (Moderator)

Early in the history of the United States, physicians commonly discussed medical issues in newspapers and other public forums. But a remark attributed to Osler, “Never trust anything you read in a newspaper…and if you do, immediately doubt it at once,” was used by the medical profession for decades to justify avoiding public discussion of medical issues. This retreat by physicians from the public discourse was particularly harmful in that it overlapped with the period when the public began paying for most medical research via federal research funding. Recently the medical profession has again started to discuss medical matters openly with the public, but this step has been taken reluctantly, in response to public pressure.

This resurgence in physicians’ engagement with the public has come not a moment too soon, as factors and players outside the operating room—economic forces, regulators, legislators, lawyers, and others—today may have as much influence on what goes on in US operating rooms as do the surgeons, nurses, and technicians who work there. Our panel will address some of these influences on surgical innovation from outside the operating room, touching on historical and current examples of attempts to regulate innovation as well as the points of view of device companies, investors, lawyers, government, and health economists.

By Michael A. Mussallem

I am honored to be here to represent industry. Although medical technology companies compete fiercely with one another in the marketplace, we also have a broad common interest: we want to develop innovations to help patients.

DEVICE AND DRUG DEVELOPMENT DIFFER

Discussing ethical challenges involving industry is easier in the context of pharmaceutical development, for a number of reasons. The pharmaceutical industry is so large that it tends to dominate the discussion. But medical devices, which are primarily what is involved when we speak of surgical innovation, differ from pharmaceuticals in key ways.

The physician-company relationship is central

First, medical devices are not used directly by patients but are tools for physicians, which makes the relationship between industry and physicians more closely intertwined when devices are involved.

An iterative process by nature

Second, it takes years of development and enormous sums of money before a drug is finally approved. The final product then has a market life of 10 or 20 years. In contrast, device development is an inherently iterative process. After Thomas Edison developed the light bulb, attempts to improve the product were immediate and constant: “Can the light be made softer? The bulb smaller? Can it be turned off?” The same type of continuous improvement process happens with medical devices, which typically are refined every 12 to 18 months. Occasional breakthroughs occur and open up a whole new way of thinking, but far more often device innovation is about incremental modifications and improvements.

SUCCESS BREEDS CONFLICTS…AND REGULATION

The development of medical devices is an American success story; we tend to be better at it than any other country. Our system works well and rewards risks and innovation. When technology is racing forward to address an unmet patient need, a tremendous amount of value is created in the form of patients living longer and healthier lives. People pay for that value, which can create substantial payoffs for successful innovators and companies. I believe that six of the companies in the Fortune 500 are medical device companies, and the medical device industry has a $450 billion market capitalization in total.

The medical device business is like an ecosystem with many interacting components. Someone with a bright idea puts a physician and an engineer together, starts a company, attracts some capital, and develops a product. Because they need startup money for production, they might offer physicians a share of the company and some stock options, and immediately an opportunity for conflict of interest arises.

As a result of these many interacting components and the conflicts they can create, medical device companies today are highly regulated by a long list of entities, including the Securities and Exchange Commission, the Food and Drug Administration (FDA), the Department of Justice, the Internal Revenue Service, the Environmental Protection Agency, the New York and NASDAQ stock exchanges, the Office of the Inspector General, and the Foreign Practices Act. This degree of regulation makes every part of the medical device development process more time-consuming and expensive.

LONG-TERM SUCCESS REQUIRES THAT COMPANIES SERVE PATIENTS

The motivation of medical technology companies is often called into question. Medical device companies are certainly motivated to make money, and they certainly have obligations to shareholders. But for a company to be successful for many years, it cannot be single-minded about the constituencies that it serves. Great medical device companies have employees who want to work for them, physicians who want to buy products from them, communities that welcome them, and shareholders who want to own their stock, but the primary goal is always to serve patients: if that is done really well over the long term, the company can count on those other success factors being present. To have a sustainable competitive advantage, one must think beyond the next quarter and run a highly respectable business on an ongoing basis.

It is true that there are outlier medical device companies who do not always operate with full integrity, as there are in any industry. The challenge, both for the medical technology industry and for the broader health care community, is to raise the standards and encourage everyone to operate at a highly ethical level. I refuse to believe that doing so requires pulling apart companies, engineers, scientists, and physicians. Instead, we need to find ways for these various players to engage together.

A good start may be the revised Physician Payments Sunshine Act, proposed by US Senator Charles Grassley. This legislation, which is supported by the Advanced Medical Technology Association (AdvaMed), would establish a national registry of payments made to physicians by medical device, medical supply, and pharmaceutical companies, and seems to make a lot of sense. As we move forward on this and other efforts to raise the ethical bar in health care innovation, it is important that there be a place at the table for everyone involved.

By Rebecca Dresser, JD

My comments will focus on off-label use of medical devices, which is a topic rife with ethical questions. I will begin by reviewing recent experience with drug-eluting coronary stents, which are regulated by the FDA as Class III devices, as this experience touches on many of the challenges that arise from off-label product use.

CASE STUDY: DRUG-ELUTING STENTS

The earliest coronary stents were made of bare metal. Over time, arteries treated with these stents tend to become blocked again, requiring patients to return for repeat revascularization. Drug-eluting stents were developed to extend the time that the artery stays open.

Earlier this decade, a couple of device manufacturers sought FDA approval to market their drug-eluting stents. Each manufacturer submitted data from randomized clinical trials in otherwise healthy patients with small, newly diagnosed heart blockages. The trials showed that patients who had received drug-eluting stents had reduced reclogging rates after 9 months compared with those who had received bare metal stents. Risks appeared to be similar between the two types of stents. On the basis of this evidence, the FDA approved the initial drug-eluting stents for marketing in 2003 and 2004.¹

Soon after they were approved, drug-eluting stents were being used in about 80% of patients who received coronary stents. However, although these new stents had been tested and approved for use in otherwise healthy patients with small, newly diagnosed heart blockages, about 60% of their real-world use was off label—specifically, in patients with large blockages or additional health problems such as diabetes.

Reports of adverse events with drug-eluting stents began to emerge, so the FDA issued a statement of concern in September 2006 and subsequently convened an advisory panel of outside experts to review the data and make recommendations. In January 2007, that advisory panel concluded that off-label use of drug-eluting stents is associated with an increased risk of thrombosis, death, or myocardial infarction compared with on-label use. The panel noted, however, that data on off-label use were limited and that additional studies were needed to determine optimal treatments for more complex patients.²

So research on the safety of off-label use of drug-eluting stents continues. Recent data—including studies published in the New England Journal of Medicine and JAMA earlier this year^3,4—suggest that some off-label uses are safe and effective, but much uncertainty remains.

PHYSICIANS SHOULDER THE ETHICAL BURDEN

The story of drug-eluting stents illustrates some of the issues that can arise with off-label use of devices. Currently, the FDA gives physicians discretion to prescribe approved products for uses that deviate from the products’ FDA-approved package inserts. Although the FDA is imperfect, it provides the most thorough and systematic review we have of medical product safety and efficacy. However, an FDA review typically addresses the risks and benefits of a product in only one context or patient population, which might not apply to another context or population. For instance, children and the elderly are generally not well studied in clinical trials, so off-label use of therapies is particularly common in these populations. Of course, patients can be harmed if off-label use presents unappreciated risks or does not provide an adequate benefit. Even if no adverse effects result from off-label therapy, other harms are possible: an alternative therapy might have been superior or the treatment may simply be a waste of money.

In this absence of regulation, the questions of whether and when to prescribe off label—and what the guiding ethical standards should be—fall to physicians. A few professional groups provide some guidance. The American Medical Association states that off-label use is justified when “based upon sound scientific evidence and sound medical opinion.”⁵ The American Academy of Pediatrics (AAP) has issued what is perhaps the best statement6 (although it focuses on drugs, its principles can be applied to devices as well). The AAP maintains that off-label use should be based on “sound scientific evidence, expert medical judgment, or published literature” and notes that physicians who prescribe off label have “a public and professional responsibility to assist in the systematic development of the information” about a particular off-label use. The AAP also advocates that prescribers consider discussing with patients (or their parents) the off-label status of a therapy and the degree of the therapy’s acceptance among physicians for the proposed off-label use.

SPECIFIC ETHICAL ISSUES

How to evaluate evidence about off-label use?

The justification for off-label use is not to advance knowledge but to best meet the needs of an individual patient. But how can a physician know that a therapy is best for a proposed use when it has not been through the FDA approval process for that use or for the particular type of patient at hand? Some off-label uses are supported by strong data while others are not. Physicians have the responsibility to evaluate the available evidence with integrity and to promote rigorous research when the available evidence is inadequate.

Healthy skepticism of industry promotion warranted

One problem is that the pharmaceutical and device industries are heavily involved in communicating about off-label uses of products. Since 1997, the FDA has permitted drug and device companies to engage in limited promotion of off-label product uses through distribution of “enduring materials”

such as textbook chapters and peer-reviewed articles. Industry has also been allowed to sponsor education sessions about off-label uses so long as an independent continuing medical education provider is involved in planning the sessions. The authorization for such off-label promotion expired recently, however, and was not renewed in the FDA reauthorization law passed in the fall of 2007. The FDA has since proposed a similar rule regarding off-label promotion,⁷ but it has been criticized for being a bit more lenient toward such promotion.

Concerns about off-label promotion and communication remain. Manufacturers sometimes violate the spirit of the rules that require independence, for example, through compensating physicians who speak favorably about off-label uses. Similarly, manufacturers sometimes design studies of off-label uses of therapies so that the results are especially likely to turn out favorably.

Data collection: Easier said than done

The aim of promoting information gathering and systematic research on off-label uses may be viewed as a professional duty,⁶ but in practice this duty is complicated by the question of who will pay for it. Often product manufacturers are already making plenty of money from an off-label use and therefore have little financial incentive to conduct trials to obtain FDA approval to add a new indication or population to the label. At the same time, there is very little money available in the public sector for such studies.

No consensus on patient consent

The principle of informing patients about off-label use is also controversial. Not much litigation has been brought on this issue. The few courts that have addressed it have ruled that no obligation exists to specifically inform patients of off-label status and that physicians are obliged only to inform patients about risks, anticipated benefits, and alternatives to an off-label treatment. Some writers think that most patients do not understand the concept of off-label use and that informing patients will only confuse them. Others argue that off-label uses ought to be disclosed, especially in situations involving very innovative off-label applications or when insurers may not provide coverage. Interestingly, a recent Harris Interactive poll found that about half of the US public feels that doctors should only be allowed to prescribe drugs for diseases for which they are FDA-approved.⁸

WHAT SHOULD BE DONE?

Some people argue that the regulatory approach to off-label use already works well. Others want more government oversight. Probably no one would argue that every variation from the label should be subjected to the FDA approval process. There is debate over exactly how to define an off-label use—ie, how different it must be from the approved use to legitimately warrant the “off label” title. This is similar to the question of how to define when a change in surgical technique is innovative enough to require formal evaluation.

Some argue that better postmarketing surveillance is needed to assess the effects of off-label device use in patients. Additional help could come from a 2007 amendment to federal law that strengthens requirements to make clinical trial information publicly available through clinical trial registries. This will make it difficult for sponsors to conceal unfavorable data from trials involving off-label uses. More information exchange and independent assessments of off-label uses are also needed to promote better and safer off-label use of medical devices.

By Paul A. Lombardo, PhD, JD

As a historian and a lawyer, I tend to look back to established precedents, a tendency that often leads to a conservative and cautious perspective. This kind of temperament is slow to reach sweeping conclusions, slow to push for change, and slow to believe that anything is really very new. This temperament is in stark contrast to that of the successful surgeon, who tends—again, speaking in stereotypes—to be aggressive, bold, courageous, pathbreaking, and, at the best moments, even heroic.

This contrast in temperaments may bring a different and perhaps helpful perspective to the task I have at hand—to look to the past for examples of ethical challenges in surgical innovation. In gathering these examples I was struck by how many of the foundational ethical issues that surgeons have faced over the years remain with us today.

CASE 1, 1649: ‘STANDARD OF CARE’ CONCEPT ARTICULATED

In 1649, an ordinance passed by the Massachusetts Bay Colony made it a crime to operate on a person without consent. It also stated that no person employed as a surgeon may perform any act contrary to “the known approved rules of the art” as laid out by one’s medical peers. The ordinance pointed out that this rule was meant not to discourage “the legal use of the skills of healers” but rather to inhibit those who might not be restrained from “the presumptuous arrogance of their own skill.”

This law mandated three things that are a foundation of what we think of as surgical ethics today:

• The notion of a standard of care (“the known approved rules of the art”)
• Peer review (the need to consult preoperatively with peers regarding that standard)
• Patient consent.

Interestingly, this ordinance was adopted at a time when most surgery was performed on visible pathologies or deformities, and elective surgery was all but unknown. Only about 150 years later did surgeons open a body cavity on a regular basis.

CASE 2, 1809: INNOVATION IN THE FACE OF CONDEMNATION

In 1809, Ephraim McDowell, a Kentucky surgeon, described the desperation of his patients as a motive for attempting a new procedure to fix a problem that was otherwise incurable. In his most famous case, McDowell reported visiting a woman some 60 miles from his home who thought she was pregnant but who actually had a large ovarian tumor. McDowell told her that there was no cure but invited her to come to his home if she were willing to undergo an experiment. He thought she would not make the trip, but, to his surprise, she arrived on Christmas Day in 1809.

As McDowell prepared for surgery, his nephew, who was a physician and his partner, argued that the procedure was a terrible thing to try. McDowell was also condemned from the pulpit by a preacher, who declared that the surgery was tantamount to murder if it failed.

While his patient recited psalms from the Bible, McDowell removed a 22-pound lump of tissue without anesthetic or antisepsis. The patient returned home about a month later and lived for more than 30 more years.

After having performed this oophorectomy procedure three times, McDowell deemed it less perilous than any other mode of treatment and the only certain cure for diseased ovaries. Later, surgeons in England who read about his work criticized McDowell for not explaining the operation sufficiently for others to replicate it, although he denied this charge.

In pioneering oophorectomy, McDowell did something quite innovative in the face of considerable professional and community opposition. Moreover, he took care to obtain patient consent and to include his patient in decision making.

CASE 3, MID-1800s: J.MARION SIMS AND ‘THERAPEUTIC MISCONCEPTION’

J. Marion Sims, considered the father of American gynecologic surgery, is famous not only for his technique as a surgeon but also for inventing several instruments, including the speculum. Yet he is criticized by historians and ethicists, primarily because he often performed experimental procedures on slaves, who probably were not in a position to give true consent. He kept patients as boarders for many months, doing a variety of experiments on them, and described in his writings how much pain his patients endured from his mistakes or from the prolonged operations.

Sims’ work is an example of “therapeutic misconception”: while he told his patients that he was going to cure them, he often had no idea whether he could. Thus, his patients believed that the operations were primarily for their benefit although he seems, as critical colleagues came to believe over time, to have sometimes been simply experimenting on patients who were uniquely vulnerable.

CASE 4, 1903: EARLY EXAMPLE OF MODERN INFORMED CONSENT

In contrast to the record of Sims, some 50 years later Dr. Franklin Martin described the painstaking approach he took to advising a patient who would undergo one of the first ovarian transplants, performed around 1903. Martin wrote:

I carefully explained to her the difficulties which we had to surmount…. I also clearly informed her that the operation must be looked upon entirely in the light of an experiment, and that she must be prepared to assume all responsibility with regard to failure in the outcome. Being a woman of unusual intelligence and one who was thoroughly in earnest in her efforts to regain her normal condition, these preliminaries were very easily settled.⁹

Without being required to do so, 100 years ago Martin went through a process equal to any informed consent disclosure that one might encounter today.

CASE 5, EARLY 1900s: A CALL FOR RESTRAINT IN EXPERIMENTATION

Around the same time, at the beginning of the 20th century, a surgeon writing in the Boston Medical and Surgical Journal condemned “over-confidence in the benefits to be derived from mechanical interference and an unrestrained enthusiasm for doing something tangible and heroic.”¹⁰ He urged his colleagues to “be brave enough to refrain from the mutilation and suffering caused by too late and hopeless operations.”¹⁰ He noted the habit of experimentation with new methods, arguing that advances in surgery led to a disproportionate focus on surgery as an art and too little attention to surgery as a science.

These arguments from a century ago make clear that today’s debates about the evidence required to move forward with innovative procedures are certainly not new.

CASE 6, 1913: COMPLEX INSTITUTIONAL MOTIVATIONS

In his 1913 book, The Modern Hospital: Its Inspiration, Its Architecture, Its Equipment, Its Operation, Dr. John Allen Hornsby wrote:

Benefactors of institutions, before giving their money, will want to know just what care the poor…are actually receiving at the hands of the institutions asking for their aid….Yet there must be a difference between the service given to a millionaire and a pauper, but that service should be wholly of the luxuries. The pauper need not have broiled quail and asparagus tips for dinner, and he need not have a private room with adjoining bath, with roses on every stand and the odor of perfumes scenting the room; but these extras should be the only ones that the man of millions should have that the pauper should not have; and patrons of wealth and refinement and of humanitarian instincts will give thousands annually to the institution where they know the poor are getting everything a rich man can get that is needful, where they will give begrudgingly a few paltry dollars to the institution that they know is neglecting the wants and welfare of the poor.¹¹

While this excerpt is notable for Hornsby’s eloquence in arguing for meeting a standard of care for the poor, it is just as notable for demonstrating how complex Hornsby’s motivations were. Not only should we care for the poor, but we have to do it right or the institution will not get money from the rich. In other words, “give the donors what they want.” Then, as now, it took large sums of money to run institutions, as well as to put new innovations in place. And then, as now, institutions had to grapple with complicated motives.

SAME ISSUES, NEW CONTEXTS

This historical review makes clear that the ethical issues we face today are not new. The foundational questions about the ethics of biomedical research as applied to surgery consistently revolve around consent, how thoroughly to inform patients, the use of vulnerable populations as research subjects, distinguishing between experimentation and therapy, and, of course, money and the best use of resources. Variations on these questions continue to loom for surgeons and other physicians.

By Peter A. Ubel, MD

I am a fan of innovation: my patients benefit from it every day. But I am also concerned about the cost of health care. In the Veterans Affairs health system, I see patients who cannot afford their medications and who cannot afford to get private insurance; such problems are largely due to the high cost of health care.

As an example, consider a new pharmaceutical innovation, bevacizumab (Avastin), which costs approximately $106,000 per year when used to treat lung cancer.¹² On average, the treatment leads to a 2-month increase in survival, making the cost of this intervention more than $600,000 per quality-adjusted life-year. Or consider the use of a left ventricular assist device rather than medical management for patients with congestive heart failure who are not eligible for transplantation. The estimated cost is approximately $900,000 per quality-adjusted life-year.

These examples illustrate that some benefits to patients can come at a very high cost. For this reason, I believe that we need to set limits in (ie, ration) health care. I will outline here why we need to do so and why third-party payors—both government and private insurance companies—need to consider the cost-effectiveness of health care interventions in deciding whether to pay for them. In the process, I will discuss common thresholds for defining the price of life and explore whether special moral considerations are required for life-saving treatments—ie, whether the price of life should be higher for severely ill patients.

WHY IS IT TIME TO RATION MEDICAL CARE?

Spending on health care in the United States has risen steadily in the last few decades both in real dollars and as a percentage of the gross domestic product. One important reason for setting limits on health care spending is that we have other things to spend our money on. Medicare budgets compete with tax cuts, education, military spending, homeland security, and many other national interests. Economics teaches us that we have to make difficult choices: when we spend more on health care, we have less money to spend on other things.

Cost-effectiveness analysis provides insight on why it is important to set limits. When I trained at the Mayo Clinic, we used to send patients home with six fecal occult blood test cards to screen for colon cancer. (Patients smear stool on a card and mail it to the laboratory, where it is tested for blood; if blood is present, the patient needs a colonoscopy. The six card samples are taken and mailed at periodic intervals to maximize sensitivity.) What is the cost-effectiveness of the sixth card? The answer is surprising: although the cards cost only a couple of dollars, the cost per life saved is an estimated $26 million, which most would agree is more than we can afford to spend to save a life from cancer.

Why is the sixth card so expensive? If any of the first five cards shows blood, the sixth card is worthless, as it provides no new information. On the other hand, if none of the first five cards shows blood, the chance is minuscule that the sixth card will show blood that actually comes from a precancerous lesion that can be removed and save a person’s life.

This example illustrates that cost-effectiveness does not apply only to expensive new therapies like Avastin; it also applies to really inexpensive items like fecal occult blood test cards.

WHAT IS A YEAR OF LIFE WORTH?

If our own child were sick, we would say that a year’s life is worth an infinite amount of money; we would do anything we could to save our child’s life. But the job of the cost-effectiveness community is to address this question from a societal perspective, and they have a different answer. The most commonly cited view among experts in cost-effectiveness analysis is about $50,000 per quality-adjusted life-year, although it typically ranges up to $100,000.¹³

This figure has not risen with inflation, and it probably should not. If enough new technologies were developed at the threshold of $50,000 per quality-adjusted life-year, the entire budget of the country would quickly be used up.¹⁴ Making payment decisions based on a certain cost-effectiveness threshold sets no real limit on health care spending. The threshold is not meant to be a realistic number but should illustrate the kind of thinking required about how much we want to spend on health care relative to other things. The aim is to help us decide how much “bang for the buck” we should expect from our dollars spent on health care.

WHAT DO PEOPLE VALUE WHEN SETTING LIMITS?

In light of the above, how do we set limits when trying to decide what the price of life is? Might our limit-setting be changed if we are facing a desperately ill patient? Examination of questions like these reveals that people value other factors beyond just economic efficiency, as can be illustrated with a couple of theoretical policy dilemmas.

Dilemma 1: Cost-effectiveness vs fairness

Imagine that the Medicaid program decides to screen for colon cancer. They have enough money either to offer an inexpensive test (“Test 1”) to everyone and save 1,000 lives or to offer a more expensive test (“Test 2”) to half the population (selected randomly) and save 1,100 lives.

If the decision were made according to rational cost-effectiveness principles, the choice would be to go with Test 2 in half the population, as it saves 10% more lives and thus maximizes the average health of the population. However, a survey found that the option of offering Test 1 to everyone was favored by 55% of the general US public, as well as by 55% of medical ethicists and even by 45% of cost-effectiveness experts, all of whom were willing to give up some cost-effectiveness for fairness.¹⁵

This tendency to favor fairness suggests that moral considerations affect health policy decisions in important ways. Yet further analysis raises questions about the extent to which these considerations are based truly on moral values as opposed to psychological quirks.

For instance, my colleagues and I presented this same choice of colon cancer testing scenarios to a separate survey sample, and again a highly similar rate of respondents—56%—favored offering Test 1 to the full population as opposed to offering Test 2 to half the population. However, to test whether this preference for equity over efficiency persists when neither test can be offered to the entire population, we changed the scenarios for a separate group of randomly selected participants. In one version of the scenario, we told participants that only 90% of the population could receive Test 1 and only 40% could receive Test 2. (As in the original scenario, we indicated that Test 1 saves 1,000 lives, whereas Test 2 saves 1,100 lives.) With just this small variation in test availability, the proportion of respondents favoring Test 1 plummeted to 27%. Similarly, we randomly selected another group of participants to receive a third version of the scenario, in which 50% of the population could receive Test 1 and 25% could receive Test 2, saving 1,000 and 1,100 lives, respectively. Once again, the proportion of the respondents favoring Test 1 remained low (28%).¹⁶

These results suggest that people’s preference for equity versus efficiency depends, in large part, on whether the more equitable option can be offered to everyone in a population. But people’s preferences are actually not nearly that coherent. Consider a follow-up study in which we repeated the scenario again for each respondent, but with a twist.

In one group, we began with our original scenario: 100% of the population can receive Test 1, saving 1,000 lives, or 50% can receive Test 2, saving 1,100 lives. As expected, 60% of participants chose Test

1. But then we told this same group of participants that the number of people qualifying for Medicaid had doubled, so that the tests could be offered to only 50% and 25% of the population, respectively (still saving 1,000 and 1,100 lives, of course, since the population was now twice as large). Remember that when people were initially presented with this 50% versus 25% option (without any other scenario being presented first), the preference for Test 1 plummeted. In this case, however, almost no one changed their mind: the majority (60%) still favored Test 1.¹⁷

People’s preferences for how to allocate scarce health care resources—the moral values that they believe should guide our health system choices—are often disturbingly arbitrary.¹⁸

Dilemma 2: Targeting severe vs moderate illness

Now imagine a new scenario. A treatment is available that will help patients with an illness that causes severe health problems, but it provides only modest benefit. Another treatment helps patients with an illness that causes moderate health problems, and it provides considerable benefit. The cost of the two treatments is the same. How should funding be allocated?

Although a majority (60%) of survey respondents say that most funding should go toward treating the moderate illness where considerable benefit is expected, a sizeable share of people (40%) favor devoting most funding to the severe illness despite the more modest benefit.¹⁹ This is another instance where moral values seem to come into play, as a large minority will favor helping the severely ill even at the expense of efficiency.

A variation of this dilemma illustrates another salient point—that people like “easy outs.” When we present people with an additional option—“How about spending money equally between the two treatments?”—the vast majority (75%) choose that “compromise” option over the option of devoting most funds to either of the individual illnesses.¹⁹ The lesson is that we hate making difficult decisions, both as individuals and as a society.

COST-EFFECTIVENESS IS THE MOST RATIONAL AND ETHICAL WAY TO SET LIMITS

These surveys make clear that many of the moral values that people express are fragile at best or even psychological quirks. I have heard no compelling moral arguments to support treatments that cost more than $500,000 per quality-adjusted life-year, which leads me to conclude that many new medical interventions are unaffordable. The resistance to limiting such treatments is psychological and political, but it is not ethical.

The appropriate response is for third-party payors, such as Medicare and insurance companies, to let industry know that cost-effectiveness matters. If a treatment is not cost-effective, it should be limited to people who pay out of pocket or for experimental purposes. To make this happen, we need cost-effectiveness analyses of new technologies. Because such studies are expensive and time-consuming, we should develop new incentives to motivate companies to conduct such studies of their products, perhaps by extending patent protection for products that are shown to be cost-effective. We need to work with industry on how to implement such a plan. But continuing to ignore the cost-effectiveness of interventions when they come to market is harming patients who can no longer afford insurance, which has real consequences on people’s health and well-being.

By Christopher L. White, Esq

I serve as general counsel of the Advanced Medical Technology Association (AdvaMed), a Washington (DC)-based trade association that advocates on behalf of the medical device innovation community. Most of the approximately 1,600 companies we represent are small, having fewer than 100 employees. All of our member companies have a great interest in creating an environment that will sustain innovation to fuel additional benefits in patient care.

PHYSICIANS AND THE DEVICE INDUSTRY: INTERACTIONS ARE MANY, VARIED, ESSENTIAL

As noted earlier in this session by Mike Mussallem, who serves as chairman of AdvaMed’s board of directors, the medical device industry is very different from the pharmaceutical industry. Device innovation requires a great deal of collaboration with physicians in the field. Moreover, devices are not simply prescribed—they are used. That is, many of the inventions are an extension of the surgeon’s hand, such that technique influences how devices are deployed and used. As a result, with each incremental innovation, there is often a need for retraining.

Physicians wear many hats in their relationships with the medical device industry. Not only are they purchasers of products but they are collaborators, inventors, trainers, and trainees. They are also recipients of charitable contributions and of research grants. We recognize that these multiple relationships can become intertwined and, from a distance, can arouse confusion or suspicion. But simply because these relationships exist does not mean that there is a conflict of interest—there may be dualities of interest. In most cases we have a common interest and are working toward a common objective: to provide care in the best interest of the patient.

THE ADVAMED CODE OF ETHICS

The key question from industry’s perspective is how best to manage these relationships with physicians and any potential conflicts of interest. To that end, AdvaMed has developed a code of ethics to provide guidance relevant to the most common interactions between device manufacturers and health care professionals.²⁰ The AdvaMed code has been adopted by international device trade associations and embraced or cross-referenced by physician specialty societies.

Although the AdvaMed code has become a “gold standard,” it is a living document, and we are in the process of reviewing and revising it in an effort to address challenging new issues such as royalty payments, among others, which have become the focus of public questions and scrutiny.

MOVING FORWARD AFTER THE JUSTICE DEPARTMENT DEFERRED PROSECUTION AGREEMENTS

Recently, five orthopedic hip and knee implant manufacturers entered into novel deferred prosecution and non-prosecution agreements with the US Department of Justice following a Justice Department investigation into financial relationships and consulting agreements between these companies and orthopedic surgeons. The agreements include the appointment of federal monitors to review virtually every transaction that these companies have with physicians. These agreements impose a level of governmental review over the device industry that has never been seen before.

The agreements also require the five companies to disclose on their public Web sites all payments made to physicians. The disclosures must follow a specified format listing each physician’s name and location, the amount of the payments, and limited information regarding the purpose of the payments (eg, for consulting, royalties, charitable contributions, research grants). This requirement has created much interest as well as a good deal of confusion.

These developments have also spurred AdvaMed to work aggressively on federal and state legislative efforts. We are taking a proactive position on the disclosure of financial arrangements between industry and physicians in the context of the proposed Physician Payments Sunshine Act mentioned earlier by Mike Mussallem. If passed, this legislation would change the landscape by requiring that all pharmaceutical and device companies report to a single federal database all transfers of value or other payments, subject to certain exceptions, from industry to physicians. Similar to the federal agreements with the orthopedic implant manufacturers, the bill would require that the name and location of the physicians receiving payments be disclosed, along with the payment amount, but with greater context regarding the purpose of the payment. AdvaMed has been advocating for providing detailed explanations of this context so that everyone, including the public, can understand why such payments are made and how they can be beneficial.

Moderated by Lawrence K. Altman, MD

Dr. Lawrence Altman: Let us start by opening the discussion to the audience.

Comment from audience: Considerable discussion has focused on the conflict between regulation and innovation, but I find very little evidence that such a conflict actually exists. It was pointed out that the United States is by far the biggest producer and user of medical devices and has been since World War II. Economists estimate that 50% of the growth of the US economy since then has resulted directly from innovations in science and technology. During that same period, the regulatory apparatus—including the FDA—has vastly expanded. Apparently, innovation has not been stifled by regulation but actually seems to thrive in a regulated environment.

I speak often with venture capitalists who finance science technology. They know this history, and they know that regulation is inevitable. Rather than opposing it, they want clarity about regulation. For instance, many of them avoid financing human embryonic stem cell research because the rules around it are not clear, owing to the stigma and political controversy surrounding it.

Michael Mussallem: You make great points. People who invest in medical innovation would like an idea of the rules before they make investment decisions. And good, solid regulation—such as when the FDA pushes companies for the kind of science and evidence needed to clear a hurdle—is absolutely appropriate. But as regulation increases, the time and costs to bring an innovation to market increase. At the moment, the innovation equation is fragile. When too many obstacles are put in the way, the risk of failure becomes too high.

Keep in mind that the success rate in innovation is low. Although I have been in this field my entire career, it would be much easier for me to hit a major league fastball than it is to successfully innovate in medical technology. We are wrong many more times than we are right. For every success, there may be 9 failures, or 19 failures, or even 99 failures.

Rebecca Dresser: I agree that regulation sometimes does not effectively advance its goal. When that is the case, I think we need to be willing to negotiate rather than condemn; we need to show where regulation is not meeting agreed-upon goals (such as protecting patients) and figure out how to reach those goals more efficiently.

We also should keep in mind the cliché, “If professions do not adequately self-regulate, external regulation will come in.” Perhaps that is what has happened. Professionals need to self-examine and organizations need to develop voluntary standards to help avoid stupid regulation.

Christopher White: We need to be mindful of the unique relationships that we have within this niche sector of the health care industry. Issues that might not appear to threaten us directly may have unanticipated implications. Some of the barriers that regulation can impose may not be immediately perceptible and can be masked by otherwise beneficial public policies. For example, we now have a patent reform debate on Capitol Hill promoted by the information technology industry as pro-innovation, but in the context of the life sciences industry, many of the proposed patent reforms threaten innovation by devaluing device improvements.

Also, much of the regulation the device industry confronts is responsive to dynamics in the pharmaceutical industry. For example, one house of the Massachusetts legislature recently passed a bill that would ban gifts to health care professionals and require licensure of pharmaceutical and device sales representatives who work in the state. The term “gift” is defined very broadly and could include not only meals and the other things that we read about regularly but also rebates, educational grants, and training. [Editor’s note: A modified version of this legislation was signed by Massachusetts’ governor in August 2008 and will take effect January 1, 2009.]

Question from audience: As a practicing surgeon, I think the major problem lies in the area of off-label use. If one accepts that the device manufacturer is well-intentioned and living up to the AdvaMed code of ethics, the system falls apart once the device has cleared the hurdle of FDA approval for a labeled indication. The product then reaches the broad market, where it is subject to commission-based sales. Whether or not to use the device in innovative ways is generally at the discretion of the physician, until it reaches the threshold of research and institutional review board approval. We have virtually no post-market surveillance by the manufacturer. At what point is the manufacturer culpable for the off-label use of its product when patients are harmed and no surveillance exists until enough casualties occur that the problem becomes obvious?

Mr. Mussallem: Put yourself in the shoes of a physician who is facing a difficult situation that has not been studied and is outside the realm of any approved, “on-label” therapies. A classic case is for children with congenital heart defects. Since no one advances a medical device for such small patient populations, physicians treating such cases are forced to be creative. They take devices that were intended and tested for adults and apply them to a child. Do you punish those physicians? Do you punish the company that created the devices?

When you look at the question down at this level, where it becomes quite practical and quite personal, the issue of off-label use takes on a different color. In many ways, it comes down to how much we trust physicians and to what extent we think they should be regulated. I would want to give physicians the freedom to try to do what is best for their patients and to use their judgment to apply a device in a different way—one that they understand has not been tested or approved for that use. But I would also want transparency: I would want them to explain to the patient (or the parents) what is known and unknown about the situation. It is in the absence of that transparency that you enter dangerous ground.

Paul Lombardo: When a new law is passed or a new regulation comes down, it is usually in response to a scandal: something bad enough happened to scare everyone to death. If I were advising industry, I would tell them to go to any length to avoid the kind of scandals that we have seen that challenge the trust of the public. So I agree that transparency is critical. It is one thing to say, “I am trying to do what is best for my patients and trying new things because I do not have access to tools especially designed for children.” But when we find out that a doctor or a manufacturer has hidden data about a method of using equipment that has never been approved, and is covertly pushing that use, the predictable result is that somebody will want to regulate it.

Ms. Dresser: Of course, malpractice suits are an option, but they will cover only a few cases, generally the most extreme ones. I think the greatest need is for information gathering. The medical profession should think about how to encourage data collection for off-label use so that problems can be detected earlier than they are now. This type of data collection is also in device manufacturers’ best interest, as it helps to avoid scandal.

Another approach is to extend the patent exclusivity of products whose manufacturers conduct trials in underserved patient populations, thus providing a financial incentive to do such studies. This approach has in fact been adopted in the case of pediatric trials and for orphan diseases. Interestingly, some pediatric trials prompted by this patent extension incentive have shown that certain medications or dosages previously accepted as standard medical practice turned out to be harmful in children once they were formally studied.

Dr. Altman: What about proposals to use published literature—which also is subject to abuse—as a criterion for off-label use?

Ms. Dresser: Peer-reviewed journals do not have access to raw data, which can be manipulated in a lot of ways, so they cannot completely substitute for FDA review. Recent articles in JAMA addressed these concerns.^21,22

Comment from audience: There seems to be a misguided desire to look to our regulatory agencies to tell us how we should manage a patient. As a practicing surgeon who does minimally invasive procedures, I never look to regulatory agencies to tell me what the optimal therapy is for a patient; rather, I look to them to tell me whether a product is a therapeutic option for a patient, and then I use my judgment to decide whether it is the best option for this particular patient.

Consider how Britain’s National Institute for Clinical Excellence (NICE) has approached drug-eluting stents. They looked specifically at off-label uses of these stents and determined that the stents confer a benefit in these off-label areas, based on subgroup analysis. But then they did a cost-effectiveness analysis and determined that the benefit was not great enough to offset the cost to society based on the quality-adjusted life-years gained. Well, that may be a fine theoretical discussion, but when I am sitting in front of a 75-year-old who I think will do better with a particular device, it is hard to be concerned about whether it is on label or off label, or does or does not meet cost-effectiveness criteria.

Mr. Mussallem: This comes back to the trust that we have in our physicians. Should product manufacturers be allowed to hand out peer-reviewed journal articles? If physicians are provided with those articles, does that provide too much information for them and steer them inappropriately? Well, if physicians single-mindedly made such articles the sole basis for a treatment pattern, then it absolutely would be inappropriate, but we should give physicians a little bit of credit. Their job is to take a tremendous amount of data—everything that they have learned through their own experiences, plus journal articles and other sources—and apply it to design the best course of treatment they can for a specific patient.

If we try to overprescribe how a physician behaves, we will find it is too complex to regulate or legislate from the top. We should have a lighter hand and design incentives appropriately so that physicians are first and foremost motivated to take care of the patient. We should not try to tell them too much about exactly how to practice; after all, a large study that finds that one treatment has a 62% chance of being superior does not prove that it is the best treatment for a specific patient. You always want to preserve physician judgment.

Dr. Peter Ubel: I agree, but if we are to avoid overmanaging the day-to­day decisions that doctors make, we doctors also have to think more broadly about our responsibilities. If our duty is only to the patient in front of us, we can ignore being told that a treatment offers only a very small benefit for the cost. If we doctors say that it is not our job to be mindful of costs, then somebody is eventually going to have the job of telling us when we can and cannot use those stents, as a way to rein in costs because no one can afford insurance anymore.

For physicians to maintain more room for our judgment in influencing clinical practice, we have to remember that we are stewards not just of individual patients but of the general health care system. The cost of technology plays a huge role in driving up the cost of medical care.