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Hundreds of new – but noninnovative – drugs have been approved in the United States in the last 20 years using expedited review programs designed especially to push forward first-in-class agents for unmet medical needs.
An extensive review of publicly available Food and Drug Administration records also concluded that few of these drugs rely on the more rigorous clinical trials intended to screen out ineffectively or potentially harmful drugs – potentially increasing the availability of poorly investigated agents that may or may not provide much clinical benefit*.
“These data have important implications for patient care,” Dr. Aaron S. Kesselheim and his colleagues wrote (BMJ 2015;351:h4679 doi: 10.1136/bmj.h4679).
“Special regulatory designations allow drugs to be approved at earlier stages based on less rigorous clinical testing; for example, one review showed drugs with orphan designations or granted accelerated approval are also more likely than drugs without these designations to be tested in single-arm studies without placebo or active comparators,” said Dr. Kesselheim of Harvard University and his coinvestigators. “While many physicians and patients trust that FDA-approved products are effective and safe for use, products approved on the basis of more limited data are at greater risk for later changes to their effectiveness or safety profiles.”
A twin study, published in the same issue, found that a lesser class of evidence often supports the approval of supplemental indications. Of 295 supplemental indications approved since 2005, only about one-third were based on trials with active comparators. The rest used nonclinical endpoints like historical controls and biomarkers or imaging data.
Most striking of all, most of the supplemental indications were aimed at pediatric patients, and many extrapolated adult evidence to these young patients, said the authors.
“Although we do not conclude that any of these approvals were mistaken, pediatric patients have unique physiologies and pharmacokinetic characteristics that may require more rigorous trials to confirm both the efficacy and the safety of drugs previously approved only for use in adults.”
Study 1: Expedited review
The authors used the Drugs@FDA database, FDA annual reports, and the Federal Register to identify 774 new agents representing first-in-class agents. Overall, this accounted for a significant increase of 2.6% per year in the number of expedited review and approval programs for each new agent (rate ratio, 1.06) and a 2.4% increase per year in the proportion of agents involved in at least one of these programs. Many approvals were associated with more than one program, and this proportion increased over the study period, from a low of 0.54 in 1987 to a high of 1.72 in 2014.
“Driving this trend was an increase in the proportion of approved, non–first-in-class drugs,” associated with at least one [expedited] program,” the authors noted.
Additionally, not all of the drugs could reasonably be considered as treatments for an urgent, unmet medical need. “For example, bimatoprost (Latisse: Allergan, Dublin) was granted priority review when it was first approved in 2008 for hypotrichosis of the eyelids, a clearly less serious condition.”
While the “breakthrough therapy” pathway was intended for only a handful of drug approvals each year, the FDA received nearly 250 applications in the first 2 years; 68 of these were granted, despite the agency’s prediction than only 2-4 such applications would be approved.
Four of these were for chronic lymphocytic anemia alone – a number the authors suggested might be excessive. “It is doubtful that a single disease condition can be the subject of four true ‘breakthroughs’ in such a short time frame.”
The situation is likely to accelerate, they noted. The 21st Century Cures Act, passed in July by the U.S. House of Representatives, instructs the FDA to develop a new pathway for repurposing approved drugs on the basis of early stage investigators and “high-risk, high-reward research. ... The FDA would also be permitted to approve such indications on the basis of only summaries of data in such circumstances, rather than being required to review the data in detail.”
New antibiotics and antifungals would have particularly lenient evidence requirements, according to the investigators.
However, expedited review is a double-edged sword, the paper noted. An FDA review found that most cancer drugs are later found to be safe and effective in postapproval studies, although such studies are often delayed or – in some cases – never conducted.
The FDA should be granted more authority to punish manufacturers who lag behind these requirements, including having the ability to impose fines and even suspend approval until additional studies are complete, the investigators said.
Study 2: Approval evidence for supplemental indications
The second study concluded that the FDA increasingly approves supplemental indications with less than level I evidence (randomized, controlled trials with placebo or active comparator (BMJ. 2015;351:h4679. doi: 10.1136/bmj.h4679).
Of an examined 295 such approvals since 2005, the largest portion was for oncology (27%). Other indications were infectious disease (15%); cardiovascular disease and prevention (12%); psychiatry (12%); musculoskeletal and rheumatology (10%); neurology (8%); gastroenterology (6%); and other (1%). Orphan drug status accounted for 20% of the approvals.
Only 30% of modified indications were supported by efficacy trials with active comparators. Level I evidence supported half of modified use approvals and 11% of approvals expanding the patient population. Almost all of the expansion approvals were into pediatric populations, and the vast majority (94%) of evidence for those was extrapolated from adult clinical trials.
Uncontrolled trials supported 34% of expanded population approvals, and nine (14%) of these supplemental approvals had no trials with clinical endpoints.
Findings were similar with other approval pathways. Among new indications, 32% had clinical endpoints, as did 30% of modified indications. Only 22% of expanded population indications rested on clinical endpoint data.
“Clinical outcomes were most often used in trials supporting supplemental indication approvals of neurologic (48%) and infectious disease drugs (45%); by contrast, 70% of oncology supplemental indications were supported exclusively by trials using surrogate outcomes.”
Uncontrolled trials supported one-third of expanded population supplements; 14% of these had no clinical trial evidence. Similarly, one-third of orphan drug indications were supported by uncontrolled or historical cohort studies. Significantly fewer orphan than nonorphan approvals were supported by clinical trials (18% vs. 35%).
Again, the situation is likely to accelerate. The Best Pharmaceuticals for Children Act provides up to 6 months of additional market exclusivity for a new approval, “which can be extremely lucrative for the sponsor,” the authors noted. The 21st Century Cures Act will also play into the situation, they said.
“The high degree of heterogeneity of supporting evidence for supplemental indications, in the setting of legislation promoting drug approvals based on decreasing evidentiary standards, underscores the need for a robust system of postapproval drug monitoring for efficacy and safety, timely confirmatory studies, and reexamination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”
Both studies were supported in part by the Greenwall Faculty Scholars Program in bioethics and the Harvard program in therapeutic science. Dr. Kesselheim and his coinvestigators had no financial disclosures.
On Twitter @alz_gal
*Correction, 9/24/2015: An earlier version of this article misstated the review's findings.
The FDA provides too many expanded drug indications with too little supporting research.
Independent examinations of the agency’s records, including the two studies by Dr. Aaron S. Kesselheim and colleagues, are finding that up to 90% of these approvals provide few or no advantages for patients. The FDA’s flexible criteria and low threshold for approval do not reward more research for breakthroughs but instead reward more research for minor variations that can clear this low threshold.
Patients and doctors have clamored for expedited approval pathways that allow clinical access to new drugs sooner – a process that also generates revenue for drug companies to fund more breakthrough research. But faster approval means taking less time to prove these drugs safe and effective for their new indications. And in an age when prescription drugs are the fourth-leading cause of death in the United States and the third-leading cause in Europe, according to some reports, this doesn’t seem to be a wise move.
Expedited trials – and approvals based on nonclinical data – are incapable of providing patients or doctors with valid information on what new clinical benefits a drug provides.
Patients and doctors must trust the FDA to live up to its claims of providing drugs that work not only for their approved indications, but help more than they harm. But its expedited approval processes only require, in most cases, that the drugs provide “nonzero” levels of effectiveness.
The United States and other countries need an alternative paradigm – one in which research focuses on better medicines for patients rather than for profits, where clinical trials with low risk of bias look for real benefits and faithfully report harms.
Dr. Donald W. Light, an osteopathic physician at Rowan University, Cherry Hill, N.J., and Dr. Joel Lexchin of the School of Health Policy and Management at York University in Toronto made these comments in an accompanying editorial (BMJ 2015;351:h4897). They had no disclosures.
The FDA provides too many expanded drug indications with too little supporting research.
Independent examinations of the agency’s records, including the two studies by Dr. Aaron S. Kesselheim and colleagues, are finding that up to 90% of these approvals provide few or no advantages for patients. The FDA’s flexible criteria and low threshold for approval do not reward more research for breakthroughs but instead reward more research for minor variations that can clear this low threshold.
Patients and doctors have clamored for expedited approval pathways that allow clinical access to new drugs sooner – a process that also generates revenue for drug companies to fund more breakthrough research. But faster approval means taking less time to prove these drugs safe and effective for their new indications. And in an age when prescription drugs are the fourth-leading cause of death in the United States and the third-leading cause in Europe, according to some reports, this doesn’t seem to be a wise move.
Expedited trials – and approvals based on nonclinical data – are incapable of providing patients or doctors with valid information on what new clinical benefits a drug provides.
Patients and doctors must trust the FDA to live up to its claims of providing drugs that work not only for their approved indications, but help more than they harm. But its expedited approval processes only require, in most cases, that the drugs provide “nonzero” levels of effectiveness.
The United States and other countries need an alternative paradigm – one in which research focuses on better medicines for patients rather than for profits, where clinical trials with low risk of bias look for real benefits and faithfully report harms.
Dr. Donald W. Light, an osteopathic physician at Rowan University, Cherry Hill, N.J., and Dr. Joel Lexchin of the School of Health Policy and Management at York University in Toronto made these comments in an accompanying editorial (BMJ 2015;351:h4897). They had no disclosures.
The FDA provides too many expanded drug indications with too little supporting research.
Independent examinations of the agency’s records, including the two studies by Dr. Aaron S. Kesselheim and colleagues, are finding that up to 90% of these approvals provide few or no advantages for patients. The FDA’s flexible criteria and low threshold for approval do not reward more research for breakthroughs but instead reward more research for minor variations that can clear this low threshold.
Patients and doctors have clamored for expedited approval pathways that allow clinical access to new drugs sooner – a process that also generates revenue for drug companies to fund more breakthrough research. But faster approval means taking less time to prove these drugs safe and effective for their new indications. And in an age when prescription drugs are the fourth-leading cause of death in the United States and the third-leading cause in Europe, according to some reports, this doesn’t seem to be a wise move.
Expedited trials – and approvals based on nonclinical data – are incapable of providing patients or doctors with valid information on what new clinical benefits a drug provides.
Patients and doctors must trust the FDA to live up to its claims of providing drugs that work not only for their approved indications, but help more than they harm. But its expedited approval processes only require, in most cases, that the drugs provide “nonzero” levels of effectiveness.
The United States and other countries need an alternative paradigm – one in which research focuses on better medicines for patients rather than for profits, where clinical trials with low risk of bias look for real benefits and faithfully report harms.
Dr. Donald W. Light, an osteopathic physician at Rowan University, Cherry Hill, N.J., and Dr. Joel Lexchin of the School of Health Policy and Management at York University in Toronto made these comments in an accompanying editorial (BMJ 2015;351:h4897). They had no disclosures.
Hundreds of new – but noninnovative – drugs have been approved in the United States in the last 20 years using expedited review programs designed especially to push forward first-in-class agents for unmet medical needs.
An extensive review of publicly available Food and Drug Administration records also concluded that few of these drugs rely on the more rigorous clinical trials intended to screen out ineffectively or potentially harmful drugs – potentially increasing the availability of poorly investigated agents that may or may not provide much clinical benefit*.
“These data have important implications for patient care,” Dr. Aaron S. Kesselheim and his colleagues wrote (BMJ 2015;351:h4679 doi: 10.1136/bmj.h4679).
“Special regulatory designations allow drugs to be approved at earlier stages based on less rigorous clinical testing; for example, one review showed drugs with orphan designations or granted accelerated approval are also more likely than drugs without these designations to be tested in single-arm studies without placebo or active comparators,” said Dr. Kesselheim of Harvard University and his coinvestigators. “While many physicians and patients trust that FDA-approved products are effective and safe for use, products approved on the basis of more limited data are at greater risk for later changes to their effectiveness or safety profiles.”
A twin study, published in the same issue, found that a lesser class of evidence often supports the approval of supplemental indications. Of 295 supplemental indications approved since 2005, only about one-third were based on trials with active comparators. The rest used nonclinical endpoints like historical controls and biomarkers or imaging data.
Most striking of all, most of the supplemental indications were aimed at pediatric patients, and many extrapolated adult evidence to these young patients, said the authors.
“Although we do not conclude that any of these approvals were mistaken, pediatric patients have unique physiologies and pharmacokinetic characteristics that may require more rigorous trials to confirm both the efficacy and the safety of drugs previously approved only for use in adults.”
Study 1: Expedited review
The authors used the Drugs@FDA database, FDA annual reports, and the Federal Register to identify 774 new agents representing first-in-class agents. Overall, this accounted for a significant increase of 2.6% per year in the number of expedited review and approval programs for each new agent (rate ratio, 1.06) and a 2.4% increase per year in the proportion of agents involved in at least one of these programs. Many approvals were associated with more than one program, and this proportion increased over the study period, from a low of 0.54 in 1987 to a high of 1.72 in 2014.
“Driving this trend was an increase in the proportion of approved, non–first-in-class drugs,” associated with at least one [expedited] program,” the authors noted.
Additionally, not all of the drugs could reasonably be considered as treatments for an urgent, unmet medical need. “For example, bimatoprost (Latisse: Allergan, Dublin) was granted priority review when it was first approved in 2008 for hypotrichosis of the eyelids, a clearly less serious condition.”
While the “breakthrough therapy” pathway was intended for only a handful of drug approvals each year, the FDA received nearly 250 applications in the first 2 years; 68 of these were granted, despite the agency’s prediction than only 2-4 such applications would be approved.
Four of these were for chronic lymphocytic anemia alone – a number the authors suggested might be excessive. “It is doubtful that a single disease condition can be the subject of four true ‘breakthroughs’ in such a short time frame.”
The situation is likely to accelerate, they noted. The 21st Century Cures Act, passed in July by the U.S. House of Representatives, instructs the FDA to develop a new pathway for repurposing approved drugs on the basis of early stage investigators and “high-risk, high-reward research. ... The FDA would also be permitted to approve such indications on the basis of only summaries of data in such circumstances, rather than being required to review the data in detail.”
New antibiotics and antifungals would have particularly lenient evidence requirements, according to the investigators.
However, expedited review is a double-edged sword, the paper noted. An FDA review found that most cancer drugs are later found to be safe and effective in postapproval studies, although such studies are often delayed or – in some cases – never conducted.
The FDA should be granted more authority to punish manufacturers who lag behind these requirements, including having the ability to impose fines and even suspend approval until additional studies are complete, the investigators said.
Study 2: Approval evidence for supplemental indications
The second study concluded that the FDA increasingly approves supplemental indications with less than level I evidence (randomized, controlled trials with placebo or active comparator (BMJ. 2015;351:h4679. doi: 10.1136/bmj.h4679).
Of an examined 295 such approvals since 2005, the largest portion was for oncology (27%). Other indications were infectious disease (15%); cardiovascular disease and prevention (12%); psychiatry (12%); musculoskeletal and rheumatology (10%); neurology (8%); gastroenterology (6%); and other (1%). Orphan drug status accounted for 20% of the approvals.
Only 30% of modified indications were supported by efficacy trials with active comparators. Level I evidence supported half of modified use approvals and 11% of approvals expanding the patient population. Almost all of the expansion approvals were into pediatric populations, and the vast majority (94%) of evidence for those was extrapolated from adult clinical trials.
Uncontrolled trials supported 34% of expanded population approvals, and nine (14%) of these supplemental approvals had no trials with clinical endpoints.
Findings were similar with other approval pathways. Among new indications, 32% had clinical endpoints, as did 30% of modified indications. Only 22% of expanded population indications rested on clinical endpoint data.
“Clinical outcomes were most often used in trials supporting supplemental indication approvals of neurologic (48%) and infectious disease drugs (45%); by contrast, 70% of oncology supplemental indications were supported exclusively by trials using surrogate outcomes.”
Uncontrolled trials supported one-third of expanded population supplements; 14% of these had no clinical trial evidence. Similarly, one-third of orphan drug indications were supported by uncontrolled or historical cohort studies. Significantly fewer orphan than nonorphan approvals were supported by clinical trials (18% vs. 35%).
Again, the situation is likely to accelerate. The Best Pharmaceuticals for Children Act provides up to 6 months of additional market exclusivity for a new approval, “which can be extremely lucrative for the sponsor,” the authors noted. The 21st Century Cures Act will also play into the situation, they said.
“The high degree of heterogeneity of supporting evidence for supplemental indications, in the setting of legislation promoting drug approvals based on decreasing evidentiary standards, underscores the need for a robust system of postapproval drug monitoring for efficacy and safety, timely confirmatory studies, and reexamination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”
Both studies were supported in part by the Greenwall Faculty Scholars Program in bioethics and the Harvard program in therapeutic science. Dr. Kesselheim and his coinvestigators had no financial disclosures.
On Twitter @alz_gal
*Correction, 9/24/2015: An earlier version of this article misstated the review's findings.
Hundreds of new – but noninnovative – drugs have been approved in the United States in the last 20 years using expedited review programs designed especially to push forward first-in-class agents for unmet medical needs.
An extensive review of publicly available Food and Drug Administration records also concluded that few of these drugs rely on the more rigorous clinical trials intended to screen out ineffectively or potentially harmful drugs – potentially increasing the availability of poorly investigated agents that may or may not provide much clinical benefit*.
“These data have important implications for patient care,” Dr. Aaron S. Kesselheim and his colleagues wrote (BMJ 2015;351:h4679 doi: 10.1136/bmj.h4679).
“Special regulatory designations allow drugs to be approved at earlier stages based on less rigorous clinical testing; for example, one review showed drugs with orphan designations or granted accelerated approval are also more likely than drugs without these designations to be tested in single-arm studies without placebo or active comparators,” said Dr. Kesselheim of Harvard University and his coinvestigators. “While many physicians and patients trust that FDA-approved products are effective and safe for use, products approved on the basis of more limited data are at greater risk for later changes to their effectiveness or safety profiles.”
A twin study, published in the same issue, found that a lesser class of evidence often supports the approval of supplemental indications. Of 295 supplemental indications approved since 2005, only about one-third were based on trials with active comparators. The rest used nonclinical endpoints like historical controls and biomarkers or imaging data.
Most striking of all, most of the supplemental indications were aimed at pediatric patients, and many extrapolated adult evidence to these young patients, said the authors.
“Although we do not conclude that any of these approvals were mistaken, pediatric patients have unique physiologies and pharmacokinetic characteristics that may require more rigorous trials to confirm both the efficacy and the safety of drugs previously approved only for use in adults.”
Study 1: Expedited review
The authors used the Drugs@FDA database, FDA annual reports, and the Federal Register to identify 774 new agents representing first-in-class agents. Overall, this accounted for a significant increase of 2.6% per year in the number of expedited review and approval programs for each new agent (rate ratio, 1.06) and a 2.4% increase per year in the proportion of agents involved in at least one of these programs. Many approvals were associated with more than one program, and this proportion increased over the study period, from a low of 0.54 in 1987 to a high of 1.72 in 2014.
“Driving this trend was an increase in the proportion of approved, non–first-in-class drugs,” associated with at least one [expedited] program,” the authors noted.
Additionally, not all of the drugs could reasonably be considered as treatments for an urgent, unmet medical need. “For example, bimatoprost (Latisse: Allergan, Dublin) was granted priority review when it was first approved in 2008 for hypotrichosis of the eyelids, a clearly less serious condition.”
While the “breakthrough therapy” pathway was intended for only a handful of drug approvals each year, the FDA received nearly 250 applications in the first 2 years; 68 of these were granted, despite the agency’s prediction than only 2-4 such applications would be approved.
Four of these were for chronic lymphocytic anemia alone – a number the authors suggested might be excessive. “It is doubtful that a single disease condition can be the subject of four true ‘breakthroughs’ in such a short time frame.”
The situation is likely to accelerate, they noted. The 21st Century Cures Act, passed in July by the U.S. House of Representatives, instructs the FDA to develop a new pathway for repurposing approved drugs on the basis of early stage investigators and “high-risk, high-reward research. ... The FDA would also be permitted to approve such indications on the basis of only summaries of data in such circumstances, rather than being required to review the data in detail.”
New antibiotics and antifungals would have particularly lenient evidence requirements, according to the investigators.
However, expedited review is a double-edged sword, the paper noted. An FDA review found that most cancer drugs are later found to be safe and effective in postapproval studies, although such studies are often delayed or – in some cases – never conducted.
The FDA should be granted more authority to punish manufacturers who lag behind these requirements, including having the ability to impose fines and even suspend approval until additional studies are complete, the investigators said.
Study 2: Approval evidence for supplemental indications
The second study concluded that the FDA increasingly approves supplemental indications with less than level I evidence (randomized, controlled trials with placebo or active comparator (BMJ. 2015;351:h4679. doi: 10.1136/bmj.h4679).
Of an examined 295 such approvals since 2005, the largest portion was for oncology (27%). Other indications were infectious disease (15%); cardiovascular disease and prevention (12%); psychiatry (12%); musculoskeletal and rheumatology (10%); neurology (8%); gastroenterology (6%); and other (1%). Orphan drug status accounted for 20% of the approvals.
Only 30% of modified indications were supported by efficacy trials with active comparators. Level I evidence supported half of modified use approvals and 11% of approvals expanding the patient population. Almost all of the expansion approvals were into pediatric populations, and the vast majority (94%) of evidence for those was extrapolated from adult clinical trials.
Uncontrolled trials supported 34% of expanded population approvals, and nine (14%) of these supplemental approvals had no trials with clinical endpoints.
Findings were similar with other approval pathways. Among new indications, 32% had clinical endpoints, as did 30% of modified indications. Only 22% of expanded population indications rested on clinical endpoint data.
“Clinical outcomes were most often used in trials supporting supplemental indication approvals of neurologic (48%) and infectious disease drugs (45%); by contrast, 70% of oncology supplemental indications were supported exclusively by trials using surrogate outcomes.”
Uncontrolled trials supported one-third of expanded population supplements; 14% of these had no clinical trial evidence. Similarly, one-third of orphan drug indications were supported by uncontrolled or historical cohort studies. Significantly fewer orphan than nonorphan approvals were supported by clinical trials (18% vs. 35%).
Again, the situation is likely to accelerate. The Best Pharmaceuticals for Children Act provides up to 6 months of additional market exclusivity for a new approval, “which can be extremely lucrative for the sponsor,” the authors noted. The 21st Century Cures Act will also play into the situation, they said.
“The high degree of heterogeneity of supporting evidence for supplemental indications, in the setting of legislation promoting drug approvals based on decreasing evidentiary standards, underscores the need for a robust system of postapproval drug monitoring for efficacy and safety, timely confirmatory studies, and reexamination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”
Both studies were supported in part by the Greenwall Faculty Scholars Program in bioethics and the Harvard program in therapeutic science. Dr. Kesselheim and his coinvestigators had no financial disclosures.
On Twitter @alz_gal
*Correction, 9/24/2015: An earlier version of this article misstated the review's findings.
FROM BMJ
