Elizabeth Mechcatie

All adults born between 1945 and 1965 should have a one-time blood test for hepatitis C, according to recommendations proposed by the Centers for Disease Control and Prevention.

People in this age group are being targeted because they are five times more likely to have hepatitis C virus infection than are the rest of the U.S. population. They also account for three-fourths of hepatitis C infections and deaths among U.S. adults every year, according to Dr. John Ward, director of the division of viral hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, at the CDC.

Courtesy U.S. Department of Veterans Affairs

But most of these adults, sometimes referred to as the "baby boomers," are not aware they are infected.

"We believe that by adding a one-time blood test for hepatitis C to every baby boomer’s medical checklist, we can identify hundreds of thousands of hidden infections and get these men and women the care and treatment they need to prevent life-threatening liver disease and death," Dr. Ward said during a May 18 telebriefing announcing the CDC’s proposal.

Dr. Ward explained that most people in this age group who have hepatitis C were infected decades ago when they were in their teens or 20s. Some of the possible causes of infection at that time might have been blood transfusions or other exposures in health care settings, or risky behaviors. People in the target age group may have forgotten about their risk or are not aware that they are at risk.

The CDC estimates that implementation of the one-time test for people born between 1945 and 1965 could detect infections in 800,000 people who would not otherwise be diagnosed based on the current risk-based testing strategy. This will prevent an estimated 120,000 deaths if those identified are treated appropriately. Dr. Ward compared the cost effectiveness of hepatitis C testing to that of cervical cancer or cholesterol screening.

Currently, hepatitis C testing is recommended for groups of people with known risk factors, which remains important but is missing too many infections, mostly among baby boomers, he said. The majority – about 75% – of the 3.2 million people infected with hepatitis C in the United States are not aware they are infected, and by the time they find out, they usually have irreversible liver damage. This is because hepatitis C slowly causes liver damage with few noticeable symptoms. Hepatitis C is the most common reason for liver transplants, is the leading cause of liver cancer, and is the fastest rising cause of cancer deaths, according to the CDC.

Currently, treatment for hepatitis C can cure up to 75% of patients, and those who are not cured can take precautions to reduce liver damage, such as reducing alcohol use and getting vaccinated against hepatitis A and B.

The CDC plans to issue final recommendations on testing later this year. During the briefing, Dr. Ward announced the availability of $6.5 million in funds to health departments, community health centers, and other organizations that provide testing for hepatitis and linkage to care, to expand hepatitis B and C testing. People born between 1945 and 1965, as well as intravenous drug users, people born in countries where the infection rates are known to be high, and other groups will be targeted.

The draft recommendations are open for public comment from May 22 through June 8 and are available at http://www.regulations.gov, docket number CDC-2012-0005.

All adults born between 1945 and 1965 should have a one-time blood test for hepatitis C, according to recommendations proposed by the Centers for Disease Control and Prevention.

People in this age group are being targeted because they are five times more likely to have hepatitis C virus infection than are the rest of the U.S. population. They also account for three-fourths of hepatitis C infections and deaths among U.S. adults every year, according to Dr. John Ward, director of the division of viral hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, at the CDC.

Courtesy U.S. Department of Veterans Affairs

But most of these adults, sometimes referred to as the "baby boomers," are not aware they are infected.

"We believe that by adding a one-time blood test for hepatitis C to every baby boomer’s medical checklist, we can identify hundreds of thousands of hidden infections and get these men and women the care and treatment they need to prevent life-threatening liver disease and death," Dr. Ward said during a May 18 telebriefing announcing the CDC’s proposal.

Dr. Ward explained that most people in this age group who have hepatitis C were infected decades ago when they were in their teens or 20s. Some of the possible causes of infection at that time might have been blood transfusions or other exposures in health care settings, or risky behaviors. People in the target age group may have forgotten about their risk or are not aware that they are at risk.

The CDC estimates that implementation of the one-time test for people born between 1945 and 1965 could detect infections in 800,000 people who would not otherwise be diagnosed based on the current risk-based testing strategy. This will prevent an estimated 120,000 deaths if those identified are treated appropriately. Dr. Ward compared the cost effectiveness of hepatitis C testing to that of cervical cancer or cholesterol screening.

Currently, hepatitis C testing is recommended for groups of people with known risk factors, which remains important but is missing too many infections, mostly among baby boomers, he said. The majority – about 75% – of the 3.2 million people infected with hepatitis C in the United States are not aware they are infected, and by the time they find out, they usually have irreversible liver damage. This is because hepatitis C slowly causes liver damage with few noticeable symptoms. Hepatitis C is the most common reason for liver transplants, is the leading cause of liver cancer, and is the fastest rising cause of cancer deaths, according to the CDC.

Currently, treatment for hepatitis C can cure up to 75% of patients, and those who are not cured can take precautions to reduce liver damage, such as reducing alcohol use and getting vaccinated against hepatitis A and B.

The CDC plans to issue final recommendations on testing later this year. During the briefing, Dr. Ward announced the availability of $6.5 million in funds to health departments, community health centers, and other organizations that provide testing for hepatitis and linkage to care, to expand hepatitis B and C testing. People born between 1945 and 1965, as well as intravenous drug users, people born in countries where the infection rates are known to be high, and other groups will be targeted.

The draft recommendations are open for public comment from May 22 through June 8 and are available at http://www.regulations.gov, docket number CDC-2012-0005.

All adults born between 1945 and 1965 should have a one-time blood test for hepatitis C, according to recommendations proposed by the Centers for Disease Control and Prevention.

People in this age group are being targeted because they are five times more likely to have hepatitis C virus infection than are the rest of the U.S. population. They also account for three-fourths of hepatitis C infections and deaths among U.S. adults every year, according to Dr. John Ward, director of the division of viral hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, at the CDC.

Courtesy U.S. Department of Veterans Affairs

But most of these adults, sometimes referred to as the "baby boomers," are not aware they are infected.

"We believe that by adding a one-time blood test for hepatitis C to every baby boomer’s medical checklist, we can identify hundreds of thousands of hidden infections and get these men and women the care and treatment they need to prevent life-threatening liver disease and death," Dr. Ward said during a May 18 telebriefing announcing the CDC’s proposal.

Dr. Ward explained that most people in this age group who have hepatitis C were infected decades ago when they were in their teens or 20s. Some of the possible causes of infection at that time might have been blood transfusions or other exposures in health care settings, or risky behaviors. People in the target age group may have forgotten about their risk or are not aware that they are at risk.

The CDC estimates that implementation of the one-time test for people born between 1945 and 1965 could detect infections in 800,000 people who would not otherwise be diagnosed based on the current risk-based testing strategy. This will prevent an estimated 120,000 deaths if those identified are treated appropriately. Dr. Ward compared the cost effectiveness of hepatitis C testing to that of cervical cancer or cholesterol screening.

Currently, hepatitis C testing is recommended for groups of people with known risk factors, which remains important but is missing too many infections, mostly among baby boomers, he said. The majority – about 75% – of the 3.2 million people infected with hepatitis C in the United States are not aware they are infected, and by the time they find out, they usually have irreversible liver damage. This is because hepatitis C slowly causes liver damage with few noticeable symptoms. Hepatitis C is the most common reason for liver transplants, is the leading cause of liver cancer, and is the fastest rising cause of cancer deaths, according to the CDC.

Currently, treatment for hepatitis C can cure up to 75% of patients, and those who are not cured can take precautions to reduce liver damage, such as reducing alcohol use and getting vaccinated against hepatitis A and B.

The CDC plans to issue final recommendations on testing later this year. During the briefing, Dr. Ward announced the availability of $6.5 million in funds to health departments, community health centers, and other organizations that provide testing for hepatitis and linkage to care, to expand hepatitis B and C testing. People born between 1945 and 1965, as well as intravenous drug users, people born in countries where the infection rates are known to be high, and other groups will be targeted.

The draft recommendations are open for public comment from May 22 through June 8 and are available at http://www.regulations.gov, docket number CDC-2012-0005.

UPDATED 5/19/12: Just as Sanofi-Aventis loses its exclusivity for its blockbuster drug Plavix (clopidogrel) this month, several generic formulations of the antiplatelet agent have been approved, the Food and Drug Administration announced on May 17.

In the FDA statement announcing the approval, Keith Webber, Ph.D., deputy director of the Office of Pharmaceutical Science in the FDA’s Center for Drug Evaluation and Research, referred to the importance of having effective and affordable medications available for people with chronic health conditions. “The generic products approved today will expand those options for patients,” he said.

The anticipated reduction in cost is expected to keep the drug on its perch as the leading non-aspirin antiplatelet agent, experts agree.

Dr. Sanjay Kaul said that the availability of generic clopidogrel was welcome news “especially for cost-prohibitive environments, where affordability is a major detriment to long-term treatment adherence and, consequently, an optimal benefit-risk balance,” in an interview,

“It must, however, be acknowledged that for a drug that never got the claim of superiority over aspirin, its rise to be the second highest selling pharmaceutical agent speaks more to the miracle of marketing than the miracle of medicine,” added Dr. Kaul, director of the cardiovascular diseases fellowship training program at Cedars-Sinai Heart Institute, Los Angeles. “Nonetheless, clopidogrel will continue to be the dominant oral antiplatelet agent (besides aspirin) that will be used for a broad spectrum of cardiovascular disease indications in the foreseeable future.”

Dr. Eric R. Bates, professor of internal medicine at the University of Michigan, Ann Arbor, said that it will be interesting to follow pricing trends over the next 1-2 years and to see how the availability of generic clopidogrel affects the market shares of the new entrants to the antiplatelet field, prasugrel (Effient) and ticagrelor (Brilinta). “It is possible that the large payers will require genetic or platelet function testing proof of poor clopidogrel responsiveness before they agree to pay for prasugrel or ticagrelor,” he said in an interview.

Dr. Peter Kowey, professor of medicine at Thomas Jefferson University in Philadelphia, noted that the availability of generic clopidogrel will help many patients who have a difficult time paying for the proprietary formulation, but said he has two concerns. First, “generic reproduction of cardiac drugs can expose patients to risk if the quality of the generic is compromised in any way,” he said. And second, “the availability of cheaper clopidogrel will discourage doctors from using prasugrel or ticlopidine, even though we know that those drugs are superior for the indication and may have real advantages for some of our patients.”

“As with so many things in medicine these days, economics may become the most compelling issue in drug selection and patient care – and that is not something any doctor desires,” added Dr. Kowey.

Clopidogrel, a P2Y12 platelet inhibitor taken orally once a day, is approved for the treatment of acute coronary syndrome and for patients who have had a recent myocardial infarction, recent stroke, or established peripheral artery disease. The approved indication includes the statement that clopidogrel "has been shown to reduce the combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death."

Clopidogrel was initially approved by the FDA in 1997, and has been marketed as Plavix by Sanofi-Aventis. The agent generated $5 billion in sales in 2010 alone.

Generic formulations of both the 75-mg daily dose and the 300-mg loading dose have been approved, according to the FDA.

The manufacturers of the approved 300-mg generic formulations are Dr. Reddy’s Laboratories, Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals. The manufacturers of the approved 75-mg doses are Mylan, Teva, Apotex Corporation, Aurobindo Pharma, Roxane Laboratories, Sun Pharma, and Torrent Pharmaceuticals.

The clopidogrel prescribing information includes a boxed warning about the smaller effect of clopidogrel on platelet function in people who are poor metabolizers of CYP2C19, and the higher rate of cardiovascular events in this population, when treated with recommended doses after acute coronary syndrome or percutaneous coronary intervention.

The FDA statement also points out the interactions with omeprazole (Prilosec) and esomeprazole (Nexium), which reduce the antiplatelet activity of clopidogrel, and says that these drugs should be avoided in people taking clopidogrel.

Dr. Kaul had no relevant disclosures. Dr. Bates receives advisory board honoraria from all antiplatelet manufacturers. Dr. Kowey said he serves as a consultant for Sanofi and Bristol Myers Squibb, which markets Plavix with Sanofi; he has no equity interest in those companies or any other drug company.

UPDATED 5/19/12: Just as Sanofi-Aventis loses its exclusivity for its blockbuster drug Plavix (clopidogrel) this month, several generic formulations of the antiplatelet agent have been approved, the Food and Drug Administration announced on May 17.

In the FDA statement announcing the approval, Keith Webber, Ph.D., deputy director of the Office of Pharmaceutical Science in the FDA’s Center for Drug Evaluation and Research, referred to the importance of having effective and affordable medications available for people with chronic health conditions. “The generic products approved today will expand those options for patients,” he said.

The anticipated reduction in cost is expected to keep the drug on its perch as the leading non-aspirin antiplatelet agent, experts agree.

Dr. Sanjay Kaul said that the availability of generic clopidogrel was welcome news “especially for cost-prohibitive environments, where affordability is a major detriment to long-term treatment adherence and, consequently, an optimal benefit-risk balance,” in an interview,

“It must, however, be acknowledged that for a drug that never got the claim of superiority over aspirin, its rise to be the second highest selling pharmaceutical agent speaks more to the miracle of marketing than the miracle of medicine,” added Dr. Kaul, director of the cardiovascular diseases fellowship training program at Cedars-Sinai Heart Institute, Los Angeles. “Nonetheless, clopidogrel will continue to be the dominant oral antiplatelet agent (besides aspirin) that will be used for a broad spectrum of cardiovascular disease indications in the foreseeable future.”

Dr. Eric R. Bates, professor of internal medicine at the University of Michigan, Ann Arbor, said that it will be interesting to follow pricing trends over the next 1-2 years and to see how the availability of generic clopidogrel affects the market shares of the new entrants to the antiplatelet field, prasugrel (Effient) and ticagrelor (Brilinta). “It is possible that the large payers will require genetic or platelet function testing proof of poor clopidogrel responsiveness before they agree to pay for prasugrel or ticagrelor,” he said in an interview.

Dr. Peter Kowey, professor of medicine at Thomas Jefferson University in Philadelphia, noted that the availability of generic clopidogrel will help many patients who have a difficult time paying for the proprietary formulation, but said he has two concerns. First, “generic reproduction of cardiac drugs can expose patients to risk if the quality of the generic is compromised in any way,” he said. And second, “the availability of cheaper clopidogrel will discourage doctors from using prasugrel or ticlopidine, even though we know that those drugs are superior for the indication and may have real advantages for some of our patients.”

“As with so many things in medicine these days, economics may become the most compelling issue in drug selection and patient care – and that is not something any doctor desires,” added Dr. Kowey.

Clopidogrel, a P2Y12 platelet inhibitor taken orally once a day, is approved for the treatment of acute coronary syndrome and for patients who have had a recent myocardial infarction, recent stroke, or established peripheral artery disease. The approved indication includes the statement that clopidogrel "has been shown to reduce the combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death."

Clopidogrel was initially approved by the FDA in 1997, and has been marketed as Plavix by Sanofi-Aventis. The agent generated $5 billion in sales in 2010 alone.

Generic formulations of both the 75-mg daily dose and the 300-mg loading dose have been approved, according to the FDA.

The manufacturers of the approved 300-mg generic formulations are Dr. Reddy’s Laboratories, Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals. The manufacturers of the approved 75-mg doses are Mylan, Teva, Apotex Corporation, Aurobindo Pharma, Roxane Laboratories, Sun Pharma, and Torrent Pharmaceuticals.

The clopidogrel prescribing information includes a boxed warning about the smaller effect of clopidogrel on platelet function in people who are poor metabolizers of CYP2C19, and the higher rate of cardiovascular events in this population, when treated with recommended doses after acute coronary syndrome or percutaneous coronary intervention.

The FDA statement also points out the interactions with omeprazole (Prilosec) and esomeprazole (Nexium), which reduce the antiplatelet activity of clopidogrel, and says that these drugs should be avoided in people taking clopidogrel.

Dr. Kaul had no relevant disclosures. Dr. Bates receives advisory board honoraria from all antiplatelet manufacturers. Dr. Kowey said he serves as a consultant for Sanofi and Bristol Myers Squibb, which markets Plavix with Sanofi; he has no equity interest in those companies or any other drug company.

UPDATED 5/19/12: Just as Sanofi-Aventis loses its exclusivity for its blockbuster drug Plavix (clopidogrel) this month, several generic formulations of the antiplatelet agent have been approved, the Food and Drug Administration announced on May 17.

In the FDA statement announcing the approval, Keith Webber, Ph.D., deputy director of the Office of Pharmaceutical Science in the FDA’s Center for Drug Evaluation and Research, referred to the importance of having effective and affordable medications available for people with chronic health conditions. “The generic products approved today will expand those options for patients,” he said.

The anticipated reduction in cost is expected to keep the drug on its perch as the leading non-aspirin antiplatelet agent, experts agree.

Dr. Sanjay Kaul said that the availability of generic clopidogrel was welcome news “especially for cost-prohibitive environments, where affordability is a major detriment to long-term treatment adherence and, consequently, an optimal benefit-risk balance,” in an interview,

“It must, however, be acknowledged that for a drug that never got the claim of superiority over aspirin, its rise to be the second highest selling pharmaceutical agent speaks more to the miracle of marketing than the miracle of medicine,” added Dr. Kaul, director of the cardiovascular diseases fellowship training program at Cedars-Sinai Heart Institute, Los Angeles. “Nonetheless, clopidogrel will continue to be the dominant oral antiplatelet agent (besides aspirin) that will be used for a broad spectrum of cardiovascular disease indications in the foreseeable future.”

Dr. Eric R. Bates, professor of internal medicine at the University of Michigan, Ann Arbor, said that it will be interesting to follow pricing trends over the next 1-2 years and to see how the availability of generic clopidogrel affects the market shares of the new entrants to the antiplatelet field, prasugrel (Effient) and ticagrelor (Brilinta). “It is possible that the large payers will require genetic or platelet function testing proof of poor clopidogrel responsiveness before they agree to pay for prasugrel or ticagrelor,” he said in an interview.

Dr. Peter Kowey, professor of medicine at Thomas Jefferson University in Philadelphia, noted that the availability of generic clopidogrel will help many patients who have a difficult time paying for the proprietary formulation, but said he has two concerns. First, “generic reproduction of cardiac drugs can expose patients to risk if the quality of the generic is compromised in any way,” he said. And second, “the availability of cheaper clopidogrel will discourage doctors from using prasugrel or ticlopidine, even though we know that those drugs are superior for the indication and may have real advantages for some of our patients.”

“As with so many things in medicine these days, economics may become the most compelling issue in drug selection and patient care – and that is not something any doctor desires,” added Dr. Kowey.

Clopidogrel, a P2Y12 platelet inhibitor taken orally once a day, is approved for the treatment of acute coronary syndrome and for patients who have had a recent myocardial infarction, recent stroke, or established peripheral artery disease. The approved indication includes the statement that clopidogrel "has been shown to reduce the combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death."

Clopidogrel was initially approved by the FDA in 1997, and has been marketed as Plavix by Sanofi-Aventis. The agent generated $5 billion in sales in 2010 alone.

Generic formulations of both the 75-mg daily dose and the 300-mg loading dose have been approved, according to the FDA.

The manufacturers of the approved 300-mg generic formulations are Dr. Reddy’s Laboratories, Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals. The manufacturers of the approved 75-mg doses are Mylan, Teva, Apotex Corporation, Aurobindo Pharma, Roxane Laboratories, Sun Pharma, and Torrent Pharmaceuticals.

The clopidogrel prescribing information includes a boxed warning about the smaller effect of clopidogrel on platelet function in people who are poor metabolizers of CYP2C19, and the higher rate of cardiovascular events in this population, when treated with recommended doses after acute coronary syndrome or percutaneous coronary intervention.

The FDA statement also points out the interactions with omeprazole (Prilosec) and esomeprazole (Nexium), which reduce the antiplatelet activity of clopidogrel, and says that these drugs should be avoided in people taking clopidogrel.

Dr. Kaul had no relevant disclosures. Dr. Bates receives advisory board honoraria from all antiplatelet manufacturers. Dr. Kowey said he serves as a consultant for Sanofi and Bristol Myers Squibb, which markets Plavix with Sanofi; he has no equity interest in those companies or any other drug company.

The Food and Drug Administration reviewed new drug applications significantly faster, and approved more new drugs first, than did its European and Canadian counterparts between 2001 and 2010.

These and other findings of practices at the three agencies raise question about whether speeding the review process further in the renewal of the Prescription Drug User Fee Act (PDUFA) is justified, according to Nicholas Downing, of Yale University, New Haven, Conn., and his associates. The findings were published May 16 in the New England Journal of Medicine.

Passed in 1992, PDUFA authorizes the FDA to collect fees from companies for each new drug application filed; the fees are used to speed of the review process, which includes hiring extra staff members. The law is reauthorized every 5 years, including this year (PDUFA V).

Previous renewals have identified areas of specific emphasis, such as drug safety and postmarketing surveillance (in 2007). This year, the FDA has worked with the pharmaceutical industry on how to make the new drug and biologic approval process more effective and efficient, and how to increase the number of agents approved in a single review cycle. The emphasis reflects "a response to criticism that the FDA has focused on safety at the expense of timely reviews," the researchers noted.

But their findings "contradict recent criticisms of the speed of review by the FDA and lead to question about whether the speed of the review process is justified as an emphasis for PDUFA V, particularly since the FDA continues to outpace its European and Canadian peers."

Mr. Downing and his colleagues used publicly available information from the FDA, the European Medicines Agency (EMA) and Health Canada for 2001-2010 to compare the speed of review of new prescription drugs and biologics; they excluded reformulated drugs and combination drugs (N. Engl. J. Med. 2012 May 16 [doi:10.1056/NEJMsa1200223]).

Until their review, little objective information has been available regarding the time it takes the FDA to review applications for new therapeutic agents, and how that review time compares with those of agencies in other countries, they noted.

Of the 510 applications for new drugs that were approved during this time, 225 were approved by the FDA, 186 by the EMA, and 99 by Health Canada. Of these drugs, 289 were considered unique new therapeutic agents, including 72 that were approved by all three agencies.

There were no significant differences in the therapeutic drug class reviewed or whether a priority review was used between the three agencies, with one exception: the proportion of orphan products approved by the EMA was significantly higher than that of the FDA (28% vs. almost 17%).

Of the 289 new agents, 190 were approved in the United States and in Europe. Of these, 121 64%) were approved in the United States first. Of the 154 that were approved in the United States and in Canada, 132 (86%) were first approved in the United States.

Most of the new agents were approved within a single cycle, but the rate was highest at the EMA (96%) compared with 62% at the FDA and 69% at Health Canada.

The median time to complete the first review (the number of days from the time the application was submitted to the date the agency notified the applicant of its decision) was 303 days for FDA-approved applications, 366 days for the EMA, and 352 days for Health Canada – a statistically significant difference across the agencies.

For the 72 new agents approved by all three agencies, the median time of the first review was about 100 days faster at the FDA: 254 days, compared with a median of 356 days at the EMA and 346 days at Health Canada.

The study was supported by the Pew Charitable Trusts. The authors disclosed no relevant conflicts of interest.

The Food and Drug Administration reviewed new drug applications significantly faster, and approved more new drugs first, than did its European and Canadian counterparts between 2001 and 2010.

These and other findings of practices at the three agencies raise question about whether speeding the review process further in the renewal of the Prescription Drug User Fee Act (PDUFA) is justified, according to Nicholas Downing, of Yale University, New Haven, Conn., and his associates. The findings were published May 16 in the New England Journal of Medicine.

Passed in 1992, PDUFA authorizes the FDA to collect fees from companies for each new drug application filed; the fees are used to speed of the review process, which includes hiring extra staff members. The law is reauthorized every 5 years, including this year (PDUFA V).

Previous renewals have identified areas of specific emphasis, such as drug safety and postmarketing surveillance (in 2007). This year, the FDA has worked with the pharmaceutical industry on how to make the new drug and biologic approval process more effective and efficient, and how to increase the number of agents approved in a single review cycle. The emphasis reflects "a response to criticism that the FDA has focused on safety at the expense of timely reviews," the researchers noted.

But their findings "contradict recent criticisms of the speed of review by the FDA and lead to question about whether the speed of the review process is justified as an emphasis for PDUFA V, particularly since the FDA continues to outpace its European and Canadian peers."

Mr. Downing and his colleagues used publicly available information from the FDA, the European Medicines Agency (EMA) and Health Canada for 2001-2010 to compare the speed of review of new prescription drugs and biologics; they excluded reformulated drugs and combination drugs (N. Engl. J. Med. 2012 May 16 [doi:10.1056/NEJMsa1200223]).

Until their review, little objective information has been available regarding the time it takes the FDA to review applications for new therapeutic agents, and how that review time compares with those of agencies in other countries, they noted.

Of the 510 applications for new drugs that were approved during this time, 225 were approved by the FDA, 186 by the EMA, and 99 by Health Canada. Of these drugs, 289 were considered unique new therapeutic agents, including 72 that were approved by all three agencies.

There were no significant differences in the therapeutic drug class reviewed or whether a priority review was used between the three agencies, with one exception: the proportion of orphan products approved by the EMA was significantly higher than that of the FDA (28% vs. almost 17%).

Of the 289 new agents, 190 were approved in the United States and in Europe. Of these, 121 64%) were approved in the United States first. Of the 154 that were approved in the United States and in Canada, 132 (86%) were first approved in the United States.

Most of the new agents were approved within a single cycle, but the rate was highest at the EMA (96%) compared with 62% at the FDA and 69% at Health Canada.

The median time to complete the first review (the number of days from the time the application was submitted to the date the agency notified the applicant of its decision) was 303 days for FDA-approved applications, 366 days for the EMA, and 352 days for Health Canada – a statistically significant difference across the agencies.

For the 72 new agents approved by all three agencies, the median time of the first review was about 100 days faster at the FDA: 254 days, compared with a median of 356 days at the EMA and 346 days at Health Canada.

The study was supported by the Pew Charitable Trusts. The authors disclosed no relevant conflicts of interest.

The Food and Drug Administration reviewed new drug applications significantly faster, and approved more new drugs first, than did its European and Canadian counterparts between 2001 and 2010.

These and other findings of practices at the three agencies raise question about whether speeding the review process further in the renewal of the Prescription Drug User Fee Act (PDUFA) is justified, according to Nicholas Downing, of Yale University, New Haven, Conn., and his associates. The findings were published May 16 in the New England Journal of Medicine.

Passed in 1992, PDUFA authorizes the FDA to collect fees from companies for each new drug application filed; the fees are used to speed of the review process, which includes hiring extra staff members. The law is reauthorized every 5 years, including this year (PDUFA V).

Previous renewals have identified areas of specific emphasis, such as drug safety and postmarketing surveillance (in 2007). This year, the FDA has worked with the pharmaceutical industry on how to make the new drug and biologic approval process more effective and efficient, and how to increase the number of agents approved in a single review cycle. The emphasis reflects "a response to criticism that the FDA has focused on safety at the expense of timely reviews," the researchers noted.

But their findings "contradict recent criticisms of the speed of review by the FDA and lead to question about whether the speed of the review process is justified as an emphasis for PDUFA V, particularly since the FDA continues to outpace its European and Canadian peers."

Mr. Downing and his colleagues used publicly available information from the FDA, the European Medicines Agency (EMA) and Health Canada for 2001-2010 to compare the speed of review of new prescription drugs and biologics; they excluded reformulated drugs and combination drugs (N. Engl. J. Med. 2012 May 16 [doi:10.1056/NEJMsa1200223]).

Until their review, little objective information has been available regarding the time it takes the FDA to review applications for new therapeutic agents, and how that review time compares with those of agencies in other countries, they noted.

Of the 510 applications for new drugs that were approved during this time, 225 were approved by the FDA, 186 by the EMA, and 99 by Health Canada. Of these drugs, 289 were considered unique new therapeutic agents, including 72 that were approved by all three agencies.

There were no significant differences in the therapeutic drug class reviewed or whether a priority review was used between the three agencies, with one exception: the proportion of orphan products approved by the EMA was significantly higher than that of the FDA (28% vs. almost 17%).

Of the 289 new agents, 190 were approved in the United States and in Europe. Of these, 121 64%) were approved in the United States first. Of the 154 that were approved in the United States and in Canada, 132 (86%) were first approved in the United States.

Most of the new agents were approved within a single cycle, but the rate was highest at the EMA (96%) compared with 62% at the FDA and 69% at Health Canada.

The median time to complete the first review (the number of days from the time the application was submitted to the date the agency notified the applicant of its decision) was 303 days for FDA-approved applications, 366 days for the EMA, and 352 days for Health Canada – a statistically significant difference across the agencies.

For the 72 new agents approved by all three agencies, the median time of the first review was about 100 days faster at the FDA: 254 days, compared with a median of 356 days at the EMA and 346 days at Health Canada.

The study was supported by the Pew Charitable Trusts. The authors disclosed no relevant conflicts of interest.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on May 10 supported the approval of lorcaserin, voting 18-4 with 1 abstention that the potential benefits of the centrally acting drug outweighed its potential risks as a long-term weight loss treatment in obese and overweight people.

At the meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, panelists voting in favor of approval said that although the weight loss associated with the drug in clinical trials was modest, the results were significant and met one of the FDA criteria for efficacy for a weight loss drug. Although there were some concerns about safety, the panel agreed safety could be followed after approval and recommended that the manufacturer conduct a postmarketing study evaluating cardiovascular outcomes associated with treatment and that patients be monitored for valvular heart disease with echocardiography.

The proposed indication for lorcaserin, at a dosage of 10 mg twice a day, is as an adjunct to diet and exercise for weight management in adults, with a body mass index (BMI) equal to or greater than 30 kg/m² or a BMI equal to or greater than 27 kg/m² if accompanied by weight-related comorbidities.

This is the second time the panel has met to review lorcaserin, a selective serotonin 2C receptor agonist manufactured by Arena Pharmaceuticals Inc., as a treatment for weight loss in obese adults and in overweight adults with comorbidities. At the first meeting in September 2010, the majority of the panel did not support approval, citing an unfavorable risk-benefit ratio, specifically the marginal weight loss with treatment, concerns that the study population was not representative of the real-world population of probable lorcaserin candidates, and unresolved concerns about increases in mammary tumors and astrocytomas in rats exposed to lorcaserin.

Arena resubmitted the application for approval with new data and analyses, including evaluations of rat carcinogenicity data and echocardiographic data evaluating the rate of valvulopathy associated with treatment.

The company provided 1-year data from two phase III studies of 7,190 adults, who did not have diabetes; and a phase III study of 604 patients with type 2 diabetes. Patients were overweight or obese, with BMIs from 27 to 45, and all followed a 600-calorie deficit diet, exercise program, and monthly counseling,

Compared with placebo, those treated with lorcaserin lost significantly more weight, which was associated with significant improvements in glycemic control, lipids, blood pressure, and other metabolic parameters. At 1 year, 47% of those on lorcaserin lost at least 5% of their baseline body weight, compared with 22% of those on placebo. In the study of patients with type 2 diabetes, significantly more of those on lorcaserin also lost at least 5% of their baseline body weight (37.5% vs. 16%); weight loss was associated with significant improvements in glycemic control at 1 year.

The most common side effects associated with treatment included headache, dizziness, nausea, fatigue, and dry mouth. Neuropsychiatric effects, including depression and euphoria, were also more common among those treated with lorcaserin. At 1 year of treatment, the rate of valvulopathy was 2.37% among those on lorcaserin, compared with 2.04% of those on placebo.

Several panelists agreed that the higher rate of valvulopathy associated with treatment was a signal, but they recommended that patients be monitored with echocardiography periodically during treatment to check for valvulopathy. Several panelists said they were reassured that blood pressure and heart rate remained the same or decreased in patients on the drug.

The FDA usually follows the recommendations of its advisory panels. The panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally, a panelist may be given a waiver. At this meeting, one panelist had a potential conflict (he serves on a data safety monitoring board for a competing product with an indication related to the product discussed by the panel), but was granted a waiver because his expertise was considered essential to the meeting and outweighed the potential for a conflict of interest, according to the FDA.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on May 10 supported the approval of lorcaserin, voting 18-4 with 1 abstention that the potential benefits of the centrally acting drug outweighed its potential risks as a long-term weight loss treatment in obese and overweight people.

At the meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, panelists voting in favor of approval said that although the weight loss associated with the drug in clinical trials was modest, the results were significant and met one of the FDA criteria for efficacy for a weight loss drug. Although there were some concerns about safety, the panel agreed safety could be followed after approval and recommended that the manufacturer conduct a postmarketing study evaluating cardiovascular outcomes associated with treatment and that patients be monitored for valvular heart disease with echocardiography.

The proposed indication for lorcaserin, at a dosage of 10 mg twice a day, is as an adjunct to diet and exercise for weight management in adults, with a body mass index (BMI) equal to or greater than 30 kg/m² or a BMI equal to or greater than 27 kg/m² if accompanied by weight-related comorbidities.

This is the second time the panel has met to review lorcaserin, a selective serotonin 2C receptor agonist manufactured by Arena Pharmaceuticals Inc., as a treatment for weight loss in obese adults and in overweight adults with comorbidities. At the first meeting in September 2010, the majority of the panel did not support approval, citing an unfavorable risk-benefit ratio, specifically the marginal weight loss with treatment, concerns that the study population was not representative of the real-world population of probable lorcaserin candidates, and unresolved concerns about increases in mammary tumors and astrocytomas in rats exposed to lorcaserin.

Arena resubmitted the application for approval with new data and analyses, including evaluations of rat carcinogenicity data and echocardiographic data evaluating the rate of valvulopathy associated with treatment.

The company provided 1-year data from two phase III studies of 7,190 adults, who did not have diabetes; and a phase III study of 604 patients with type 2 diabetes. Patients were overweight or obese, with BMIs from 27 to 45, and all followed a 600-calorie deficit diet, exercise program, and monthly counseling,

Compared with placebo, those treated with lorcaserin lost significantly more weight, which was associated with significant improvements in glycemic control, lipids, blood pressure, and other metabolic parameters. At 1 year, 47% of those on lorcaserin lost at least 5% of their baseline body weight, compared with 22% of those on placebo. In the study of patients with type 2 diabetes, significantly more of those on lorcaserin also lost at least 5% of their baseline body weight (37.5% vs. 16%); weight loss was associated with significant improvements in glycemic control at 1 year.

The most common side effects associated with treatment included headache, dizziness, nausea, fatigue, and dry mouth. Neuropsychiatric effects, including depression and euphoria, were also more common among those treated with lorcaserin. At 1 year of treatment, the rate of valvulopathy was 2.37% among those on lorcaserin, compared with 2.04% of those on placebo.

Several panelists agreed that the higher rate of valvulopathy associated with treatment was a signal, but they recommended that patients be monitored with echocardiography periodically during treatment to check for valvulopathy. Several panelists said they were reassured that blood pressure and heart rate remained the same or decreased in patients on the drug.

The FDA usually follows the recommendations of its advisory panels. The panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally, a panelist may be given a waiver. At this meeting, one panelist had a potential conflict (he serves on a data safety monitoring board for a competing product with an indication related to the product discussed by the panel), but was granted a waiver because his expertise was considered essential to the meeting and outweighed the potential for a conflict of interest, according to the FDA.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on May 10 supported the approval of lorcaserin, voting 18-4 with 1 abstention that the potential benefits of the centrally acting drug outweighed its potential risks as a long-term weight loss treatment in obese and overweight people.

At the meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, panelists voting in favor of approval said that although the weight loss associated with the drug in clinical trials was modest, the results were significant and met one of the FDA criteria for efficacy for a weight loss drug. Although there were some concerns about safety, the panel agreed safety could be followed after approval and recommended that the manufacturer conduct a postmarketing study evaluating cardiovascular outcomes associated with treatment and that patients be monitored for valvular heart disease with echocardiography.

The proposed indication for lorcaserin, at a dosage of 10 mg twice a day, is as an adjunct to diet and exercise for weight management in adults, with a body mass index (BMI) equal to or greater than 30 kg/m² or a BMI equal to or greater than 27 kg/m² if accompanied by weight-related comorbidities.

This is the second time the panel has met to review lorcaserin, a selective serotonin 2C receptor agonist manufactured by Arena Pharmaceuticals Inc., as a treatment for weight loss in obese adults and in overweight adults with comorbidities. At the first meeting in September 2010, the majority of the panel did not support approval, citing an unfavorable risk-benefit ratio, specifically the marginal weight loss with treatment, concerns that the study population was not representative of the real-world population of probable lorcaserin candidates, and unresolved concerns about increases in mammary tumors and astrocytomas in rats exposed to lorcaserin.

Arena resubmitted the application for approval with new data and analyses, including evaluations of rat carcinogenicity data and echocardiographic data evaluating the rate of valvulopathy associated with treatment.

The company provided 1-year data from two phase III studies of 7,190 adults, who did not have diabetes; and a phase III study of 604 patients with type 2 diabetes. Patients were overweight or obese, with BMIs from 27 to 45, and all followed a 600-calorie deficit diet, exercise program, and monthly counseling,

Compared with placebo, those treated with lorcaserin lost significantly more weight, which was associated with significant improvements in glycemic control, lipids, blood pressure, and other metabolic parameters. At 1 year, 47% of those on lorcaserin lost at least 5% of their baseline body weight, compared with 22% of those on placebo. In the study of patients with type 2 diabetes, significantly more of those on lorcaserin also lost at least 5% of their baseline body weight (37.5% vs. 16%); weight loss was associated with significant improvements in glycemic control at 1 year.

The most common side effects associated with treatment included headache, dizziness, nausea, fatigue, and dry mouth. Neuropsychiatric effects, including depression and euphoria, were also more common among those treated with lorcaserin. At 1 year of treatment, the rate of valvulopathy was 2.37% among those on lorcaserin, compared with 2.04% of those on placebo.

Several panelists agreed that the higher rate of valvulopathy associated with treatment was a signal, but they recommended that patients be monitored with echocardiography periodically during treatment to check for valvulopathy. Several panelists said they were reassured that blood pressure and heart rate remained the same or decreased in patients on the drug.

The FDA usually follows the recommendations of its advisory panels. The panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although occasionally, a panelist may be given a waiver. At this meeting, one panelist had a potential conflict (he serves on a data safety monitoring board for a competing product with an indication related to the product discussed by the panel), but was granted a waiver because his expertise was considered essential to the meeting and outweighed the potential for a conflict of interest, according to the FDA.

The Food and Drug Administration has added a warning about second-cancer risk to the label of lenalidomide, a widely used multiple myeloma drug, after a safety review lasting about 1 year.

Treatment with lenalidomide (Revlimid) for newly diagnosed multiple myeloma is associated with almost a threefold increased risk of developing secondary primary malignancies, the agency announced on May 7. The finding was based on three postapproval trials of lenalidomide as maintenance therapy in newly diagnosed patients.

"Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma," the FDA said. No increase was seen in incidence of nonmelanoma skin cancers and solid tumors.

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It noted that as of Feb. 28, 2011, a pooled analysis showed there were 65 second primary malignancies among 824 patients treated with lenalidomide vs. 19 second primary malignancies among 665 patients in treatment arms that did not include lenalidomide maintenance (7.9% vs. 2.8%, respectively; P less than .001). "The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years," the agency said.

The three studies were designed to evaluate the effect of lenalidomide as maintenance therapy, compared with placebo, after patients with newly diagnosed multiple myeloma had received initial chemotherapy or chemotherapy plus a hematopoietic stem cell transplant. A thalidomide analogue, lenalidomide is approved in combination with dexamethasone to treat patients with multiple myeloma who have been treated previously.

The FDA also analyzed data from two clinical trials that were the basis of the approval in these patients – and it also found a higher incidence of second primary malignancies with lenalidomide plus dexamethasone, compared with dexamethasone alone. A higher incidence of nonmelanoma skin cancers accounted for most of this difference, however, and the agency said this was no longer significant after adjusting for the time on treatment.

The FDA recommends that clinicians monitor patients treated with lenalidomide for the development of secondary primary malignancies, and "take into account both the potential benefit of Revlimid and the risk of second primary malignancies when considering treatment with Revlimid."

The new safety information is being added to the warnings and precautions section of the label, and to the patient Medication Guide. Clinicians encourage patients treated with lenalidomide to read the Medication Guide, a handout that is distributed with each filled prescription, including refills, the FDA said, and patients should consult their health care professionals if they have any questions or concerns.

The FDA statement is available at http://www.fda.gov/Drugs/DrugSafety/ucm302939.htm. Adverse events associated with lenalidomide should be reported to the FDA’s MedWatch program at www.fda.gov/medwatch/ or 800-332-1088.

The Food and Drug Administration has added a warning about second-cancer risk to the label of lenalidomide, a widely used multiple myeloma drug, after a safety review lasting about 1 year.

Treatment with lenalidomide (Revlimid) for newly diagnosed multiple myeloma is associated with almost a threefold increased risk of developing secondary primary malignancies, the agency announced on May 7. The finding was based on three postapproval trials of lenalidomide as maintenance therapy in newly diagnosed patients.

"Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma," the FDA said. No increase was seen in incidence of nonmelanoma skin cancers and solid tumors.

----------------------------------------------------------------------------------------------

----------------------------------------------------------------------------------------------

It noted that as of Feb. 28, 2011, a pooled analysis showed there were 65 second primary malignancies among 824 patients treated with lenalidomide vs. 19 second primary malignancies among 665 patients in treatment arms that did not include lenalidomide maintenance (7.9% vs. 2.8%, respectively; P less than .001). "The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years," the agency said.

The three studies were designed to evaluate the effect of lenalidomide as maintenance therapy, compared with placebo, after patients with newly diagnosed multiple myeloma had received initial chemotherapy or chemotherapy plus a hematopoietic stem cell transplant. A thalidomide analogue, lenalidomide is approved in combination with dexamethasone to treat patients with multiple myeloma who have been treated previously.

The FDA also analyzed data from two clinical trials that were the basis of the approval in these patients – and it also found a higher incidence of second primary malignancies with lenalidomide plus dexamethasone, compared with dexamethasone alone. A higher incidence of nonmelanoma skin cancers accounted for most of this difference, however, and the agency said this was no longer significant after adjusting for the time on treatment.

The FDA recommends that clinicians monitor patients treated with lenalidomide for the development of secondary primary malignancies, and "take into account both the potential benefit of Revlimid and the risk of second primary malignancies when considering treatment with Revlimid."

The new safety information is being added to the warnings and precautions section of the label, and to the patient Medication Guide. Clinicians encourage patients treated with lenalidomide to read the Medication Guide, a handout that is distributed with each filled prescription, including refills, the FDA said, and patients should consult their health care professionals if they have any questions or concerns.

The FDA statement is available at http://www.fda.gov/Drugs/DrugSafety/ucm302939.htm. Adverse events associated with lenalidomide should be reported to the FDA’s MedWatch program at www.fda.gov/medwatch/ or 800-332-1088.

The Food and Drug Administration has added a warning about second-cancer risk to the label of lenalidomide, a widely used multiple myeloma drug, after a safety review lasting about 1 year.

Treatment with lenalidomide (Revlimid) for newly diagnosed multiple myeloma is associated with almost a threefold increased risk of developing secondary primary malignancies, the agency announced on May 7. The finding was based on three postapproval trials of lenalidomide as maintenance therapy in newly diagnosed patients.

"Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma," the FDA said. No increase was seen in incidence of nonmelanoma skin cancers and solid tumors.

----------------------------------------------------------------------------------------------

----------------------------------------------------------------------------------------------

It noted that as of Feb. 28, 2011, a pooled analysis showed there were 65 second primary malignancies among 824 patients treated with lenalidomide vs. 19 second primary malignancies among 665 patients in treatment arms that did not include lenalidomide maintenance (7.9% vs. 2.8%, respectively; P less than .001). "The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years," the agency said.

The three studies were designed to evaluate the effect of lenalidomide as maintenance therapy, compared with placebo, after patients with newly diagnosed multiple myeloma had received initial chemotherapy or chemotherapy plus a hematopoietic stem cell transplant. A thalidomide analogue, lenalidomide is approved in combination with dexamethasone to treat patients with multiple myeloma who have been treated previously.

The FDA also analyzed data from two clinical trials that were the basis of the approval in these patients – and it also found a higher incidence of second primary malignancies with lenalidomide plus dexamethasone, compared with dexamethasone alone. A higher incidence of nonmelanoma skin cancers accounted for most of this difference, however, and the agency said this was no longer significant after adjusting for the time on treatment.

The FDA recommends that clinicians monitor patients treated with lenalidomide for the development of secondary primary malignancies, and "take into account both the potential benefit of Revlimid and the risk of second primary malignancies when considering treatment with Revlimid."

The new safety information is being added to the warnings and precautions section of the label, and to the patient Medication Guide. Clinicians encourage patients treated with lenalidomide to read the Medication Guide, a handout that is distributed with each filled prescription, including refills, the FDA said, and patients should consult their health care professionals if they have any questions or concerns.

The FDA statement is available at http://www.fda.gov/Drugs/DrugSafety/ucm302939.htm. Adverse events associated with lenalidomide should be reported to the FDA’s MedWatch program at www.fda.gov/medwatch/ or 800-332-1088.

The risk of birth defects associated with assisted reproductive technology treatments was significantly increased compared with spontaneously conceived births in a large Australian observational study, but after adjustment for parental factors, the increased risk associated with in vitro fertilization was no longer significant.

The risk of birth defects associated with intracytoplasmic sperm injection (ICSI), however, remained significantly elevated, even after adjustment for maternal age and other risk factors, reported Michael Davies, Ph.D., from the Robinson Institute and School of Pediatrics and Reproductive Health, at the University of Adelaide (Australia), and his associates.

"Although we cannot rule out the possibility that other patient factors contribute to or explain the observed associations, our findings can help provide guidance in counseling patients who are considering treatment for infertility," they added in reporting the study, which was published online May 5 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1008095). The publication coincided with Dr. Davies’ presentation of the results at the World Congress on Building Consensus in Gynecology, Infertility, and Perinatology in Barcelona.

Using different databases in South Australia, the investigators compared the risks of birth defects, including cerebral palsy, diagnosed before age 5 years, among 308,974 births in South Australia, from a census of births resulting from assisted reproductive technology (ART) treatment, a registry of births and pregnancy terminations, and birth defect registries. Of the total number of births, 6,163 resulted from ART.

As in previous studies, they found an association between ART and an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy, although they pointed out that there were no birth defects for the "large majority" of births resulting from assisted conception.

Overall, there were 513 birth defects among pregnancies resulting from assisted conception (8.3%), compared with 17,546 birth defects among those that did not involve assisted conception (5.8%) – with an unadjusted odds ratio of 1.47. After adjustment for maternal age, maternal conditions during pregnancy, and other potential confounders, the odds ratio was 1.28.

The odds ratio for birth defects associated with IVF was 1.26 in unadjusted analysis, but was only 1.07 in multivariate analysis and no longer statistically significant.

The unadjusted odds ratio for birth defects associated with ICSI was 1.77, and after adjustment for other confounding factors, the risk was 1.57, which remained significant. The authors said that it was "biologically plausible" that the effects of treatment with ICSI explain the increased risk of birth defects, but added that differences in male infertility factors that lead to the use of ICSI "may also underlie the association."

The birth defect risk was also significantly increased among women with a history of infertility but no treatment with ART, which was also found in a Danish registry study, and "implicates patient factors in this increased risk," they said.

Among the study’s other findings are the increased risk of birth defects associated with the home use of clomiphene citrate, which has also been found in previous case control studies. But the authors said that this finding should be interpreted cautiously, because of the small number of women who received this treatment, and that they could not rule out "residual confounding or chance" as an explanation.

In a statement issued by the University of Adelaide, Dr. Davies said that this group was small and the result needed to be confirmed with more research. But he added that the finding raises concerns because clomiphene citrate is widely available at a low cost, and "may easily be used contrary to manufacturers’ very specific instructions to avoid use if pregnant, as it may cause fetal malformations."

He and his associates also found a significant increase in the birth defect risk associated with fresh-embryo cycles of IVF or ICSI, but no increased risk associated with frozen-embryo cycles of either method. This finding could possibly be explained by the possibility that cryopreservation reduces the likelihood that "developmentally compromised embryos will survive the thawing process and the temporal separation of the developing embryo from exposure to hormonal stimulation drugs used early" in ART treatment, the researchers said in the study.

In a statement issued by the American Society for Reproductive Medicine (ASRM), the society’s president, Dr. Linda Giudice, said that the study "confirms what has been known for quite some time: Patients who need medical assistance to conceive have a somewhat higher risk of having children with birth defects than parents able to conceive on their own.  

"Patients considering medically assisted conception have been, and should continue to be, counseled on those risks prior to undergoing any treatment," said Dr. Giudice, distinguished professor and chair of reproductive endocrinology and infertility, and the Robert B. Jaffe, M.D. Endowed Professor in the Reproductive Sciences at the University of California, San Francisco.

In a statement issued by the Society for Assisted Reproductive Technology (SART), Dr. Glenn Schattman, the society’s president, said: "It is important to note that women with a history of infertility who did not undergo ART treatments also had a higher increase of having children with birth defects. This, combined with the finding that those using ICSI ... also had slightly elevated risks of birth defects, suggests that the underlying problem that led them to seek medical assistance in the first place is likely contributing to the elevated risk of birth defects in their children."

Dr. Schattman, an ob.gyn. and reproductive endocrinologist at Weill Medical College of Cornell University, New York, pointed out that some of the results were reassuring, including the finding that in cycles that did not involve ICSI, the adjusted odds ratio for IVF-conceived children did not show a significant difference in birth defects, and the risk of birth defects among children born after embryo freezing was not higher than the risk among naturally conceived children. "These are interesting and important findings, and we will need much more research to allow us to help patients overcome their infertility with treatments that are as safe as possible for them and the children born from the treatments," he added.

In the University of Adelaide statement, Dr. Davies said that the study needs to be expanded to include more recent years of treatment, because continuing advances in reproductive technologies may have an effect on risks associated with treatment. He also said in the statement that while previous studies have found that the risk of birth defects is increased with ARTs, this was the first study to compare all forms of ART treatments available and to compare pregnancies between women by the treatments they received.

The study was supported by grants from the National Health and Medical Research Council and the Australian Research Council. The authors said they had no relevant financial disclosures.

The risk of birth defects associated with assisted reproductive technology treatments was significantly increased compared with spontaneously conceived births in a large Australian observational study, but after adjustment for parental factors, the increased risk associated with in vitro fertilization was no longer significant.

The risk of birth defects associated with intracytoplasmic sperm injection (ICSI), however, remained significantly elevated, even after adjustment for maternal age and other risk factors, reported Michael Davies, Ph.D., from the Robinson Institute and School of Pediatrics and Reproductive Health, at the University of Adelaide (Australia), and his associates.

"Although we cannot rule out the possibility that other patient factors contribute to or explain the observed associations, our findings can help provide guidance in counseling patients who are considering treatment for infertility," they added in reporting the study, which was published online May 5 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1008095). The publication coincided with Dr. Davies’ presentation of the results at the World Congress on Building Consensus in Gynecology, Infertility, and Perinatology in Barcelona.

Using different databases in South Australia, the investigators compared the risks of birth defects, including cerebral palsy, diagnosed before age 5 years, among 308,974 births in South Australia, from a census of births resulting from assisted reproductive technology (ART) treatment, a registry of births and pregnancy terminations, and birth defect registries. Of the total number of births, 6,163 resulted from ART.

As in previous studies, they found an association between ART and an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy, although they pointed out that there were no birth defects for the "large majority" of births resulting from assisted conception.

Overall, there were 513 birth defects among pregnancies resulting from assisted conception (8.3%), compared with 17,546 birth defects among those that did not involve assisted conception (5.8%) – with an unadjusted odds ratio of 1.47. After adjustment for maternal age, maternal conditions during pregnancy, and other potential confounders, the odds ratio was 1.28.

The odds ratio for birth defects associated with IVF was 1.26 in unadjusted analysis, but was only 1.07 in multivariate analysis and no longer statistically significant.

The unadjusted odds ratio for birth defects associated with ICSI was 1.77, and after adjustment for other confounding factors, the risk was 1.57, which remained significant. The authors said that it was "biologically plausible" that the effects of treatment with ICSI explain the increased risk of birth defects, but added that differences in male infertility factors that lead to the use of ICSI "may also underlie the association."

The birth defect risk was also significantly increased among women with a history of infertility but no treatment with ART, which was also found in a Danish registry study, and "implicates patient factors in this increased risk," they said.

Among the study’s other findings are the increased risk of birth defects associated with the home use of clomiphene citrate, which has also been found in previous case control studies. But the authors said that this finding should be interpreted cautiously, because of the small number of women who received this treatment, and that they could not rule out "residual confounding or chance" as an explanation.

In a statement issued by the University of Adelaide, Dr. Davies said that this group was small and the result needed to be confirmed with more research. But he added that the finding raises concerns because clomiphene citrate is widely available at a low cost, and "may easily be used contrary to manufacturers’ very specific instructions to avoid use if pregnant, as it may cause fetal malformations."

He and his associates also found a significant increase in the birth defect risk associated with fresh-embryo cycles of IVF or ICSI, but no increased risk associated with frozen-embryo cycles of either method. This finding could possibly be explained by the possibility that cryopreservation reduces the likelihood that "developmentally compromised embryos will survive the thawing process and the temporal separation of the developing embryo from exposure to hormonal stimulation drugs used early" in ART treatment, the researchers said in the study.

In a statement issued by the American Society for Reproductive Medicine (ASRM), the society’s president, Dr. Linda Giudice, said that the study "confirms what has been known for quite some time: Patients who need medical assistance to conceive have a somewhat higher risk of having children with birth defects than parents able to conceive on their own.  

"Patients considering medically assisted conception have been, and should continue to be, counseled on those risks prior to undergoing any treatment," said Dr. Giudice, distinguished professor and chair of reproductive endocrinology and infertility, and the Robert B. Jaffe, M.D. Endowed Professor in the Reproductive Sciences at the University of California, San Francisco.

In a statement issued by the Society for Assisted Reproductive Technology (SART), Dr. Glenn Schattman, the society’s president, said: "It is important to note that women with a history of infertility who did not undergo ART treatments also had a higher increase of having children with birth defects. This, combined with the finding that those using ICSI ... also had slightly elevated risks of birth defects, suggests that the underlying problem that led them to seek medical assistance in the first place is likely contributing to the elevated risk of birth defects in their children."

Dr. Schattman, an ob.gyn. and reproductive endocrinologist at Weill Medical College of Cornell University, New York, pointed out that some of the results were reassuring, including the finding that in cycles that did not involve ICSI, the adjusted odds ratio for IVF-conceived children did not show a significant difference in birth defects, and the risk of birth defects among children born after embryo freezing was not higher than the risk among naturally conceived children. "These are interesting and important findings, and we will need much more research to allow us to help patients overcome their infertility with treatments that are as safe as possible for them and the children born from the treatments," he added.

In the University of Adelaide statement, Dr. Davies said that the study needs to be expanded to include more recent years of treatment, because continuing advances in reproductive technologies may have an effect on risks associated with treatment. He also said in the statement that while previous studies have found that the risk of birth defects is increased with ARTs, this was the first study to compare all forms of ART treatments available and to compare pregnancies between women by the treatments they received.

The study was supported by grants from the National Health and Medical Research Council and the Australian Research Council. The authors said they had no relevant financial disclosures.

The risk of birth defects associated with assisted reproductive technology treatments was significantly increased compared with spontaneously conceived births in a large Australian observational study, but after adjustment for parental factors, the increased risk associated with in vitro fertilization was no longer significant.

The risk of birth defects associated with intracytoplasmic sperm injection (ICSI), however, remained significantly elevated, even after adjustment for maternal age and other risk factors, reported Michael Davies, Ph.D., from the Robinson Institute and School of Pediatrics and Reproductive Health, at the University of Adelaide (Australia), and his associates.

"Although we cannot rule out the possibility that other patient factors contribute to or explain the observed associations, our findings can help provide guidance in counseling patients who are considering treatment for infertility," they added in reporting the study, which was published online May 5 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1008095). The publication coincided with Dr. Davies’ presentation of the results at the World Congress on Building Consensus in Gynecology, Infertility, and Perinatology in Barcelona.

Using different databases in South Australia, the investigators compared the risks of birth defects, including cerebral palsy, diagnosed before age 5 years, among 308,974 births in South Australia, from a census of births resulting from assisted reproductive technology (ART) treatment, a registry of births and pregnancy terminations, and birth defect registries. Of the total number of births, 6,163 resulted from ART.

As in previous studies, they found an association between ART and an increased risk of cardiovascular, musculoskeletal, urogenital, and gastrointestinal defects, as well as cerebral palsy, although they pointed out that there were no birth defects for the "large majority" of births resulting from assisted conception.

Overall, there were 513 birth defects among pregnancies resulting from assisted conception (8.3%), compared with 17,546 birth defects among those that did not involve assisted conception (5.8%) – with an unadjusted odds ratio of 1.47. After adjustment for maternal age, maternal conditions during pregnancy, and other potential confounders, the odds ratio was 1.28.

The odds ratio for birth defects associated with IVF was 1.26 in unadjusted analysis, but was only 1.07 in multivariate analysis and no longer statistically significant.

The unadjusted odds ratio for birth defects associated with ICSI was 1.77, and after adjustment for other confounding factors, the risk was 1.57, which remained significant. The authors said that it was "biologically plausible" that the effects of treatment with ICSI explain the increased risk of birth defects, but added that differences in male infertility factors that lead to the use of ICSI "may also underlie the association."

The birth defect risk was also significantly increased among women with a history of infertility but no treatment with ART, which was also found in a Danish registry study, and "implicates patient factors in this increased risk," they said.

Among the study’s other findings are the increased risk of birth defects associated with the home use of clomiphene citrate, which has also been found in previous case control studies. But the authors said that this finding should be interpreted cautiously, because of the small number of women who received this treatment, and that they could not rule out "residual confounding or chance" as an explanation.

In a statement issued by the University of Adelaide, Dr. Davies said that this group was small and the result needed to be confirmed with more research. But he added that the finding raises concerns because clomiphene citrate is widely available at a low cost, and "may easily be used contrary to manufacturers’ very specific instructions to avoid use if pregnant, as it may cause fetal malformations."

He and his associates also found a significant increase in the birth defect risk associated with fresh-embryo cycles of IVF or ICSI, but no increased risk associated with frozen-embryo cycles of either method. This finding could possibly be explained by the possibility that cryopreservation reduces the likelihood that "developmentally compromised embryos will survive the thawing process and the temporal separation of the developing embryo from exposure to hormonal stimulation drugs used early" in ART treatment, the researchers said in the study.

In a statement issued by the American Society for Reproductive Medicine (ASRM), the society’s president, Dr. Linda Giudice, said that the study "confirms what has been known for quite some time: Patients who need medical assistance to conceive have a somewhat higher risk of having children with birth defects than parents able to conceive on their own.  

"Patients considering medically assisted conception have been, and should continue to be, counseled on those risks prior to undergoing any treatment," said Dr. Giudice, distinguished professor and chair of reproductive endocrinology and infertility, and the Robert B. Jaffe, M.D. Endowed Professor in the Reproductive Sciences at the University of California, San Francisco.

In a statement issued by the Society for Assisted Reproductive Technology (SART), Dr. Glenn Schattman, the society’s president, said: "It is important to note that women with a history of infertility who did not undergo ART treatments also had a higher increase of having children with birth defects. This, combined with the finding that those using ICSI ... also had slightly elevated risks of birth defects, suggests that the underlying problem that led them to seek medical assistance in the first place is likely contributing to the elevated risk of birth defects in their children."

Dr. Schattman, an ob.gyn. and reproductive endocrinologist at Weill Medical College of Cornell University, New York, pointed out that some of the results were reassuring, including the finding that in cycles that did not involve ICSI, the adjusted odds ratio for IVF-conceived children did not show a significant difference in birth defects, and the risk of birth defects among children born after embryo freezing was not higher than the risk among naturally conceived children. "These are interesting and important findings, and we will need much more research to allow us to help patients overcome their infertility with treatments that are as safe as possible for them and the children born from the treatments," he added.

In the University of Adelaide statement, Dr. Davies said that the study needs to be expanded to include more recent years of treatment, because continuing advances in reproductive technologies may have an effect on risks associated with treatment. He also said in the statement that while previous studies have found that the risk of birth defects is increased with ARTs, this was the first study to compare all forms of ART treatments available and to compare pregnancies between women by the treatments they received.

The study was supported by grants from the National Health and Medical Research Council and the Australian Research Council. The authors said they had no relevant financial disclosures.

"Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research said in the FDA statement. He noted that drug development for sarcomas "has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas."

Approval was based on the phase III PALETTE study of 369 patients with more than 20 subtypes of advanced soft tissue sarcomas who had received prior chemotherapy. Progression-free survival reached a median of 4.6 months among those randomized to treatment with pazopanib, compared with a median of 1.6 months among those randomized to placebo, a 65% reduced risk that was a statistically significant difference.

Soft tissue sarcoma, which has many subtypes, is diagnosed in about 10,000 people every year in the United States, according to the FDA. The drug received orphan drug status for this indication. It is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors (GIST).

Pazopanib, a tyrosine kinase inhibitor taken orally, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was initially approved in October 2009 for the treatment of advanced renal cell carcinoma.

The approval comes about a month after the FDA’s Oncologic Drugs Advisory Committee voted 11-2 that the pazopanib had a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcomas, in patients who have received prior chemotherapy. Panelists said that while the effects of drug were marginal, they believed the effect was real and that a benefit of a few months was meaningful to patients, especially with few treatment options available.

The most common side effects in pazopanib-treated patients included fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.

The pazopanib label has a boxed warning about the potential for hepatotoxicity with treatment, which can be fatal, and the need to monitor hepatic function in patients treated with the drug.

Pazopanib is marketed by GlaxoSmithKline.

"Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research said in the FDA statement. He noted that drug development for sarcomas "has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas."

Approval was based on the phase III PALETTE study of 369 patients with more than 20 subtypes of advanced soft tissue sarcomas who had received prior chemotherapy. Progression-free survival reached a median of 4.6 months among those randomized to treatment with pazopanib, compared with a median of 1.6 months among those randomized to placebo, a 65% reduced risk that was a statistically significant difference.

Soft tissue sarcoma, which has many subtypes, is diagnosed in about 10,000 people every year in the United States, according to the FDA. The drug received orphan drug status for this indication. It is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors (GIST).

Pazopanib, a tyrosine kinase inhibitor taken orally, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was initially approved in October 2009 for the treatment of advanced renal cell carcinoma.

The approval comes about a month after the FDA’s Oncologic Drugs Advisory Committee voted 11-2 that the pazopanib had a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcomas, in patients who have received prior chemotherapy. Panelists said that while the effects of drug were marginal, they believed the effect was real and that a benefit of a few months was meaningful to patients, especially with few treatment options available.

The most common side effects in pazopanib-treated patients included fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.

The pazopanib label has a boxed warning about the potential for hepatotoxicity with treatment, which can be fatal, and the need to monitor hepatic function in patients treated with the drug.

Pazopanib is marketed by GlaxoSmithKline.

"Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research said in the FDA statement. He noted that drug development for sarcomas "has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas."

Approval was based on the phase III PALETTE study of 369 patients with more than 20 subtypes of advanced soft tissue sarcomas who had received prior chemotherapy. Progression-free survival reached a median of 4.6 months among those randomized to treatment with pazopanib, compared with a median of 1.6 months among those randomized to placebo, a 65% reduced risk that was a statistically significant difference.

Soft tissue sarcoma, which has many subtypes, is diagnosed in about 10,000 people every year in the United States, according to the FDA. The drug received orphan drug status for this indication. It is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors (GIST).

Pazopanib, a tyrosine kinase inhibitor taken orally, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was initially approved in October 2009 for the treatment of advanced renal cell carcinoma.

The approval comes about a month after the FDA’s Oncologic Drugs Advisory Committee voted 11-2 that the pazopanib had a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcomas, in patients who have received prior chemotherapy. Panelists said that while the effects of drug were marginal, they believed the effect was real and that a benefit of a few months was meaningful to patients, especially with few treatment options available.

The most common side effects in pazopanib-treated patients included fatigue, diarrhea, nausea, weight loss, hypertension, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.

The pazopanib label has a boxed warning about the potential for hepatotoxicity with treatment, which can be fatal, and the need to monitor hepatic function in patients treated with the drug.

Pazopanib is marketed by GlaxoSmithKline.

Everolimus has become the first drug approved for the treatment of noncancerous renal angiomyolipomas that do not require immediate surgery in patients with tuberous sclerosis complex, the Food and Drug Administration announced April 26.

The new indication is based on a double-blind, randomized, placebo-controlled study of 118 patients with tuberous sclerosis complex and bilateral kidney tumors. The angiomyolipoma response rate among those treated with everolimus (Afinitor) was 42%, compared with zero among those on placebo, according to the FDA statement and revised drug label. The median duration of the response was at least 5.3 months.

Along with common side effects including inflamed or sore mouth, nausea, or vomiting, skin problems (acne or eczema), cough, headache, diarrhea, abdominal pain, joint pains, swelling of legs or arms, and upper respiratory infection, the FDA noted that about 15% of female patients receiving everolimus missed one or more menstrual periods during the study.

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. Taken orally once a day, it blocks a protein that "plays a critical role in the development and growth of the various noncancerous tumors occurring in patients with tuberous sclerosis complex, a rare genetic disorder, the statement said.

An estimated 40,000 people in the United States have tuberous sclerosis complex, a genetic condition that causes multiple noncancerous tumors in the brain, kidney, and other vital organs; about 70%-80% develop kidney problems, according to the FDA.

First approved in 2009, everolimus is marketed by Novartis. It was previously approved for subependymal giant cell astrocytoma associated with tuberous sclerosis complex in adults and children who require therapeutic intervention but are not candidates for curative surgical resection.

It is also approved for treatment of adults with progressive neuroendocrine tumors of pancreatic origin that is unresectable, locally advanced, or metastatic, and for adults with advanced renal cell carcinoma after treatment with sunitinib (Sutent) or sorafenib (Nexavar) has failed.

The new indication is an accelerated approval, which requires Novartis to follow patients for at least 4 years "to determine the duration of these responses and how responses affect the need for surgery and the control of the disease."

Everolimus has become the first drug approved for the treatment of noncancerous renal angiomyolipomas that do not require immediate surgery in patients with tuberous sclerosis complex, the Food and Drug Administration announced April 26.

The new indication is based on a double-blind, randomized, placebo-controlled study of 118 patients with tuberous sclerosis complex and bilateral kidney tumors. The angiomyolipoma response rate among those treated with everolimus (Afinitor) was 42%, compared with zero among those on placebo, according to the FDA statement and revised drug label. The median duration of the response was at least 5.3 months.

Along with common side effects including inflamed or sore mouth, nausea, or vomiting, skin problems (acne or eczema), cough, headache, diarrhea, abdominal pain, joint pains, swelling of legs or arms, and upper respiratory infection, the FDA noted that about 15% of female patients receiving everolimus missed one or more menstrual periods during the study.

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. Taken orally once a day, it blocks a protein that "plays a critical role in the development and growth of the various noncancerous tumors occurring in patients with tuberous sclerosis complex, a rare genetic disorder, the statement said.

An estimated 40,000 people in the United States have tuberous sclerosis complex, a genetic condition that causes multiple noncancerous tumors in the brain, kidney, and other vital organs; about 70%-80% develop kidney problems, according to the FDA.

First approved in 2009, everolimus is marketed by Novartis. It was previously approved for subependymal giant cell astrocytoma associated with tuberous sclerosis complex in adults and children who require therapeutic intervention but are not candidates for curative surgical resection.

It is also approved for treatment of adults with progressive neuroendocrine tumors of pancreatic origin that is unresectable, locally advanced, or metastatic, and for adults with advanced renal cell carcinoma after treatment with sunitinib (Sutent) or sorafenib (Nexavar) has failed.

The new indication is an accelerated approval, which requires Novartis to follow patients for at least 4 years "to determine the duration of these responses and how responses affect the need for surgery and the control of the disease."

Everolimus has become the first drug approved for the treatment of noncancerous renal angiomyolipomas that do not require immediate surgery in patients with tuberous sclerosis complex, the Food and Drug Administration announced April 26.

The new indication is based on a double-blind, randomized, placebo-controlled study of 118 patients with tuberous sclerosis complex and bilateral kidney tumors. The angiomyolipoma response rate among those treated with everolimus (Afinitor) was 42%, compared with zero among those on placebo, according to the FDA statement and revised drug label. The median duration of the response was at least 5.3 months.

Along with common side effects including inflamed or sore mouth, nausea, or vomiting, skin problems (acne or eczema), cough, headache, diarrhea, abdominal pain, joint pains, swelling of legs or arms, and upper respiratory infection, the FDA noted that about 15% of female patients receiving everolimus missed one or more menstrual periods during the study.

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. Taken orally once a day, it blocks a protein that "plays a critical role in the development and growth of the various noncancerous tumors occurring in patients with tuberous sclerosis complex, a rare genetic disorder, the statement said.

An estimated 40,000 people in the United States have tuberous sclerosis complex, a genetic condition that causes multiple noncancerous tumors in the brain, kidney, and other vital organs; about 70%-80% develop kidney problems, according to the FDA.

First approved in 2009, everolimus is marketed by Novartis. It was previously approved for subependymal giant cell astrocytoma associated with tuberous sclerosis complex in adults and children who require therapeutic intervention but are not candidates for curative surgical resection.

It is also approved for treatment of adults with progressive neuroendocrine tumors of pancreatic origin that is unresectable, locally advanced, or metastatic, and for adults with advanced renal cell carcinoma after treatment with sunitinib (Sutent) or sorafenib (Nexavar) has failed.

The new indication is an accelerated approval, which requires Novartis to follow patients for at least 4 years "to determine the duration of these responses and how responses affect the need for surgery and the control of the disease."

GAITHERSBURG, MD. – The results of a clinical trial of a cardioverter defibrillator that is implanted subcutaneously and does not require transvenous leads support the approval of the device as a treatment for ventricular tachyarrhythmias, the majority of a Food and Drug Administration Advisory panel agreed at a meeting on April 26.

The FDA’s Circulatory System Devices Panel voted 7-1 that the benefits of the subcutaneous implantable cardioverter defibrillator (S-ICD) system outweighed its risks in patients who meet the criteria in the indication proposed by the manufacturer, Cameron Health: to provide "defibrillation therapy for the treatment of life-threatening ventricular tachyarrhythmias in patients who do not have symptomatic bradycardia; incessant ventricular tachycardia; or spontaneous, frequently recurring ventricular tachycardia that is reliably terminated with antitachycardia pacing."

Photo courtesy Cameron Health Inc.

The components of the S-ICD system include a pulse generator, which is implanted subcutaneously in the lateral thoracic region and is connected to an electrode, with a defibrillation coil that is subcutaneously implanted along the rib margin to the sternum, without radiographic guidance, according to the company. The device has the capacity to deliver more than 100 shocks; with typical usage, it is expected to last a little more than 5 years.

Although they agreed that further follow-up of the safety and effectiveness of the device was needed and pointed out the importance of proper physician training and patient selection, the panel unanimously voted that there was "reasonable assurance" that the device was safe, and voted 7-1 that there was "reasonable assurance" that it was effective for this group of patients.

Panelists voting in favor of the risk-benefit profile said that the S-ICD would be a useful addition to the transvenous ICDs that are currently available. They agreed that the inappropriate shock rate in the clinical trial was comparable to the rates seen with currently available transvenous ICDs.

"This device is a substantial additional adjunctive tool for electrophysiologists to manage patients who are at high risk for sudden cardiac death," said Dr. Ralph Brindis, senior advisor for cardiovascular disease at Kaiser Permanente in Oakland, Calif. The availability of a device "in particular to manage patients who have infections of transvenous systems is a very important adjunct in the armamentarium." he added.

The dissenting panelist, Dr. David Milan, an electrophysiologist at Massachusetts General Hospital, Boston, said that it was important to balance enthusiasm for the device with "a cautious approach," noting that the standard for efficacy was quite high for the transvenous devices.

His concerns included whether the clinical effectiveness of the device was up to par with currently available devices, which he noted could not be assuaged by the number of patients and relatively short follow-up of patients in the pivotal trial.

The primary and safety effectiveness end points were met in the pivotal study, a prospective single arm study of 330 people with a class I, IIa, or IIb ICD indication, including patients who needed a replacement ICD, conducted in the United States, Europe, and New Zealand from January 2010 through May 2011, to evaluate the device in treating life-threatening ventricular arrhythmias. Their mean age was 52 years, which was younger than other contemporary ICD studies, but 60% were older than 50 years. In all, 74% were male; 65% were white and 24% were black; about 85% were on a beta-blocker; and about 8% were on antiarrhythmic drugs. More than half (61%) had heart failure, predominantly NYHA class II.

Among the 304 evaluable patients, the device was 98.8% effective in converting acute induced ventricular fibrillation, with 95% of the events treated in less than 21 seconds and 88% in less than 18 seconds. During the study, there were 109 spontaneous episodes of VT/VF. Of the 68 for which evaluable recorded data were available, all were successfully converted with the S-ICD, except for one case that terminated spontaneously and another case of VT/VF storm that required an external shock, according to the FDA. There were about 18 infections, of which 5 required surgical treatment, including four explants. The device was explanted in another seven patients for reasons that included repositioning, and a depleted battery. None of the eight deaths in the study was attributed to the device.

The S-ICD is distributed in 10 other countries, and so far, more than 1,200 patients have been implanted worldwide, according to Cameron Health.

The company has proposed a postmarketing study, a prospective multicenter observational registry to evaluate the long-term safety of the device.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERSBURG, MD. – The results of a clinical trial of a cardioverter defibrillator that is implanted subcutaneously and does not require transvenous leads support the approval of the device as a treatment for ventricular tachyarrhythmias, the majority of a Food and Drug Administration Advisory panel agreed at a meeting on April 26.

The FDA’s Circulatory System Devices Panel voted 7-1 that the benefits of the subcutaneous implantable cardioverter defibrillator (S-ICD) system outweighed its risks in patients who meet the criteria in the indication proposed by the manufacturer, Cameron Health: to provide "defibrillation therapy for the treatment of life-threatening ventricular tachyarrhythmias in patients who do not have symptomatic bradycardia; incessant ventricular tachycardia; or spontaneous, frequently recurring ventricular tachycardia that is reliably terminated with antitachycardia pacing."

Photo courtesy Cameron Health Inc.

The components of the S-ICD system include a pulse generator, which is implanted subcutaneously in the lateral thoracic region and is connected to an electrode, with a defibrillation coil that is subcutaneously implanted along the rib margin to the sternum, without radiographic guidance, according to the company. The device has the capacity to deliver more than 100 shocks; with typical usage, it is expected to last a little more than 5 years.

Although they agreed that further follow-up of the safety and effectiveness of the device was needed and pointed out the importance of proper physician training and patient selection, the panel unanimously voted that there was "reasonable assurance" that the device was safe, and voted 7-1 that there was "reasonable assurance" that it was effective for this group of patients.

Panelists voting in favor of the risk-benefit profile said that the S-ICD would be a useful addition to the transvenous ICDs that are currently available. They agreed that the inappropriate shock rate in the clinical trial was comparable to the rates seen with currently available transvenous ICDs.

"This device is a substantial additional adjunctive tool for electrophysiologists to manage patients who are at high risk for sudden cardiac death," said Dr. Ralph Brindis, senior advisor for cardiovascular disease at Kaiser Permanente in Oakland, Calif. The availability of a device "in particular to manage patients who have infections of transvenous systems is a very important adjunct in the armamentarium." he added.

The dissenting panelist, Dr. David Milan, an electrophysiologist at Massachusetts General Hospital, Boston, said that it was important to balance enthusiasm for the device with "a cautious approach," noting that the standard for efficacy was quite high for the transvenous devices.

His concerns included whether the clinical effectiveness of the device was up to par with currently available devices, which he noted could not be assuaged by the number of patients and relatively short follow-up of patients in the pivotal trial.

The primary and safety effectiveness end points were met in the pivotal study, a prospective single arm study of 330 people with a class I, IIa, or IIb ICD indication, including patients who needed a replacement ICD, conducted in the United States, Europe, and New Zealand from January 2010 through May 2011, to evaluate the device in treating life-threatening ventricular arrhythmias. Their mean age was 52 years, which was younger than other contemporary ICD studies, but 60% were older than 50 years. In all, 74% were male; 65% were white and 24% were black; about 85% were on a beta-blocker; and about 8% were on antiarrhythmic drugs. More than half (61%) had heart failure, predominantly NYHA class II.

Among the 304 evaluable patients, the device was 98.8% effective in converting acute induced ventricular fibrillation, with 95% of the events treated in less than 21 seconds and 88% in less than 18 seconds. During the study, there were 109 spontaneous episodes of VT/VF. Of the 68 for which evaluable recorded data were available, all were successfully converted with the S-ICD, except for one case that terminated spontaneously and another case of VT/VF storm that required an external shock, according to the FDA. There were about 18 infections, of which 5 required surgical treatment, including four explants. The device was explanted in another seven patients for reasons that included repositioning, and a depleted battery. None of the eight deaths in the study was attributed to the device.

The S-ICD is distributed in 10 other countries, and so far, more than 1,200 patients have been implanted worldwide, according to Cameron Health.

The company has proposed a postmarketing study, a prospective multicenter observational registry to evaluate the long-term safety of the device.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

GAITHERSBURG, MD. – The results of a clinical trial of a cardioverter defibrillator that is implanted subcutaneously and does not require transvenous leads support the approval of the device as a treatment for ventricular tachyarrhythmias, the majority of a Food and Drug Administration Advisory panel agreed at a meeting on April 26.

The FDA’s Circulatory System Devices Panel voted 7-1 that the benefits of the subcutaneous implantable cardioverter defibrillator (S-ICD) system outweighed its risks in patients who meet the criteria in the indication proposed by the manufacturer, Cameron Health: to provide "defibrillation therapy for the treatment of life-threatening ventricular tachyarrhythmias in patients who do not have symptomatic bradycardia; incessant ventricular tachycardia; or spontaneous, frequently recurring ventricular tachycardia that is reliably terminated with antitachycardia pacing."

Photo courtesy Cameron Health Inc.

The components of the S-ICD system include a pulse generator, which is implanted subcutaneously in the lateral thoracic region and is connected to an electrode, with a defibrillation coil that is subcutaneously implanted along the rib margin to the sternum, without radiographic guidance, according to the company. The device has the capacity to deliver more than 100 shocks; with typical usage, it is expected to last a little more than 5 years.

Although they agreed that further follow-up of the safety and effectiveness of the device was needed and pointed out the importance of proper physician training and patient selection, the panel unanimously voted that there was "reasonable assurance" that the device was safe, and voted 7-1 that there was "reasonable assurance" that it was effective for this group of patients.

Panelists voting in favor of the risk-benefit profile said that the S-ICD would be a useful addition to the transvenous ICDs that are currently available. They agreed that the inappropriate shock rate in the clinical trial was comparable to the rates seen with currently available transvenous ICDs.

"This device is a substantial additional adjunctive tool for electrophysiologists to manage patients who are at high risk for sudden cardiac death," said Dr. Ralph Brindis, senior advisor for cardiovascular disease at Kaiser Permanente in Oakland, Calif. The availability of a device "in particular to manage patients who have infections of transvenous systems is a very important adjunct in the armamentarium." he added.

The dissenting panelist, Dr. David Milan, an electrophysiologist at Massachusetts General Hospital, Boston, said that it was important to balance enthusiasm for the device with "a cautious approach," noting that the standard for efficacy was quite high for the transvenous devices.

His concerns included whether the clinical effectiveness of the device was up to par with currently available devices, which he noted could not be assuaged by the number of patients and relatively short follow-up of patients in the pivotal trial.

The primary and safety effectiveness end points were met in the pivotal study, a prospective single arm study of 330 people with a class I, IIa, or IIb ICD indication, including patients who needed a replacement ICD, conducted in the United States, Europe, and New Zealand from January 2010 through May 2011, to evaluate the device in treating life-threatening ventricular arrhythmias. Their mean age was 52 years, which was younger than other contemporary ICD studies, but 60% were older than 50 years. In all, 74% were male; 65% were white and 24% were black; about 85% were on a beta-blocker; and about 8% were on antiarrhythmic drugs. More than half (61%) had heart failure, predominantly NYHA class II.

Among the 304 evaluable patients, the device was 98.8% effective in converting acute induced ventricular fibrillation, with 95% of the events treated in less than 21 seconds and 88% in less than 18 seconds. During the study, there were 109 spontaneous episodes of VT/VF. Of the 68 for which evaluable recorded data were available, all were successfully converted with the S-ICD, except for one case that terminated spontaneously and another case of VT/VF storm that required an external shock, according to the FDA. There were about 18 infections, of which 5 required surgical treatment, including four explants. The device was explanted in another seven patients for reasons that included repositioning, and a depleted battery. None of the eight deaths in the study was attributed to the device.

The S-ICD is distributed in 10 other countries, and so far, more than 1,200 patients have been implanted worldwide, according to Cameron Health.

The company has proposed a postmarketing study, a prospective multicenter observational registry to evaluate the long-term safety of the device.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.