By Kimberly Lord Stewart
Are you inclined to prescribe the newest drug because it should be safer and more efficacious than older medications? Put your script pad down. Newer drugs have a one in three chance of acquiring a black box warning or being withdrawn for safety reasons within 25 years of their approval, according to a new study by researchers from Cambridge Health Alliance /Harvard Medical School, Boston Medical Center (BMC)/Boston University School of Medicine (BUSM), City University of New York School of Public Health, and Public Citizen.
The study, published today in the August issue of Health Affairs, is the largest of its type, encompassing all of the drugs approved by the U.S. Food and Drug Administration (FDA) over a 35-year period. The findings are so dramatic, Sidney M. Wolfe MD, one of the co-study authors called the FDA’s drug approval process, “an orgy of dangerous and reckless approvals.” The authors suggest that the expedited process may have led to the release of drugs before they could be adequately evaluated for safety issues, which has placed millions of American at risk.
“The FDA is under constant pressure to rush new drugs through the pipeline to approval. In its hurry, the FDA 
is apparently failing to distinguish useful drugs from toxic ones, and more dangerous drugs are slipping through,” said study lead author Cassie Frank, MD, a physician at Cambridge Health Alliance and an instructor in medicine at Harvard Medical School. “By the time many drugs receive serious safety warnings, millions of Americans have already been exposed to their side effects, which can sometimes be fatal.” From one doctor to another, Frank recommends, keeping patients safe by avoiding new drugs, especially when similar, older ones are available.
Though Wolfe, founder of Public Citizen’s Health Research Group and author of “Worst Pills, Best Pills,” emphasized that there is no apparent evidence of corrupt motives and no definitive causal factors, there are a number of alarming deductions that can be made from the study. Above all, the researchers say this dramatic upswing in withdrawals and black box warnings is in line with the passage of the 1992 with the Prescription Drug User Fee Act (PDUFA), which allowed the FDA to collect fees to expedite drug approvals. As you will see, the money trail and fees are extraordinary, but take a look at the results first.
Study Methods: The study compared warning and withdrawal rates for drugs released before and after 1992, with the implementation of PDUFA. According to the study authors, Congress passed PDUFA after heavy lobbying by the pharmaceutical industry, and PDUFA has been reauthorized by Congress several times since then (1997, 2002, 2007, 2012). Since the law’s enactment, the average drug approval time for all drugs has fallen from 34 months to 16 months.
Study Findings:
- Overall, for every 100 new drugs introduced in the market, there were 34 withdrawals or new black box warnings within the 25-year follow up.
- Very few of the 32 drugs withdrawn for safety reasons had clearly unique benefits at the time of approval, but all had unique risks that eventually led to their withdrawal.
- Nonsteroidal inflammatory drugs and antidepressants accounted for 30% of all newly approved drugs, most often they were among the most commonly prescribed drugs.
- Drugs released after the PDUFA passed were more likely to be withdrawn or have a black box warning, with 26.7 percent of these drugs receiving such a warning compared to 21.2 percent in the pre-PDUFA drugs that underwent the longer approval process.
- Half of all black box warnings appeared after a drug had been on the market for 12 years, and safety withdrawals have occurred as late as 30 years after a drug’s initial release.
“Our findings raise concern that the FDA is rushing its review of new drugs and allowing potentially unsafe medicines onto the market. As a primary care doctor, I’m wary of prescribing brand new drugs unless they’re really a breakthrough, since their full risks are often unknown. And patients should be wary too,” said senior author Karen Lasser, MD, MPH, associate professor of medicine at BUSM who practices internal medicine at BMC.
So why the rush? The act was deemed by FDA to be a benefit for public health. Patients would have access to more than 1,500 new drugs and biologics for cancer, infectious diseases, cardiovascular disease, as well as psychiatric and neurological disorders. When PDUFA passed, FDA was feeling the heat to approve more drugs faster.
Following PDUFA’s approval, there was a “burst of approval” from 1992 to 2009, according to Wolfe. “Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously. From an average, prior to PDUFA, of about three years from receipt of the drug application to FDA approval, the interval has dropped sharply to about one year, following PDUFA. These shorter review times, combined with increased FDA authority to require further studies after approval – rather than settling safety issues before approval – possibly contributes to the increased rate of withdrawals and black box warnings,” says Wolfe. This latter practice, essentially made patients unwitting members of the experiments and trials and place millions at risk.
The study did not include FDA-initiated drug withdrawals, manufacturer voluntary withdrawals and market removal because of poor sales or introductions of similar drugs. Half of the black box warnings appeared within twelve years of the drug’s introduction and half the withdrawals for dangerous side effects stayed on the market for as long as 5 years.
Now about the money. While the study does not suggest or link PDUFA fees as causality, one has to consider there has been a dramatic increase in fees, which have primarily funded staffing increases. In 1995, FDA collected $70,953,500 in user fees as compared to $760 million this fiscal year, according to FDA reports.
Wolfe says this accounts for two-thirds of the agency’s drug-review budget. In 2013, the fees allowed for 3,655 full-time equivalents (FTEs), including salary and operational expenses (a 3.1% increase in salary and benefits from 2012 to 2013). And, FDA increased fees 10% from 2013 to 2014, to $2.169 million per application (2015 fees are projected at $2.335 million per Fed. Reg Vol. 79, No. 148). While fees are not the cause of the problem, they have become a significant source of funding for FDA staff allocations.
The study authors make a number of suggestions to address the problem:
1. Doctors should have a risk-benefit conversation with patients to encourage opting for older drugs with longer tried and true safety records. Many patients think new drugs are safer.
2. Be wary of surrogate outcomes for “breakthrough drugs” that are investigational and part of the FDA Innovation Act of 2012, which is reserved for serious and life-threatening diseases and conditions.
3. Do not rely on the PDR for comprehensive drug information, as it it out of date and incomplete.
4. Support a ban on direct-to-consumer advertising, which relies heavily on new drugs within the first years of approval (the authors note that the Supreme Court may likely rule this as unconstitutional based on previous rulings).
5. Allow some new drugs, such as antibiotics, on to the market quickly in exchange for contractual promise from the manufacturer not to promote the drug outside of a specified indication. This concept is part of the Antibiotic Development to Advance Patient Treatment (ADAPT) Act, introduced to Congress in Dec. 2013.
6. Mandatory inclusion in labeling, advertising and marketing with a symbol that indicated the drug is new and poses greater risk for adverse effects. The United Kingdom uses an inverted black triangle to illustrate the drug was recently approved, however FDA fears this may lead to patient confusion and misunderstanding.
7. Increase agency and attention to post-marketing surveillance for new drugs and breakthrough drugs that are approved quickly.
To access the study, link here for the abstract.
Put the Script Pad Down: FDA’s New Drug Approvals Pose Significant Risks
By Kimberly Lord Stewart
Are you inclined to prescribe the newest drug because it should be safer and more efficacious than older medications? Put your script pad down. Newer drugs have a one in three chance of acquiring a black box warning or being withdrawn for safety reasons within 25 years of their approval, according to a new study by researchers from Cambridge Health Alliance /Harvard Medical School, Boston Medical Center (BMC)/Boston University School of Medicine (BUSM), City University of New York School of Public Health, and Public Citizen.
The study, published today in the August issue of Health Affairs, is the largest of its type, encompassing all of the drugs approved by the U.S. Food and Drug Administration (FDA) over a 35-year period. The findings are so dramatic, Sidney M. Wolfe MD, one of the co-study authors called the FDA’s drug approval process, “an orgy of dangerous and reckless approvals.” The authors suggest that the expedited process may have led to the release of drugs before they could be adequately evaluated for safety issues, which has placed millions of American at risk.
“The FDA is under constant pressure to rush new drugs through the pipeline to approval. In its hurry, the FDA
is apparently failing to distinguish useful drugs from toxic ones, and more dangerous drugs are slipping through,” said study lead author Cassie Frank, MD, a physician at Cambridge Health Alliance and an instructor in medicine at Harvard Medical School. “By the time many drugs receive serious safety warnings, millions of Americans have already been exposed to their side effects, which can sometimes be fatal.” From one doctor to another, Frank recommends, keeping patients safe by avoiding new drugs, especially when similar, older ones are available.
Though Wolfe, founder of Public Citizen’s Health Research Group and author of “Worst Pills, Best Pills,” emphasized that there is no apparent evidence of corrupt motives and no definitive causal factors, there are a number of alarming deductions that can be made from the study. Above all, the researchers say this dramatic upswing in withdrawals and black box warnings is in line with the passage of the 1992 with the Prescription Drug User Fee Act (PDUFA), which allowed the FDA to collect fees to expedite drug approvals. As you will see, the money trail and fees are extraordinary, but take a look at the results first.
So why the rush? The act was deemed by FDA to be a benefit for public health. Patients would have access to more than 1,500 new drugs and biologics for cancer, infectious diseases, cardiovascular disease, as well as psychiatric and neurological disorders. When PDUFA passed, FDA was feeling the heat to approve more drugs faster.
Following PDUFA’s approval, there was a “burst of approval” from 1992 to 2009, according to Wolfe. “Since PDUFA, the review times for the drugs that are eventually banned have decreased enormously. From an average, prior to PDUFA, of about three years from receipt of the drug application to FDA approval, the interval has dropped sharply to about one year, following PDUFA. These shorter review times, combined with increased FDA authority to require further studies after approval – rather than settling safety issues before approval – possibly contributes to the increased rate of withdrawals and black box warnings,” says Wolfe. This latter practice, essentially made patients unwitting members of the experiments and trials and place millions at risk.
The study did not include FDA-initiated drug withdrawals, manufacturer voluntary withdrawals and market removal because of poor sales or introductions of similar drugs. Half of the black box warnings appeared within twelve years of the drug’s introduction and half the withdrawals for dangerous side effects stayed on the market for as long as 5 years.
Now about the money. While the study does not suggest or link PDUFA fees as causality, one has to consider there has been a dramatic increase in fees, which have primarily funded staffing increases. In 1995, FDA collected $70,953,500 in user fees as compared to $760 million this fiscal year, according to FDA reports.
Wolfe says this accounts for two-thirds of the agency’s drug-review budget. In 2013, the fees allowed for 3,655 full-time equivalents (FTEs), including salary and operational expenses (a 3.1% increase in salary and benefits from 2012 to 2013). And, FDA increased fees 10% from 2013 to 2014, to $2.169 million per application (2015 fees are projected at $2.335 million per Fed. Reg Vol. 79, No. 148). While fees are not the cause of the problem, they have become a significant source of funding for FDA staff allocations.
The study authors make a number of suggestions to address the problem:
1. Doctors should have a risk-benefit conversation with patients to encourage opting for older drugs with longer tried and true safety records. Many patients think new drugs are safer.
2. Be wary of surrogate outcomes for “breakthrough drugs” that are investigational and part of the FDA Innovation Act of 2012, which is reserved for serious and life-threatening diseases and conditions.
3. Do not rely on the PDR for comprehensive drug information, as it it out of date and incomplete.
4. Support a ban on direct-to-consumer advertising, which relies heavily on new drugs within the first years of approval (the authors note that the Supreme Court may likely rule this as unconstitutional based on previous rulings).
5. Allow some new drugs, such as antibiotics, on to the market quickly in exchange for contractual promise from the manufacturer not to promote the drug outside of a specified indication. This concept is part of the Antibiotic Development to Advance Patient Treatment (ADAPT) Act, introduced to Congress in Dec. 2013.
6. Mandatory inclusion in labeling, advertising and marketing with a symbol that indicated the drug is new and poses greater risk for adverse effects. The United Kingdom uses an inverted black triangle to illustrate the drug was recently approved, however FDA fears this may lead to patient confusion and misunderstanding.
7. Increase agency and attention to post-marketing surveillance for new drugs and breakthrough drugs that are approved quickly.
To access the study, link here for the abstract.
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