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Black-box warnings, market withdrawals increased after PDUFA enactment
Over one-quarter of new drugs approved after the enactment of the Prescription Drug User Fee Act were subsequently withdrawn from the market or issued black-box safety warnings, according to a recent study.
The authors wrote that the Prescription Drug User Fee Act (PDUFA), which allows drug makers to pay fees to expedite approval, may play a role in these outcomes, possibly due to rushed drug approvals lacking in quality clinical trial evidence.
Researchers from Cambridge Health Alliance and Harvard Medical School; the City University of New York School of Public Health; the School of Medicine at Boston University and the Health Research Group analyzed data from a list of all new molecular entities approved by the FDA between 2000 and 2009, obtained from the Tufts Center for Drug Development. Over-the-counter medications, diagnostic agents and biologics were excluded from analysis, and researchers compared their findings to data from a previous study of drugs approved between 1975 and 1999.
They found that 26.7 of every 100 drugs approved after the enactment of PDUFA received a black-box warning or were withdrawn, compared with 21.2 of every 100 drugs prior to the passage of the law (OR=1.35; P<.05). Half of the black-box warnings occurred within 12 years of the introduction of the drug to the market, while half of the withdrawals from the market occurred within 5 years of introduction.
Nonsteroidal anti-inflammatory drugs and antidepressants accounted for 30% of the label changes; however, sensitivity analyses excluding these classes, as well as drugs removed from the market due to commercial reasons such as poor sales, indicated that 27.4 and 31.0 new warnings or withdrawals were issued, respectively, per 100 drugs post-PDUFA.
According to the FDA website, “user fees have played an important role in expediting the drug approval process” since PDUFA was passed. A schedule of fees is available on the site.
Clear decline after PDUFA
In a conference call earlier today, researchers Karen Lasser, MD, MPH, associate professor of medicine at the School of Medicine, Boston University; Cassie Frank, MD, instructor of medicine at Cambridge Health Alliance and Harvard Medical School; and Sidney M. Wolfe, MD, senior adviser at the Health Research Group at Public Citizen, a public advocacy organization in Washington, D.C.; spoke with journalists about their study.
“We identified all drugs that were pulled from the market for safety reasons or received a new serious safety warning,” Frank said. “Then we looked at why these safety problems have put more pressure on the FDA to speed up drug approvals. What we found is that, in 25 years [following approval], new drugs have a 1-in-3 chance of getting a black-box warning or being completely banned from the market because they are deemed so unsafe.”
“We asked the question — ‘Is it worse, better or the same since this law passed?’ and it’s clearly worse,” Wolfe said during the call. “There is about a 25% increase in the number of drugs being taken off the market or given a black-box warning.”
Pay for approval
Wolfe, who has previously served on an FDA committee, said the agency is funded by user fees pharmaceutical companies pay when submitting drugs. He said he has seen no evidence of corruption, as the companies have to pay the fees regardless of whether the drug is approved, but that it may add pressure to move drugs through more quickly, and attitudes at the agency have changed.
“We queried medical officers who reviewed some of the drugs, and they clearly think the standards have gone down since the law was passed,” Wolfe said. “When companies are giving the FDA $760 million, what they get in return legislatively is increasing paths to get drugs approved.” He acknowledged, however, that breakthrough drugs for life-threatening illnesses should be treated differently.
Prescribe wisely
Lasser said that physicians should avoid prescribing newer drugs to patients when older, effective drugs with known side effects are available for common conditions such as diabetes, back pain and hypertension.
“I think this study has immense implications for clinical practice,” she said during the conference call. “Doctors and patients should avoid new drugs unless they are truly breakthrough drugs.”
Wolfe said that when safety problems arise, the agency may approve the drug regardless, and perform studies afterward.
“That is really treating a lot of people in this country who are going to be given these highly-advertised drugs as experimental subjects.”
He added that many drugs removed from the market or not approved in Europe and the U.K. are still approved for use in the US.
“This law relieved Congress of paying the FDA out of US Treasury, so Congress is happy, but there is poor or little oversight over the industry,” Wolfe said.
In the paper and during the call, the authors suggested that physicians use a more comprehensive source of drug information than that contained in the Physician’s Desk Reference when making prescribing decisions. They also called for labeling additions to include a statement or symbol acknowledging that a drug is new and may cause unknown side effects.
The researchers also acknowledged limitations to their study.
“Remarkably, no comprehensive source of information on black-box warnings or withdrawals is available to clinicians,” they wrote, so the measures used in the study are “imperfect” because they only count the issuance of a new warning or withdrawal, and other influences may have contributed to the actions. They also acknowledged they could not establish causality for the enactment of PDUFA in relation to the increase in withdrawals and warning labels.
Disclosures: The researchers report no relevant financial disclosures.
Perspective
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First of all, it’s not surprising. It is important, as many of us who have concerns about drug safety have felt that PDUFA was not in the best interest of public health. The fact that so much of the budget of the FDA comes from the pharmaceutical agency has the potential for making trouble. The FDA would say it hasn’t, but this paper suggests it has. It has led to more rapid approval of drugs and more drugs that have black-box warnings.
An alternative to PDUFA is to not have the money from user fees go directly to FDA, but to Federal Treasury, then have Congress appropriate those funds to the FDA. Whether that would help or not I wouldn’t be certain, but it’s worth thinking about.
In the study, the cause and effect is implied, but not proven. There may be other reasons for the increase. Over the last decade, there has been an increasing focus on drug safety, particularly in the wake of Vioxx. It simply may be that the FDA is more likely to put a black-box warning on a drug. It may simply be that the whole tenor of society and its tolerance regarding drug safety has become more sensitive.