Does faster regulatory approval translate into safety problems?
The FDA is trying to balance input from various stakeholders while honoring the Prescription Drug User Fee Act.
In April, FDA Commissioner Dr. Margaret Hamburg gave a presentation in Cambridge, MA to a group of biotech executives. Her talk focused on the FDA’s emphasis on communication and how it has well-served the industry. However, Hamburg also spent part of her podium time defending critics who say that the FDA has been very slow in approving a new, potentially life-altering therapy for Duchenne’s muscular dystrophy, a rare disease that leaves boys in wheelchairs by age 12 and young men dead in their twenties.
The drug in question -- eteplirsen from Sarepta Therapeutics -- was developed to stop progression of Duchenne’s muscular dystrophy and had already shown positive results in early trials. Over 100,000 people signed a petition asking the FDA to expedite the approval process. The FDA did eventually agree to allow Sarepta to submit an application for eteplirsen based on data from a small clinical trial in the summer of 2013 -- but the agency reversed course, asking for a larger, more robust study.
That decision ended up costing precious time – both for Sarepta and the patients.
Finding the balance
It seems that the FDA is always walking a fine line between being overly cautious and allowing drugs to be approved, often with black-box warnings, even when there are lingering safety concerns. An article published earlier this month in Health Affairs reported a disturbing finding: Drugs approved since the implementation of the Prescription Drug Users Fee Act (PDUFA) in 1992 are more likely to receive black-box warnings or be withdrawn from the market than drugs approved before 1992.
PDUFA was supposed to be a good thing -- and, for the most part, it is. Pharma companies pay fees ($760 million so far this fiscal year) to support the FDA’s efforts to expedite the review process with the goal of bringing more drugs to market quickly.
Post-PDUFA surge in safety problems
However, when analysts looked at 748 new molecular entities (NMEs) approved between 1975 and 2009, they found that 21.2 per 100 drugs approved before 1992 were either withdrawn from the market or received black-box warnings, compared with 26.7 per 100 drugs approved after 1992. Although the researchers could not establish a causal connection, they noted that since PDUFA, the average review time has dropped from 34 months to 16 months.
In response to these findings, the researchers called for reform of the FDA drug approval process, suggesting that patients should have less exposure to unsafe drugs and that marketing materials aimed at physicians should indicate that a medication has only recently been approved.
This is not the first time that various stakeholders and thought leaders have called for reform of the review process. For a long time, companies complained about how long it took to get a drug approved, citing the negative impact on patients as a reason to implement various mechanisms to expedite the process.
No innovation, no expedited review
As a result of PDUFA and other reforms, the number of drugs approved since 1992 has increased dramatically -- but so has the number of safety issues and subsequent withdrawals. According to Sydney Wolfe, founder and senior adviser of the Health Research Group at Public Citizen in Washington, DC, the problem is not that the review process is too rapid. Rather, there are too many ‘me-too’ drugs that bring nothing to the table in terms of innovation while simultaneously carrying a great deal of risk.
In the most recent issue of BMJ, Wolfe wrote that drugs that are not breakthrough drugs -- i.e., truly innovative drugs that address an unmet medical need -- should not be eligible for expedited approval.
Meridia: A case study for caution
In 1997, 39 new drugs received FDA approval -- yet many drugs were not necessarily innovative. In fact, eight out of the 39 were eventually withdrawn from the market for a variety of reasons.
One high-profile withdrawal was Meridia (sibutramine), a widely-anticipated obesity treatment that showed significant weight loss in overweight and obese patients during clinical trials.
But on October 8, 2010, more than a decade after the drug’s initial approval, the FDA announced that Abbott was withdrawing Meridia from the market. The reason? Results from a post-marketing clinical study, the Sibutramine Cardiovascular Outcomes Trial (SCOUT), showed that Meridia increased the risk of cardiovascular (CVD) events by a shocking 16%. At the time, Dr. John Jenkins, director of the Office of New Drugs at the Center for Drug Evaluation and Research, said, “Physicians are advised to stop prescribing Meridia to their patients and patients should stop taking this medication. Patients should talk to their health care provider about alternative weight loss and weight loss maintenance programs.”
The initial approval of Meridia was based on data showing that patients taking this medication lost at least 5% of their body weight. And while there were some early signals suggesting the possibility of CVD-related problems, researchers theorized that losing weight would lead to a healthier CVD profile and offset the drug-related risks.
It didn’t work out that way. The safety data was real, and it was clear that the risks outweighed the benefits. Thirteen years after approval, Meridia was no longer available.
Wolfe points out that many physicians prefer to use older drugs that have a well-known safety profile based on long-term use. The reality is that the need for new, innovative medications is as intense as it ever was. There are many unmet medical needs in which patients are waiting for breakthrough therapies, new medications, and game-changing therapeutic interventions. The challenge is finding the perfect balance between averting unnecessary risks by paying attention to safety signals early, while continuing to support innovative research, development, and approval. That remains the key to getting the most-needed drugs to market as quickly and safely as possible.
- BMJ Does $760m a year of industry funding affect the FDA’s drug approval process?
- Health Affairs Era Of Faster FDA Drug Approval Has Also Seen Increased Black-Box Warnings And Market Withdrawals
- FDA FDA News Release: Abbott Laboratories agrees to withdraw its obesity drug Meridia
- www.bizjournals.com FDA head says agency’s work has helped shorten time needed for drug approval