Last week, after a , an FDA advisory panel voted 14-1 that 17α-hydroxyprogesterone caproate (17-OHPC; Makena) should be withdrawn from the market. Back in 2011, based on that the synthetic progestin prevented preterm birth if given during pregnancy, the FDA approved the medication under the accelerated approval program. Seven years later, a follow-up trial found the drug to be ineffective, and in 2020 the that it would begin the process for withdrawing 17-OHPC from the market. The drug's manufacturer protested, and 2 years later the drug continues to be prescribed.
The recent news about 17-OHPC is just one of many recent examples highlighting major challenges posed by the accelerated approval program. Accelerated approval was created in 1992 at the height of the AIDS epidemic to expedite the approval of antiretroviral treatments. The the FDA to approve drugs that target serious or life-threatening conditions if preliminary evidence shows that these products are "reasonably likely" to be effective. In exchange for expedited approval, the FDA requires drug manufacturers to conduct follow-up studies to confirm whether the drugs benefit patients.
In theory, this process is sensible. But in practice, the accelerated approval program has several problems.
First, manufacturers to complete follow-up trials, leaving patients and providers in the dark about whether drugs actually work and exposing patients to the risks and side effects of unproven treatments. In some cases, delays stem from patients in follow-up studies, since joining a study risks randomization to placebo and is often not necessary to access the medication. While the these delays, the agency has to compel timely trial completion.
Second, nothing prevents manufacturers of accelerated approval drugs from , often exceeding $10,000 per year, before their products have been proven effective. Since Medicaid and Medicare most FDA approved drugs, the federal government has spent on drugs of uncertain efficacy over the past few years.
Third, the FDA has found it difficult to withdraw drugs from the market if follow-up studies do not confirm efficacy. In most such cases, manufacturers the drug or indication from the market. When this does not occur, the FDA may unilaterally withdraw approval. However, as the example of 17-OHPC makes clear, the current legal process for doing so is .
The FDA has faced significant for attempting to withdraw medications from the market. In fact, the FDA has only successfully reversed an accelerated approval decision once: changing the label for bevacizumab (Avastin) based on evidence that the medication was not effective in treating breast cancer. The political and legal hurdles leading up to this action were so damaging that one FDA official "Armageddon." In some cases, the FDA has allowed manufacturers to on the market despite negative trial results.
This state of affairs is unacceptable. Patients should not have to bear the cost of expensive and potentially ineffective therapies for years on end. Researchers and advocates have proposed that would ensure the timely completion of confirmatory trials.
To prevent delays in evidence generation, FDA officials have requiring drug sponsors to begin enrolling patients in confirmatory trials and conduct an interim analysis before receiving accelerated approval. The agency also needs to address barriers that have often prevented the timely completion of postmarket trials.
Patients and insurers, especially public payers like Medicare and Medicaid, should be from paying exorbitant prices for drugs before they are proven effective. For example, the Medicaid and CHIP Payment and Access Commission (MACPAC) recently mandatory discounts for accelerated approval drugs until confirmatory studies are completed.
Meaningful reforms to the accelerated approval program will likely require congressional action. Unfortunately, members of Congress recently passed over a to reform accelerated approval as part of the Prescription Drug User Fee Act (PDUFA) reauthorization.
But there is still time for Congress to act. The would address this issue by requiring manufacturers to submit a protocol for confirmatory trials before receiving accelerated approval. The legislation would also automatically withdraw accelerated approval of products 1 year after agreed upon deadlines for completing these trials and streamline the FDA's process for unilaterally withdrawing accelerated approval when confirmatory evidence does not pan out.
The evidence that reform is needed is clear and overwhelming. Now is the time for Congress to take action and reform the accelerated approval pathway to protect patients and more effectively balance earlier access to treatments with the need for high-quality evidence of safety and effectiveness.
is a research assistant at the Program On Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women's Hospital. is an instructor at Harvard ľֱ School and a faculty member at PORTAL.
Disclosures
Rome's research is funded by grants from Arnold Ventures and the Elevance Health Public Policy Institute.