Is the FDA allowing medicines authorised via the accelerated approval process to remain so in spite of unproven clinical effectiveness? According to an investigation by the British Medical Journal (BMJ), 112 of the 253 drugs authorised by the FDA via its accelerated approval pathway established since 1992 have not been confirmed as clinically effective.
About the accelerated drug approval process
In 1992 FDA instituted the Accelerated Approval regulations. These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint. Using a surrogate endpoint enabled the FDA to approve these drugs faster.
In 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). Section 901 of the act amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint. Using surrogate or intermediate clinical endpoints can save valuable time in the drug approval process.
Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.
The BMJ analysis
Elisabeth Mahase, clinical reporter at The BMJ, carried out an in depth analysis of FDA data up to 31 December 2020, on drugs authorised via the accelerated drug approval process. Her findings are as follows:
Of the 112 drugs approved in the last 28 years via the accelerated pathway, approximately a fifth (24) have been on the market for more than five years and some have been on the market for more than two decades, often with a hefty price tag.
Further analysis of FDA data revealed that only 16 drugs approved through the pathway have ever been withdrawn. Most of these were shown to lack efficacy, but in some cases the confirmatory trials were never done e.g. Celecoxib (Celebrex) approved in 1999 for the treatment of familial adenomatous polyposis was on the market for 12 years before the FDA asked Pfizer to voluntarily withdraw it for this indication due to the efficacy trials never being done.
The BMJ asked the manufacturers of 24 treatments that have been on the market for more than five years whether they have conducted phase IV trials. Of the 24 treatments:
- Six had been withdrawn, approved, or postponed.
- Of the remaining 18, just 6 provided information on a relevant trial and of these only 4 had started to recruit patients, while 2 companies said they were still in discussion with the FDA over the final study design.
According to Mahase, “Despite the pathway’s good intentions to accelerate ‘the availability of drugs that treat serious diseases’ experts are concerned that it is now being exploited, to the detriment of patients, who may be prescribed a drug that offers little benefit and possible harm, and to taxpayers,”
In 2015, a review of the FDA’s expedited pathways by the US Government Accountability Office said that “FDA’s data on postmarket safety issues and studies were found to be incomplete, outdated, to contain inaccuracies, and to be stored in a manner that made routine, systematic analysis difficult.”
In April 2021, the Institute for Clinical and Economic Review (ICER) reported that “absent credible threats of withdrawing approval for failing to comply with postmarketing requirements, there may be little upside for study sponsors to spend the resources to seek rapid completion of confirmatory trials.”
When efficacy is unclear, the FDA uses indirect (surrogate) measures of clinical benefit. In some cases, there is a strong indication that the surrogate measure predicts meaningful benefit, explains Mahase, but where the situation is less straightforward, “inconsistencies and a lack of transparency surrounding decisions have led to serious questions over the standards of evidence being accepted.”
Despite the concerns raised, Mahase points out that all experts who spoke to The BMJ agreed that the accelerated pathway is still useful and can be truly beneficial to patients, although some changes are needed.
One effective reform could be that confirmatory trials are designed, agreed, and even started as part of the approval, she says. Other suggestions set out in the ICER white paper include strengthening the selection of surrogate endpoints, regulating the price of accelerated drugs, and regularly re-reviewing and renewing the approval to ensure that it continues to justify the risk benefit tradeoff.
In response, an FDA spokesperson said it was “committed to working with sponsors to ensure that confirmatory studies are completed in a timely manner.” They added, “We expect sponsors to commit all resources needed to move trials forward as effectively as possible, with the aim of completing trials as soon as is feasible, while assuring the quality of the data and the robustness of the results.”
Source: BMJ website