As Prescribed


The accelerated approval pathway (i.e., the pathway that permits FDA to rely on surrogate or intermediate endpoints for the approval of a drug for serious conditions with unmet medical needs) has proven to be an important tool to provide patients with access to promising products. By example, as of June 2021, the Center for Drug Evaluation and Research approved 269 drug and biologic products via accelerated approval. This does not include Center for Biologics Evaluation and Research approvals, which, as reported in the New England Journal of Medicine, has granted more than 155 accelerated approvals for oncology products alone.

However, over the past year, many questions have been raised regarding the program. For instance, the US Department of Health and Human Services Office of Inspector General announced that it will be reviewing FDA’s implementation of the accelerated approval pathway. In April of 2021, the Oncologic Drugs Advisory Committee held a three-day meeting on “dangling” indications (i.e., indications that were approved via accelerated approval but for which phase 4 studies have not confirmed the product’s clinical benefit). Congressional lawmakers are also looking into the pathway and FDA’s relationship with industry.

This is notable as many accelerated approval products have not yet received full approvals—e.g., of the 269 CDER products that received accelerated approval, 115 have not yet been converted to full approvals. FDA’s Oncology Center of Excellence Chief of Medical Oncology, Julia Beaver, and Director, Richard Pazdur, also authored a New England Journal of Medicine article focusing on dangling indications.

Confirming the benefit of products approved via accelerated approval has, in some cases, proven to be particularly difficult. As noted by Drs. Beaver and Pazdur, the failure of a confirmatory trial to demonstrate efficacy may not actually mean that the product is ineffective. Confirmatory trials can fail due to the selection of the primary endpoint, power calculations, statistical testing, biomarker selection, design issues, or subject selection issues. Drs. Beaver and Pazdur, in fact, specifically state in the New England Journal of Medicine article, “If there are clear reasons why a trial may not have achieved its primary endpoint and an unmet medical need still exists, the FDA works with sponsors to identify subsequent clinical trials that could satisfy the accelerated approval requirements.”

However, in a treatment landscape, such as oncology, where treatment options and standard of care is rapidly evolving, continuing to demonstrate an unmet medical need can present a further hurdle. Drs. Beaver and Pazdur explain:

in a competitive field in which multiple companies are developing drugs for the same or similar indications, available therapies and the definition of unmet medical need may change during the course of a confirmatory trial or review of an accelerated-approval application. When a trial does not confirm benefit, before additional confirmatory trials are discussed, the medical need and available therapies should be reassessed to determine whether the conditions for accelerated approval still exist.

Given these potential risks and the increased regulatory attention on the accelerated approval pathway, what is a product sponsor to do?

  • First, sponsors should be particularly careful when designing confirmatory studies, ensuring that the protocol requirements, procedures, and evaluations are targeted at measuring the ultimate product clinical benefit. Sponsors should also work closely with FDA to develop such protocols.
  • Sponsors should also try to expedite the conduct of confirmatory trials because the more time that passes, the increased chance there is for new treatments to come on the market.
  • Sponsors should also engage in early contingency planning. While a confirmatory trial that does not meet its primary endpoint is disappointing news, it is not necessarily the death knell for an accelerated approval indication. As noted by FDA, the agency is prepared to work with sponsors in the conduct of additional post-approval studies.
  • Sponsors should consider the continuing concern about FDA and its relationship with the pharmaceutical industry, as this may affect the timing and depth of scrutiny given to the accelerated approval program, especially under the Biden-Harris administration. Whether FDA is required to tighten up the program to make it more accountable will likely be an agenda item for the next FDA Commissioner.
  • Finally, sponsors should be ready to engage with FDA and regulators around proposed changes to the accelerated approval program. It is possible that Congress may take the program up in future legislation. At the same time, however, there may be opportunities to reshape how confirmatory trials are conducted. By example, at a Friends of Cancer Research Listening Session, Dr. Pazdur made the point that the agency shouldn’t necessarily be as focused on overall survival as the only confirmatory endpoint, noting that it is “very important that we just don’t define a very narrow criteria of what defines success.”