The Accelerated Approval Pathway: serving its drug review purpose?

September 08, 2021
Warren Smith, PharmD

Millions of people suffer from debilitating and potentially deadly health conditions, with limited (if any) treatment options available to them. The Accelerated Approval Pathway (AAP) offers patients access to promising, yet unproven, treatments in a timely manner. The question remains: Is it fulfilling its potential?

The AAP was introduced in 1992 to provide an expedited drug review pathway using an alternative to the traditional Food and Drug Administration (FDA) pathway. This alternative, called surrogate endpoints, can be used instead of clinical outcomes in some clinical trials. The pathway arose from patient advocacy in the 1980s, particularly within the HIV/AIDS community, when deaths from the pandemic were outpacing the availability of new and effective treatment options.1

Since the introduction of the AAP, more than 250 drugs have received accelerated approval, with roughly 42 percent representing drugs that treat rare diseases or conditions and 65 percent for oncology treatments. Approximately half of all drugs that received accelerated approval have ultimately received full FDA approval.

In 2012, when the FDA passed the FDA Safety and Innovation Act (FDASIA), the role of the AAP was solidified, with the requirement that surrogate endpoints needed to be “reasonably likely” to provide a clinical benefit. FDASIA also required the completion of confirming clinical trials after the accelerated approval. Although the law gives the FDA power to withdraw the approval of drugs failing to demonstrate adequate safety and efficacy, this is not a mandatory action.1

The jury is out on AAP – but improvements are possible

The AAP has been viewed positively for some drug approvals, such as with Gleevec® (imatinib) for chronic myelogenous leukemia, but there are also drugs that have been approved with a great deal of controversy, including Exondys 51® (eteplirsen) for Duchenne muscular dystrophy.1 And while the AAP is largely viewed as successful – including by the FDA and especially in oncology2 – some see the process as flawed due to confirmatory trials that are slow to materialize, produce vague results, and lack consistency in determining thresholds for changes in surrogate endpoints.1

Inconsistent regulatory decision making is also an issue, with instances of drugs retaining approval even though confirmatory trial results were not in line with the stated goals of the trial. Criticisms have targeted the FDA for allowing drugs to remain on the market despite later confirmatory trials showing no effect on the primary clinical outcome.1

Although there are challenges with completing confirmatory trials (e.g., shifting treatment models, ethics of placebo-controlled trials following approval), the FDA doesn’t seem to have a formal method to address these issues. Similarly, there is no formal process for the creation of proposed timelines to complete confirmatory trials; Biogen’s aducanumab for Alzheimer’s disease, approved in June 2021, doesn’t need results from confirmatory trials submitted to the FDA until February 2030.3

To reinforce the objectives of the AAP and FDASIA, the FDA should:

  • Be adamant about the completion of confirmatory clinical trials
  • Provide reasonable time for results from these trials to be completed and made publicly available
  • Create a formal process for translating surrogate endpoints and their definition of clinical improvement.

Drugs approved through the AAP don’t deserve universal high praise for their impact on difficult to treat conditions; however, it will be up to many parties – the FDA, drug manufacturers, patient advocacy groups, payors – to ensure the primary purpose of this critical program is not lost, while still allowing for innovations that benefit patients.

References:

  1. Kaltenboeck, A, Mehman A, Pearson S. Strengthening the accelerated approval pathway: an analysis of potential policy reforms and their impact on uncertainty, access, innovation, and costs. Boston (MA): Institute for Clinical and Economic Review: 2021 [cited 2021 July 20]. Available from: https://icer.org/wp-content/uploads/2021/04/Strengthening-the-Accelerated-Approval-Pathway-_-ICER-White-Paper-_-April-2021.pdf.
  2. Beaver JA, Howie LJ, Pelosof L, Kim T, Liu J, Goldberg KB, et al. A of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018 June 1;4(6):849-856. doi: 10.1001/jamaoncol.2017.5618. PMID: 29494733.
  3. Dunn W. BLA Accelerated Approval [monograph on the Internet]. Silver Spring (MD): Food and Drug Administration: 2021 Jun [cited 2021 July 20]. BLA 761178. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761178Orig1s000ltr.pdf.