FDA Continues to Grapple with Accelerated Approval Issues

Applied Clinical TrialsApplied Clinical Trials-08-01-2022
Volume 31
Issue 7/8

With debate swirling around products cleared through this pathway, reforms and tighter oversight likely.

The approval of certain critical medicines based on preliminary clinical evidence continues to raise questions about reliance on too-weak efficacy data and delays in sponsors submitting confirmatory evidence from postapproval trials. FDA has approved dozens of valuable therapies under the program, many of them able to confirm efficacy through subsequent clinical studies. However, the controversial approval last year of Biogen’s Aduhelm to treat Alzheimer’s disease by the Center for Drug Evaluation and Research (CDER) continues to haunt the program, triggering widespread scrutiny of accelerated approvals and generating a range of reform proposals to accelerate the conduct of confirmatory studies.

FDA’s Oncologic Drugs Advisory Committee (ODAC) added to the debate with its April 2021 meeting that challenged several “dangling approvals” for cancer therapies. That prompted some manufacturers to withdraw earlier approvals for certain indications and others to renew confirmatory study efforts. The agency recently announced another ODAC meeting to be held Sept. 22 and 23 to review additional medicines that raise questions about efforts to confirm indications in later studies.1 The expert panel will assess a multiple-myeloma treatment from Oncopeptides, where a confirmatory trial demonstrated “worse overall survival and failed to verify clinical benefit.” The FDA announcement stated also on the agenda is Secura Bio’s lymphoma therapy, which has raised questions about the benefits and risks of overall survival information.

Legislative reform?

Meanwhile, Congressional leaders have proposed measures to reform the accelerated approval program, as discussed in recent article in The New England Journal of Medicine urging legislation to halt abuses.2 A notable change would require sponsors to have confirmatory trials underway before gaining an early approval. Additional reforms would ease FDA withdrawal of an approval if further study results are not submitted within a certain period of time or grant FDA “automatic withdrawal” authority for drugs that fail to demonstrate efficacy.3 These and others proposals are included in the FDA user fee legislation recently approved by the House,4 although its fate in the Senate is not clear.

At the same time, the cancer community and numerous patient disease groups are anxious to retain the accelerated approval program as important for enhancing patient access to therapies likely to have important benefits. These advocates also recognize that FDA should be able to remove those products unable or unwilling to confirm initial efficacy to retain credibility for the program. The “Project Confirm” initiative at FDA’s Oncology Center of Excellence (OCE) aims to clarify the importance of confirming initial study results following approval to support continued early access to promising new treatments.5 OCE listings include 85 therapies for cancer and hematologic malignancies that have verified clinical benefit, 65 that have studies ongoing, and 21 where accelerated approvals have been withdrawn. OCE continues to pressure sponsors to provide postapproval data in a timely manner and to withdraw products from the market when confirmatory studies fail to confirm benefit or are not completed with due diligence.

Stricter oversight of the accelerated approval program appears likely, as product costs and benefits remain in the spotlight. A recent analysis by National Public Radio investigators highlights the harmful effects of certain drugs on patients where early indications were not confirmed and patients were unaware of the potential danger from unanswered questions about such therapies.6 The decision to limit coverage of Aduhelm by the Medicare program, moreover, is prompting health plans and insurers to scrutinize more closely the costs and utilization of drugs with conditional approval status. At the same time, patients suffering from cancer and rare conditions continue to press for early access to therapies that demonstrate limited efficacy. Even with some legislative fixes, FDA will continue to face difficult decisions on product approvals and possible withdrawals.


  1. https://public-inspection.federalregister.gov/2022-15609.pdf
  2. https://www.nejm.org/doi/full/10.1056/NEJMp2204487?query=TOC&cid=NEJM%20eToc,%20July%2021,%202022%20DM1270826_NEJM_Non_Subscriber&bid=1075464940
  3. https://energycommerce.house.gov/newsroom/press-releases/pallone-introduces-bill-to-improve-fda-s-accelerated-approval-program
  4. https://www.congress.gov/bill/117th-congress/house-bill/7667
  5. https://www.fda.gov/about-fda/oncology-center-excellence/project-confirm
  6. https://www.npr.org/sections/health-shots/2022/07/22/1110830985/drugmakers-are-slow-to-prove-medicines-that-got-a-fast-track-to-market-really-wo
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