What Is the Accelerated Approval Pathway? Understanding the Latest FDA Guidance

Question:

What is the accelerated approval pathway? What are the pros and cons of the accelerated approval pathway? What changes are being implemented as a result of the latest draft guidance on expedited programs for serious conditions published in December 2024?

Response:

What is the Accelerated Approval Pathway?

The accelerated approval pathway is a cornerstone of the Food and Drug Administration’s (FDA) efforts to address unmet medical needs and enable faster access to life-saving treatments. The accelerated approval pathway authorizes the use of investigational treatments based on preliminary evidence, such as surrogate endpoints that predict clinical benefits. This pathway is reserved for serious or life-threatening conditions with no adequate existing therapies. This pathway should not be used if it is infeasible to complete an adequate and well-controlled clinical trial to verify and describe clinical benefits, since confirmatory clinical studies will be required to be completed after approval.^{1, 2}

The FDA’s accelerated approval pathway was developed during the HIV epidemic of the 1980s as a mechanism to expedite the availability of treatments for serious and life-threatening conditions. Today, it has become an integral part of oncology drug approvals, with 80 percent of accelerated approvals granted for cancer therapies.³

FDA regulation 21 CFR Part 312 Subpart E outlines the expedited procedures to facilitate the development and marketing of these drugs.⁴ Patients and healthcare providers are often more willing to accept higher risks for treatments addressing life-threatening illnesses due to the lack of alternatives.

Benefits of the Accelerated Approval Pathway

There are many benefits to the accelerated approval pathway process, including:

1. Rapid Access to Treatments: By allowing earlier approval, patients with life-threatening conditions gain access to innovative therapies sooner.
2. Incentivizing Innovation: The pathway encourages pharmaceutical companies to invest in treatments for rare and difficult-to-treat conditions.
3. Addressing Unmet Needs: It prioritizes conditions with limited or no available therapies, meeting critical medical demands.

Challenges and Controversies

While the accelerated approval pathway is invaluable, it is not without challenges. Some of the key issues include:

1. Reliance on Surrogate Endpoints: Accelerated approval pathways are based on a product demonstrating an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality.^{1, 2} Drugs are often approved based on measures that may not translate into real-world clinical benefits, especially in oncology. For example, only 37 percent of drug-indication pairs approved between 2013 and 2023 converted to regular approval after confirmatory trials.³

2. Delayed Confirmatory Trials: Many drugs face prolonged delays before confirmatory trials are completed. Between 2013 and 2017, the average duration from approval to trial completion increased from 3.4 to 4.5 years.^{3, 6} One cause of delays may be due to the confirmatory studies not being underway at the time of accelerated approval, which may lead to a lag.⁷

3. Drug Withdrawal Issues: Over the last decade, 23 percent of accelerated approvals in oncology were withdrawn due to lack of benefit over standard of care.⁵ Withdrawing ineffective drugs can be slow and contentious. For instance, Makena, approved in 2011, was not withdrawn until 2023 despite failing confirmatory trials analyzed in 2019. This leads to concerns that patients are being treated during this withdrawal period with drugs that might not be of sufficient benefit and with possible increased toxicity.^{6, 8, 9}

4. High Costs: Accelerated approval drugs often carry significant costs, even without robust evidence of their benefits.⁶

5. Inconsistent Guidance: Withdrawn drugs are sometimes still recommended in national treatment guidelines, contributing to confusion. Over one-third of accelerated approval indications that had been withdrawn since approval by the FDA continue to be recommended in national guidelines,¹⁰ indicating a need for improved transparency and disclosure to patients regarding which treatments were approved via the accelerated pathway without having demonstrated positive confirmatory results at time of recommended treatment. The FDA Oncology Center of Excellence created the initiative “Project Confirm” to promote transparency of outcomes related to accelerated approval for oncology indications.¹¹

Recent Updates and Reforms

The FDA’s December 2024 draft guidance introduces new conditions to address existing challenges in the accelerated approval pathway. These include:

1. Requiring sponsors to initiate post-approval studies prior to or within a specified timeframe after accelerated approval.
2. Including clear limitations of the drug’s usefulness and any uncertainty of anticipated clinical benefits in the labeling under the INDICATIONS AND USAGE section with reference to the CLINICAL STUDIES section for a discussion of available evidence.
3. Requiring sponsors to submit reports on post-approval study progress approximately every 180 days.
4. Requiring that all copies of promotional materials be submitted to the FDA by the sponsor for review within specific time frames.
   • Promotional materials intended to be disseminated or published within 120 days following marketing approval need to be submitted during the preapproval review period.
   • After 120 days following marketing approval, promotional materials need to be submitted at least 30 days prior to the intended publication or dissemination of the materials.
5. The FDA will publish information provided in the sponsor progress reporting of confirmatory trials.¹

Conclusion

The accelerated approval pathway has played a vital role in addressing urgent medical needs. However, it requires continuous refinement to balance expedited access with robust evidence of safety and efficacy. Recent reforms and ongoing oversight aim to strengthen this balance, ensuring the pathway fulfills its mission to deliver life-saving innovations while protecting patient safety.

If you have any additional questions about the accelerated approval pathway guidance or other ethical review questions, please complete the form below. WCG’s nearly 200 Institutional Review Board (IRB) experts are ready to support your study and to address your specific inquiries.

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References

1. Draft FDA guidance for Industry: Expedited Program for Serious Conditions – Accelerated Approval of Drugs and Biologics. December 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/accelerated-approval-expedited-program-serious-conditions.
2. FDA Accelerated Approval Program website. https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program.
3. Ian T. T. Liu, MD, JD, MPH, MS; Aaron S. Kesselheim, MD, JD, MPH; Edward R. Scheffer Cliff, MBBS, MPH. Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval. JAMA. 2024; 331(;7) 1471-1479.
4. Regulation 21CFR https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312&showFR=1&subpartNode=21:5.0.1.1.3.5.  
5. Parikh et al. Exposure to US Cancer Drugs with Lack of Confirmed Benefit After US Food and Drug Administration Accelerated Approval. JAMA Oncology. 2023 Volume 9 (5); 567-569.
6. Gyawali et al. The Accelerated Approval Program for Cancer Drugs – Finding the Right Balance. NEJM. 2023; Volume 389(11); 968-970.
7. Jazowski et al. Time to Confirmatory Study Initiation After Accelerated Approval of Cancer and Noncancer Drugs in the US. JAMA International Medicine. 2023; Volume 183(7); 737-739.
8. NPR article. FDA pulls the only approved drug for preventing premature birth off the market. April 5, 2023. https://www.npr.org/sections/health-shots/2023/04/06/1167919912/fda-pulls-the-only-approved-drug-for-preventing-premature-birth-off-the-market.
9. Aaron et al. The FDA Struggle to Withdraw Makena: Problems with the Accelerated Approval Process. JAMA. 2022; 328(24); 2394-2395.
10. Cliff et al. National Comprehensive Cancer Network Guideline Recommendations of Cancer Drugs with Accelerated Approval. JAMA Network Open. 2023. Volume 5(11);https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2811820?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jamanetworkopen.2023.43285#google_vignette.
11. https://www.fda.gov/about-fda/oncology-center-excellence/project-confirm.