FDA Accelerated Approval: What Industry Needs to Know

December 2022

Accelerated approval is one of the four distinct approaches used by the FDA to expedite the availability of drugs that treat serious diseases (the other approaches are priority review, breakthrough therapy, and fast track).¹ A drug or biologic that is granted accelerated approval is conditionally approved for a specific indication based on a surrogate endpoint or intermediate clinical endpoint that is expected to predict clinical benefit.³ A surrogate endpoint does not require prior validation from the FDA to be used as the basis for an accelerated approval, but the surrogate must be reasonably likely to predict the intended benefit of a drug based on strong mechanistic and/or epidemiologic rationale.⁴ Sponsors are required to complete post-market confirmatory trials to verify that the drug has the expected effect on the clinical outcome of interest.²

The use of a surrogate endpoint can considerably shorten the time to receive FDA approval. For example, oncology products approved via the accelerated pathway reached the market an average of 4.7 years faster than traditionally approved oncology products.⁵ Accelerated approval is also advantageous in acute disease settings where the clinical event to demonstrate benefit occurs rarely, because far fewer participants may be required to demonstrate an effect on a surrogate endpoint compared to benefit on a clinical outcome.²

History of the Accelerated Approval Pathway

The FDA established the Accelerated Approval Program (21 CFR Subpart H) in 1992 largely in response to the HIV/AIDS epidemic in the 1980s to expedite approval of drugs that treat serious conditions and “fill an unmet medical need.”⁸ Twenty years later (2012), Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA) section 901, which amended the Federal Food, Drug, and Cosmetic Act (FD&C Act), and added the requirement that study sponsors complete confirmatory trials.⁹

Since the induction of the Accelerated Approval Program, the FDA has granted more than 250 accelerated approvals of which ~42% were for orphan indications and ~65% were for oncology indications (a drug can have both an orphan and oncology indication).⁹ The Accelerated Approval Program has been generally successful in bringing new drugs to the market. The Institute for Clinical and Economic review (ICER) found that among accelerated approvals from 1992-2016, ~77% have been converted to traditional approval.⁹

Standards for Accelerated and Traditional Approval Pathways

The FDA uses the same basic standards for approving drugs via the accelerated approval pathway as it does for the traditional approval pathway. Drugs that are approved under the Accelerated Approval Program must demonstrate that “a drug is safe for use under conditions prescribed, recommended or suggested in the proposed labeling”¹⁰ and must meet FDA’s standard for effectiveness based on evidence from “adequate and well-controlled clinical investigations.”¹¹ The European Medicine Agency’s (EMA) conditional marketing authorization pathway is similar to the FDA’s accelerated approval but is only available to first indications with approvals reviewed annually.¹² TRI provides regulatory, clinical operations, data management, safety, and pharmacovigilance support for phase 1-4 trials, which can help meet milestones for both pathways.

Qualifying Criteria for Accelerated Approval

A limitation of using surrogate or intermediate clinical endpoints over those in traditional approvals is greater uncertainty about the effectiveness and safety of a drug. Therefore, the FDA reserves the use of accelerated approval for treatments that are for a serious condition, offer a meaningful advantage over available therapy, and demonstrate an effect on an endpoint that is reasonably likely to predict clinical benefit.²

A serious disease or condition is associated with morbidity and has a substantial impact on day-to-day functioning. Seriousness is determined by clinical judgment of factors such as survival, impact on daily functioning/quality of life, or likelihood of disease progression.² For the FDA to determine if a drug provides a meaningful therapeutic benefit over existing treatments requires consideration of the lack of alternative treatments. An alternative therapy that has comparable efficacy to available therapies, but with a different mechanism of action may qualify if a significant number of patients who did not benefit from other available therapies have a beneficial response to the new therapy.² In determining whether the effect of a drug is reasonably likely to predict a clinical benefit the FDA will consider:

1. The disease process including its cause, effects that predict disease outcome, and the state of the pathophysiologic pathway leading to the clinical outcome.²
2. The relationship between the effect of the drug and the disease process.²

Sponsors that are considering using the accelerated approval pathway should request to meet with the FDA early in the trial development process to determine if these qualifying criteria are met. The FDA and sponsor must agree on the planned endpoints and on the design and conduct to support confirmation of clinical benefit for confirmatory trials.¹³

Conditions of Accelerated Approval

During the preapproval review period, the drug sponsor must submit to the FDA all promotional materials including labeling and advertisements intended for dissemination or publication within 120 days following marketing approval.² TRI’s regulatory and medical writing teams can provide post-marketing support through abstracts/manuscripts, design and management of risk evaluation, and mitigation strategies.

The drug sponsor is also required to conduct phase 4 confirmatory trials to verify clinical benefit. To expedite the start of the trial, the phase 4 protocol should be developed as early as possible and study timelines, design, and conduct must be approved by the FDA.² While the confirmatory trial will generally evaluate a clinical endpoint in the same disease population that was used for the accelerated approval, a different, but related population may be used if commercial availability of the drug impinges on enrollment of patients from the same population.² In some cases, the same surrogate endpoint in the same population used to support the accelerated approval may be measured for a longer duration to support the confirmatory trial. For example, in the treatment of HIV, viral load measured for a short duration of 24 weeks as a surrogate endpoint may be acceptable to support durable clinical benefit, if suppression is shown for a year.² The FDA may withdraw accelerated approval if confirmatory trials fail to demonstrate sufficient clinical benefit to justify the risks associated with the drug.² TRI is equipped to provide support of accelerated drug approvals through analysis of surrogate endpoint data, protocol preparation, and safety/efficacy monitoring of confirmatory trials.

Accelerated Approval Considerations for the COVID-19 Pandemic

In the context of the ongoing COVID-19 pandemic, there are currently no FDA accepted surrogate endpoints (or accelerated approvals) of a COVID-19 vaccine although recent studies in non-human primates indicate that induction of neutralizing antibody (nAb) and spike-specific CD4+ and CD8+ T cell responses provide protection against SARs-CoV-2 ^9,10 and may serve as potential surrogate endpoints for COVID-19. The availability of surrogate endpoints of COVID-19 vaccines could reduce significant time and expenses compared to large-scale field efficacy trials and facilitate approval of vaccine candidates thereby creating opportunity for accelerated approvals.¹⁶ Currently, the FDA has issued 17 emergency use authorizations (EUAs) (4 vaccines and 13 drugs and non-vaccine biological products) for COVID-19¹⁷, which authorizes unapproved medical products or unapproved uses of approved medical products to diagnose, treat, or prevent the disease.¹⁷ An EUA is only granted when there are no other approved and available alternative treatments and is only intended to last for the duration of the public health emergency for which it was granted.¹⁸

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About the Author

Jonathan Kent Gore-Langton holds a PhD in Behavioral Neuroscience from Binghamton University in Binghamton, NY. As a medical writer at TRI, he supports clinical trials in oncology and infectious diseases by preparing a variety of regulatory and scientific documents for government, academic, and the pharmaceutical industry.  

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Footnotes

1. U.S. Food and Drug Administration (2018, February). Fast Track, Breakthrough Therapy, Accelerated Approval, Priority. Department of Health and Human Services, Food and Drug Administration. Review https://www.fda.gov/patients/learn-about-drug-and-device-approvals/fast-track-breakthrough-therapy-accelerated-approval-priority-review


2. U.S. Food and Drug Administration. (2018, January). Accelerated Approval. U.S. Department of Health and Human Services, Food and Drug Administration. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval


3. U.S. Food and Drug Administration. (2014). Guidance for industry: expedited programs for serious conditions—drugs and biologics. US Food and Drug Administration: Silver Spring, MD, USA.


4. Stein, P. Brief overview of biomarkers: Value, limitations, and the Biomarker Qualification Program (BQP)[Brochure]. US Food and Drug Administration: Author.


5. Johnson, J. R., Ning, Y. M., Farrell, A., Justice, R., Keegan, P., & Pazdur, R. (2011). Accelerated approval of oncology products: the food and drug administration experience. JNCI: Journal of the National Cancer Institute, 103(8), 636-644. https://doi.org/10.1093/jnci/djr062


6. Zanolla, L., & Zardini, P. (2003). Selection of endpoints for heart failure clinical trials. European Journal of Heart Failure, 5(6), 717-723. https://doi.org/10.1016/s1388-9842(03)00101-6


7. Fiuzat, M., Lowy, N., Stockbridge, N., Sbolli, M., Latta, F., Lindenfeld, J., ... & McMurray, J. (2020). Endpoints in heart failure drug development: history and future. Heart Failure, 8(6), 429-440. https://doi.org/10.1016/j.jchf.2019.12.011


8. Stengle, K., Zalewski Z., Olsen M.W., Gustafson K., Nell A. (January 4, 2022). Understanding the History and Use of the Accelerated Approval Pathway. Avalere. https://avalere.com/insights/understanding-the-history-and-use-of-the-accelerated-approval-pathway


9. Mehlman, A., & Pearson, S. D. (2021). Strengthening the Accelerated Approval Pathway: An Analysis of Potential Policy Reforms and their Impact on Uncertainty, Access, Innovation, and Costs.


10. Federal Food, Drug, and Cosmetic Act, 21 C.F.R. § 505(d)(1)


11. Federal Food, Drug, and Cosmetic Act, 21 C.F.R. § 505(d)(5)


12. Vokinger, K. N., Kesselheim, A. S., Glaus, C. E., & Hwang, T. J. (2022, August). Therapeutic Value of Drugs Granted Accelerated Approval or Conditional Marketing Authorization in the US and Europe From 2007 to 2021. In JAMA Health Forum (Vol. 3, No. 8, pp. e222685-e222685). American Medical Association. JAMA Health Forum – Health Policy, Health Care Reform, Health Affairs | JAMA Health Forum | JAMA Network


13. Cox, E. M., Edmund, A. V., Kratz, E., Lockwood, S. H., & Shankar, A. (2020). Regulatory affairs 101: Introduction to expedited regulatory pathways. Clinical and Translational Science, 13(3), 451-461.


14. Deng, W., Bao, L., Liu, J., Xiao, C., Liu, J., Xue, J., ... & Qin, C. (2020). Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques. Science, 369(6505), 818-823. https://doi.org/10.1126/science.abc5343


15. Chandrashekar, A., Liu, J., Martinot, A. J., McMahan, K., Mercado, N. B., Peter, L., ... & Barouch, D. H. (2020). SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science, 369(6505), 812-817. https://doi.org/10.1126/science.abc4776


16. Jin, P., Li, J., Pan, H., Wu, Y., & Zhu, F. (2021). Immunological surrogate endpoints of COVID-2019 vaccines: the evidence we have versus the evidence we need. Signal transduction and targeted therapy, 6(1), 1-6.


17. U.S. Food and Drug Administration. (2022, October) Emergency Use Authorization. https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#vaccines


18. Macmillan C. (2022). Emergency Use Authorization Vs. Full FDA Approval: What’s the Difference? https://www.yalemedicine.org/news/what-does-eua-mean

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