Cancer Drugs Speed to Accelerated Approvals, Then Hit the Brakes in Timely, Clinically Beneficial Confirmatory Trials

How does the FDA balance the demand for life-saving drugs with its mandate to ensure a clinical benefit in therapies it approves? For more than 30 years, one method has been the accelerated approval (AA) pathway, which can make a drug available if it meets benchmarks that are associated with improved survival. The use of AA is not the end of the journey, however; drug sponsors have responsibilities to multiple stakeholders after a therapy reaches the market.¹

Terra Wonsettler, PharmD, MBA | Image credit: Evolent

The Accelerated Approval Pathway
The number of AA drug applications granted by the FDA has steadily risen. Since the agency instituted AA regulations in 1992, there have been 278 approvals spanning various disease types through 2021.^1,2

Notably, AA is gaining momentum in oncology, with 9 FDA-approved oncology therapies in 2024 through June, compared with 5 in the first half of 2023.² Approximately one-third of all oncology drug approvals utilize this pathway, more than any other specialty.³ The AA regulations allow drugs for serious conditions that fill an unmet medical need to be approved based upon a surrogate end point. Therefore, the value of AA lies in its ability to expedite access to potentially life-saving drugs for patients facing serious conditions such as cancer. These drugs have been shown in clinical trial findings to meet their surrogate end points (such as response rate or progression-free survival) which suggest there may be an overall survival (OS) benefit. Although AA allows drugs that address unmet needs to reach patients faster, timely completion and rigorous validation of clinical benefit in confirmatory trials is essential to ensure patient safety and efficacy, avoiding low-value, high-cost care.

Crucial Timely and Clinically Beneficial Confirmatory Trials
AAs require a confirmatory trial to demonstrate clinical benefit before the FDA grants regular approval. For oncology AAs, the FDA recommends completing this trial within 2 to 4 years.⁴ A 25-year review from December 1992 to May 2017 revealed that 55% of the 93 oncology AAs met their post-marketing requirements and verified benefit.5 The median time from AA to benefit verification was 3.4 years (range, 0.5-12.6), often with ongoing confirmatory trials at the time of approval.⁵ Unfortunately, delays in confirmatory trials have led to therapies being administered beyond their deadlines. Of 84 oncology trials completed or due by September 2021, 46% (39/84) had missed their deadlines.⁶ Timely confirmatory trials play a crucial role in validating the ongoing delivery of high-value therapies to patients, moving beyond surrogate end points.

Demonstrating clinical benefit in confirmatory trials powered to validate meaningful end points, such as OS and quality-of-life measures, is key to efficacy and patient safety. Unfortunately, confirmatory trials do not always follow this principle. Research data presented at the 2024 American Association for Cancer Research annual meeting and later published in JAMA demonstrated that from 2013 to 2023, a total of 129 cancer drug and indication pairs received AA.⁷ Among 46 indications with more than 5 years of follow-up (approved 2013-2017), approximately two-thirds (29, 63%) were converted to regular approval, even though fewer than half (20/46, 43%) demonstrated a clinical benefit in confirmatory trials.⁷ In the second analysis, 48 of the 129 drug-indication pairs granted AA were converted to regular approval. Of these, just 19 (40%) were converted based on OS as the primary end point.^7,8 The others were converted to regular approvals based upon progression-free survival (21/48, 44%), response rate plus duration of response (5/48, 10%), and response rate (2/48, 4%); 1 (2%) was converted despite a negative confirmatory trial.^7,8 Although AA provides valuable benefits in terms of speed and market access for early treatment, this investigation reveals that some cancer drugs fail to demonstrate improvements in extending or enhancing patients’ quality of life.

Ensuring that treatments provide meaningful clinical benefit is vital not only for patient outcomes and their financial health but also for cost containment within health care systems. Between 2017 and 2019, Medicare Parts B and D cumulatively spent at least $569 million on 10 cancer drug indications with a confirmed lack of OS benefit after AA, according to data from a study published in JAMA Internal Medicine.⁹ Approximately $224 million of this spending was for indications that were either voluntarily withdrawn by manufacturers or recommended by the FDA Oncologic Drugs Advisory Committee for withdrawal.⁹ The significant implications of such spending underscore the necessity for more rigorous evaluation of cancer drugs before granting AA, ensuring responsible stewardship of patient and health care system dollars.

Managing the Uncertainty of Unproved Therapies
AA grants early access to treatments based on initial safety and effectiveness evidence, even while confirmatory studies are ongoing to verify clinical benefit. Patients should understand that this pathway provides quicker access to potentially life-saving therapies. However, AAs come with inherent uncertainty. Patients receive drugs without fully verified clinical benefit, and the confirmation process may take years. Additionally, they may pay for therapies that could be withdrawn from the market and provide them with clinically insignificant benefit. During this period of uncertainty, health care providers should discuss risks and benefits, considering preliminary surrogate measures versus safe and effective oncology treatments.

To facilitate informed discussions between providers and patients, the FDA plays a pivotal role in addressing AA and its confirmatory trial progress. Resources such as educational materials and guidance on the AA pathway—highlighting benefits and risks—can enhance patient conversations. FDA guidance, covering preliminary evidence, potential benefits, and uncertainties, forms the foundation for patient-centered dialogue.

Transparent monitoring of ongoing clinical trials to verify post-approval clinical benefit further supports patient treatment expectations. Patient-informed AA treatment, followed by confirmatory trial information, ensures timely access to potentially life-saving therapies while maintaining transparency and realistic expectations regarding further clinical validation.

Health plans also play a crucial role in managing the uncertainty surrounding AA therapies, ensuring that treatments live up to their initial promise. Evolent, a specialty and primary care management company, partners with health plans and providers to enhance outcomes for patients with complex clinical conditions, including cancer. One effective approach involves summarizing clinical evidence related to treatment options across various scenarios.

Evolent specifically addresses oncology AAs lacking proven, clinically meaningful OS benefits compared with higher-value alternatives. The company’s low-value regimen program, accessible to health plans and providers, helps avoid treatments that impair quality of life or that have excessive toxicity. By leveraging system technology, proactive education, and targeted interventions, Evolent aims to promote the use of high-value medicine. The extended duration of confirmatory trials for AA drugs, coupled with their unpredictable outcomes, may place cancer patients at risk, some of which cannot be entirely mitigated. While we advocate for more stringent adherence to trial deadlines and robust validation of clinically beneficial therapies, it is essential for all stakeholders—the FDA, health care providers, and health plans—to proactively minimize these risks.

Author Information
Terra Wonsettler, PharmD, MBA, is vice president of pharmacy for Evolent, a company specializing in connecting care. At Evolent, she is responsible for oncology medical policy, pathway, and provider education in both clinical and quality initiatives. Prior to Evolent, Wonsettler started her career as an oncology hospital pharmacist before serving over a decade leading health plan medical and pharmacy benefit administration. She serves on the board for the Ohio-Kentucky Academy of Managed Care Pharmacy.

References
1. Delays in confirmatory trials for drug applications granted FDA’s accelerated approval raise concerns. US Department of Health and Human Services Office of the Inspector General. September 29, 2022. Accessed June 21, 2024. https://oig.hhs.gov/oei/reports/OEI-01-21-00401.asp
2. Ongoing: cancer accelerated approvals. FDA. Updated June 28, 2024. Accessed June 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/ongoing-cancer-accelerated-approvals
3. Hayes E. Study: accelerated approvals leave lingering uncertainty about cancer drugs’ benefits. Regulatory Affairs Professionals Society. April 8, 2024. Accessed June 14, 2024. https://www.raps.org/news-and-articles/news-articles/2024/4/study-accelerated-approvals-leave-lingering-uncert
4. Gingery D. Accelerated approvals: US FDA writing guidance on what “ongoing” means for confirmatory trials. Pink Sheet. November 15, 2023. Accessed July 10, 2024. https://pink.citeline.com/PS149359/Accelerated-Approval-US-FDA-Writing-Guidance-On-What-Ongoing-Means-For-Confirmatory-Trials
5. Beaver JA, Howie LJ, Pelosof L. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018;4(6):849-856. doi:10.1001/jamaoncol.2017.5618
6. Deshmukh AD, Kesselheim AS, Rome BN. Timing of confirmatory trials for drugs granted accelerated approval based on surrogate measures from 2012 to 2021. JAMA Health Forum. 2023;4(3):e230217. doi:10.1001/jamahealthforum.2023.0217
7. Liu ITT, Kesselheim AS, Scheffer Cliff ER. Clinical benefit and regulatory outcomes of cancer drugs receiving accelerated approval. JAMA. 2024;331(17):1471-1479. doi:10.1001/jama.2024.2396
8. Fewer than half of accelerated approval drugs showed clinical benefit in confirmatory trials after five years. American Association for Cancer Research. April 7, 2024. Accessed June 12, 2024. https://www.aacr.org/about-the-aacr/newsroom/news-releases/fewer-than-half-of-accelerated-approval-drugs-showed-clinical-benefit-in-confirmatory-trials-after-five-years/
9. Shahzad M, Naci H, Wagner AK. Estimated Medicare spending on cancer drug indications with a confirmed lack of clinical benefit after US Food and Drug Administration accelerated approval. JAMA Internal Med. 2021;181(12):1673-1675. doi:10.1001/jamainternmed.2021.5989