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On July 15, 2025, LDI Senior Fellows Steven Joffe, MD, MPH, Holly Fernandez Lynch, JD, MBE and authors Ravi B. Parikh, MD, MPP, Martin Kurian, MD, and Ronac Mamtani, MD, MSCE delivered a memo to the FDA’s Center for Drug Evaluation and Research (CDER) and Oncology Center of Excellence (OCE) entitled Policy Recommendations for Strengthening the Accelerated Approval Program for Oncology Drugs: Response to December 2024 Draft Guidance. 

In this memo, the authors assert that recent empirical research on the FDA’s Accelerated Approval (AA) program reveals critical gaps between policy intentions and real-world treatment outcomes that warrant immediate attention in finalizing the December 2024 draft guidance. The authors summarize their studies which demonstrate that current postmarketing requirement (PMR) practices are insufficiently rigorous, that prescribing patterns suggest misaligned incentives, and that substantial patient exposure to ineffective drugs occurs. They recommend the following five specific policy reforms to strengthen the Accelerated Approval program while preserving its benefits for patients with serious oncologic conditions:

1. Implement Standardized Postmarketing Statement Requirements
2. Strengthen Pre-Accelerated Approval Confirmatory Study Requirements
3. Expedite Post-Accelerated Approval Surveillance and Withdrawal Procedures
4. Enhance Postmarketing Requirements Study Design Standards
5. Implement Real-World Evidence Integration Requirements

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Re: Policy Recommendations for Strengthening the Accelerated Approval Program for Oncology Drugs: Response to December 2024 Draft Guidance

From: Ravi B. Parikh, MD, MPP (Emory University); Martin Kurian, MD (University of Pennsylvania); Steven Joffe, MD, MPH (University of Pennsylvania); Holly Fernandez Lynch, JD, MBE (University of Pennsylvania); and Ronac Mamtani, MD, MSCE (University of Pennsylvania)

Date: July 1^st, 2025

To: Center for Drug Evaluation and Research (CDER) and Oncology Center of Excellence (OCE)

Summary

Recent empirical research on the FDA’s Accelerated Approval (AA) program reveals critical gaps between policy intentions and real-world treatment outcomes that warrant immediate attention in finalizing the December 2024 draft guidance. Our studies demonstrate that current postmarketing requirement (PMR) practices are insufficiently rigorous, that prescribing patterns suggest misaligned incentives, and that substantial patient exposure to ineffective drugs occurs. We recommend five specific policy reforms to strengthen the AA program while preserving its benefits for patients with serious oncologic conditions.

Background

The AA program represents a critical pathway for bringing promising oncology therapies to patients with serious conditions and unmet medical needs. However, recent congressional attention and growing concerns about program integrity necessitate evidence-based reforms.¹ The December 2024 draft guidance, alongside January 2025 draft guidance on confirmatory trial requirements, provides an opportunity to address systemic weaknesses while maintaining the program’s core mission of accelerating access to beneficial therapies. While the January 2025 guidance represents progress by requiring confirmatory trials to be “underway” prior to approval, our empirical research suggests that stronger safeguards are needed to ensure program integrity.

Key Findings From Recent Research

Our comprehensive analysis of 161 oncology AA indications granted between 2011-2023 reveals three fundamental problems with current AA implementation:

First, PMR statements lack the specificity needed to ensure rigorous confirmatory evidence. Among 181 PMR statements analyzed, critical design elements were frequently omitted: only 30% specified follow-up duration, 26% included enrollment targets, 24% specified requiring multicenter trials, and 13% mandated double-blinding.² These gaps translate directly into weaker confirmatory studies, as PMR studies adhered to statement specifications with near-perfect fidelity (>99%).

Second, prescribing behaviors are misaligned with the robustness of evidence. Real-world prescribing data from 63,434 patients demonstrates that oncologists respond more robustly to AA (23 percentage point increase) than to conversion to regular approval (1 percentage point increase).³ This suggests that market adoption occurs rapidly upon AA, removing commercial pressure for sponsors to complete confirmatory studies expeditiously.

Third, prescribing of ineffective therapies is prevalent. Among five withdrawn AA indications with sufficient follow-up data, 26% of eligible treatment initiations involved subsequently withdrawn therapies. Although it is inherent in AA policy, given the uncertainty of unvalidated surrogate endpoints, that some AA drugs will fail, this finding reflects thousands of patients exposed to drugs without demonstrated clinical benefit.⁴ The median time from AA to withdrawal was 46 months, creating extended exposure periods.

Policy Recommendations

We recommend five specific reforms to address these identified weaknesses:

1. Implement Standardized PMR Statement Requirements

The draft guidance should mandate a comprehensive checklist of PMR statement elements, including: (a) specific enrollment targets with interim milestones, (b) defined follow-up duration sufficient to assess clinical benefit, (c) explicit randomization and blinding requirements where feasible, (d) multicenter design specifications, and (e) clinical endpoint requirements prioritizing overall survival or validated surrogates. This addresses the current variability in PMR statement specificity that undermines confirmatory study quality.⁵

2. Strengthen Pre-AA Confirmatory Study Requirements Beyond Current Guidance

FDA has undertaken important efforts to require that confirmatory trials be underway prior to AA. However, our empirical evidence suggests that merely having “enrollment initiated” at the point AA is granted is insufficient to ensure timely completion of confirmatory trials given the rapid prescribing adoption following AA. The FDA has recently responded to this by issuing recent guidance that sponsors complete all or a significant portion of enrollment prior to AA when confirmatory studies will be carried out in the approved patient population. We propose that the FDA should expect sponsors seeking AA to provide: (a) demonstrated feasible enrollment rate trajectory, (b) established data and safety monitoring procedures, and (c) interim analysis plans with prespecified stopping rules. The 23-percentage point prescribing increase immediately following AA necessitates stronger enrollment benchmarks than currently proposed.⁸

3. Expedite Post-AA Surveillance and Withdrawal Procedures

The draft guidance should establish accelerated timelines for identifying and acting upon negative confirmatory trial results. Under the recent Food and Drug Omnibus Reform Act (FDORA) of 2022, sponsors must provide progress reports on AAs every 6 months. Our data showing 26% patient exposure to withdrawn therapies underscores the urgency of robust and scrupulous tracking of emerging evidence surrounding AAs to minimize exposure periods to ineffective agents.⁶ We recommend: (a) mandatory and rapid sponsor reporting of analyses of confirmatory trials that fail to confirm effectiveness of the agent for the relevant indication, and (b) withdrawal proceedings initiated within 6 months of negative confirmatory trials, absent compelling justification for delay, unless a sponsor voluntarily withdraws. If delays continue, then tighter periods for sponsors acting on negative results will be important.

4. Enhance PMR Study Design Standards

The guidance should explicitly require that PMR studies employ design elements associated with successful regular approval conversion, including randomized, controlled designs except where explicitly justified and adequate statistical power for clinical endpoints. Our analysis showed that less rigorous PMR characteristics allowed faster completion of confirmatory trials,⁷ however, rigor is essential to resolve the uncertainty associated with AA drugs.

5. Implement Real-World Evidence Integration Requirements

Given rapid prescribing adoption following AA, FDA should require sponsors to submit real-world effectiveness analyses alongside confirmatory trial results. These analyses should: (a) assess if drug utilization patterns are consistent with approved indications, and (b) identify any emerging safety signals in clinical practice. This leverages the extensive post-AA uptake seen in our data to complement randomized trial evidence.

Conclusion

The AA program serves a vital public health function, but current implementation gaps undermine its integrity and potentially harm patients. Our empirical findings provide specific guidance for strengthening program requirements while preserving access to promising therapies. The December 2024 draft guidance, in conjunction with the January 2025 confirmatory trial guidance, represents a critical opportunity to implement these evidence-based reforms and restore confidence in this essential regulatory pathway.

The policy recommendations outlined above directly address the systematic weaknesses identified in our research while building upon existing statutory authorities and recent guidance developments. We urge CDER and OCE to incorporate these recommendations into the final guidance to ensure the AA program fulfills its promise of providing early access to effective cancer therapies while minimizing patient exposure to ineffective treatments.

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Endnotes

1. The Food and Drug Omnibus Reform Act (FDORA) of 2022 granted FDA additional authorities to strengthen the AA program, including requirements for confirmatory study conditions and expedited withdrawal procedures. Section 506(c) of the Federal Food, Drug, and Cosmetic Act, as amended by the Consolidated Appropriations Act, 2023, provides FDA with enhanced tools to specify postmarketing study parameters and accelerate withdrawal when confirmatory studies fail to verify benefit. The January 2025 draft guidance “Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway” represents important progress by establishing that confirmatory trials should generally be “underway” prior to approval, though our empirical evidence suggests stronger requirements are needed.
2. Kurian M, Ferrell WJ, Ulloa Perez E, et al. Specificity of Food and Drug Administration postmarketing requirements and associations with timely submissions and regulatory decisions for oncology accelerated approvals, 2011–2023: a cross-sectional analysis. BMJ Oncology 2025;4:e000659. Our analysis of 181 PMR statements revealed substantial variability in specificity, with critical design elements frequently omitted. PMR statements for indications granted regular approval were more likely to specify shorter follow-up duration and allow endpoints other than overall survival, suggesting that less stringent requirements may facilitate successful program completion albeit with important tradeoffs.
3. Parikh RB, Ulloa-Pérez E, Kurian M, et al. Prescribing Changes After Accelerated vs Regular Approval of Oncology Therapies. JAMA Network Open 2025 (Pending publication). Analysis of 63,434 patients receiving 128,917 eligible lines of therapy demonstrated that prescribing increased 23 percentage points after AA compared to only 1 percentage point after conversion to regular approval. This misalignment suggests that market forces create insufficient incentive for timely confirmatory study completion.
4. Parikh RB, Hubbard RA, Wang E, et al. Exposure to US Cancer Drugs With Lack of Confirmed Benefit After US Food and Drug Administration Accelerated Approval. JAMA Oncology 2023;9(4):567-569. Among five withdrawn AA indications with sufficient follow-up data, 1,361 of 5,217 treatment initiations (26.1%) involved subsequently withdrawn therapies. The median time from AA to withdrawal was 46 months, indicating substantial exposure periods that could be minimized through expedited withdrawal procedures.
5. The current variability in PMR statement content reflects inconsistent negotiation processes between FDA and sponsors. Our analysis demonstrated that PMR studies adhere to statement specifications with near-perfect fidelity, indicating that inadequate initial specifications directly translate to weaker confirmatory evidence. A standardized checklist approach would ensure consistent evidentiary standards across all AA indications while providing clear expectations for sponsors during the application process.
6. The extended timeline from negative confirmatory results to withdrawal creates unnecessary patient exposure to ineffective therapies. Our real-world evidence analysis showed that prescribing rates remained elevated even after negative trial publication, declining only after formal withdrawal. This pattern suggests that many oncologists may not be aware of or responsive to negative confirmatory trial results without clear FDA communication and action.
7. Our analysis identified specific PMR study characteristics associated with successful regular approval conversion, including fewer trial sites, less frequent blinding requirements, and use of continuous trials spanning both AA and confirmatory phases. However, these characteristics also predicted more rapid submission timelines, highlighting the inherent tension between study rigor and completion speed that must be carefully balanced in PMR statement development.
8. The January 2025 guidance appropriately establishes that confirmatory trials should be “underway” prior to AA, defining this as having “enrollment initiated” along with appropriate target completion dates and sponsor benchmarks. However, our prescribing data showing immediate 23 percentage point uptake following AA suggests that merely initiating enrollment is insufficient. The rapid market adoption creates competitive disadvantages for trial enrollment that require more substantial pre-approval accrual to ensure trial completion. Our recommendation for 25% enrollment completion prior to approval provides a more robust threshold that accounts for post-approval enrollment challenges while remaining feasible for most development programs.

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