Stakeholders want the US Food and Drug Administration (FDA) to consolidate its accelerated approval guidances. They also asked for clarification about when the agency considers a confirmatory trial to be underway and acceptable trial benchmarks.
In January, FDA proposed a guidance that would hold sponsors of drugs with accelerated approval more accountable for conducting confirmatory studies in a timely manner. The draft guidance is based on additional authorities given to the agency by Congress under the 2023 Consolidated Appropriations Act (CAA) and is intended to clarify when a trial is considered underway prior to approval. (RELATED: Accelerated approval: FDA explains when it considers confirmatory trials underway, Regulatory Focus 10 January 2025)
Several stakeholders offered feedback on the guidance, including the drug lobby group PhRMA, which asked FDA to consolidate its guidance on accelerated approvals. The group noted that just a month prior, FDA issued another draft guidance mandated by the CAA that gave the agency new authority for setting conditions for confirmatory trials and establishing new procedures for withdrawing products if they fail to demonstrate clinical benefit. (RELATED: Accelerated approval: FDA revises guidance to reflect revised withdrawal procedures, Regulatory Focus 5 December 2024)
PhRMA said that multiple guidances related to the FDA’s accelerated approval program will confuse sponsors.
“We encourage FDA to withdraw the Draft Guidance and consolidate all guidance related to accelerated approval into a single document, potentially as a revision to the Accelerated Approval Draft Guidance,” said the group. “This single guidance document would have the benefit of ensuring clarity and consistency in terminology for all accelerated approval policies and would serve as a single, authoritative resource for stakeholders.”
The Association for Accessible Medicines (AAM) also commented on both guidances and asked FDA to consolidate them.
“As we noted in our previous comments, when FDA publishes multiple separate guidances on the same subject and replaces some sections with new thinking but not others, it is confusing for stakeholders to have to piece together FDA’s thinking as it evolves over time,” said the group. “When FDA finalizes the guidance on accelerated approval, it should incorporate in a single guidance all of the topics that are relevant for stakeholders.”
PhRMA also said that consolidating the guidances would help FDA conform to President Donald Trump’s executive order to withdraw 10 regulations, rules, or guidelines for each new one issued. The group proposed several changes regardless of whether the agency decided to consolidate the guidance. (RELATED: Trump’s 10-for-1 order puts pressure on FDA to find regulations to nix, Regulatory Focus 7 February 2025)
PhRMA noted that the statute states that FDA “may require” studies to be underway before accelerated approval is granted or within a specified timeframe after the approval date. However, the group highlighted that the agency says it generally intends to require such confirmatory trials and asked it to revise the draft guidance, so the terminology aligns with the statute. It also asked the agency to use the terms “confirmatory studies” rather than “trials” to allow more flexibility.
“This approach would align with the statutory language and will enable prompt approvals of medicines for patients with unmet medical needs,” the group added.
PhRMA also asked FDA to be more flexible in general regarding how it determines whether a confirmatory study is underway. In the draft guidance, FDA states that it considers a confirmatory trial underway before granting accelerated approval if the trial has a timely and diligent target completion date, if the sponsor’s progress and plans for postapproval conduct of the trial ensure that it will complete the trial on time, and if enrollment of the confirmatory trial has started.
PhRMA said the agency should follow the statute when defining “underway” and whether the study has been initiated.
The research advocacy group Friends of Cancer Research (FoCR) also asked for clarification of FDA’s definition of “underway.” More specifically, the group said it wants clarification on what is considered meaningful trial progress and said that clearer expectations should mitigate regulatory uncertainty and prevent trial delays.
“By refining the definition of ‘underway,’ offering clearer justifications for rare disease trial flexibility, reinforcing the importance of early engagement with the FDA, and providing examples of innovative approaches, the FDA can enhance the efficiency and reliability of the confirmatory trial process,” said FoCR.
FoCR expressed concern that limiting trial recruitment to US sites may hinder timely enrollment, especially for rare diseases. Due to the low prevalence of rare diseases, the group said multiregional clinical trials (MRCT) are often necessary to recruit sufficient trial participants.
“To support efficient rare disease drug development while ensuring adequate U.S. patient representation, we encourage the FDA to provide additional clarity on how sponsors should approach global trial design in the context of confirmatory trials,” said FoCR. “Specifically, guidance on when MRCTs may be appropriate, how to determine the sufficiency of U.S. patient enrollment, and how global data can be effectively integrated into regulatory decision-making would be valuable.”
PhRMA asked FDA to provide more details on trial benchmarks that it asks for in the draft guidance. The group said that its use of benchmarks is confusing because it seems to be related to post approval studies rather than studies that are underway.
“We recommend that FDA revise the Draft Guidance to provide additional details about the Agency’s expectations and the process for setting the benchmarks to ensure that accelerated approval is not unreasonably delayed in situations where sponsors encounter a setback in the confirmatory studies,” said PhRMA.
Similarly, FoCR wants more clarity on how FDA plans to assess progress in confirmatory trials after approval.
“Establishing concrete, measurable milestones, such as enrollment benchmarks, site activation targets, and predefined interim analyses, would help sponsors better align their trial plans with FDA expectations and avoid unnecessary delays,” said the group. “Given the critical role of timely confirmatory trials in confirming clinical benefit of accelerated approval drugs, clear regulatory expectations will be essential to maintain scientific integrity and public trust in the accelerated approval process.”
In the draft guidance, FDA notes that sponsors are required to report the progress of their confirmatory trials approximately every 180 days.
FoCR said FDA’s proposed 180-day trial progress reports should include trial metrics such as recruitment rates, patient retention, and emerging safety concerns to help the agency identify potential barriers that may prevent sponsors from completing their trials. The group also asked that it should clarify what mid-trial adaptations it will accept if the sponsor fails to meet the enrollment targets.
When determining if a trial is underway, EMD Serono said requiring sponsors to provide information such as accrual to date and number of active sites to date would mean the trial is fully activated and enrolling trial participants. The company said the requirement could delay the accelerated approval application.
“We recommend that this be a last piece of evidence provided prior to approval (not prior to application submission) as a drug product in [accelerated approval] development has considerably reduced timelines,” said EMD Serono.
“In addition, we note that many of the guidance recommendations hinge on early-stage planning and frequent communication with FDA when [accelerated approval] is sought early in development,” the company added. “We propose the FDA to consider scenarios in which seeking [accelerated approval] may not be determined until later in development and it then becomes difficult to address all of the considerations FDA requests in determining if a confirmatory trial is ‘underway.'”
The draft guidance states that FDA and sponsors should agree on a draft protocol for confirmatory studies as soon as practically possible and generally soon after the end-of-phase 2 meeting. However, EMD Serono asked FDA to consider reviewing draft protocols as part of the end-of-phase 2 meeting. The company said that agreeing on draft protocols after end-of-phase 2 meetings would delay getting trials up and running.
EMD Serono also noted that the standard of care or treatment may change while the sponsor’s confirmatory trial is underway and asked the agency to clarify how the sponsor should handle such changes.
“As the change in the standard-of-care or treatment landscape may impact enrollment and outcome of the confirmatory trial, we suggest the final guidance introduces a transparent pathway for sponsors to engage with the FDA to reconsider the timelines and/or the study design,” said the company. “This pathway could enable patients to get the latest treatment options without unnecessary delay.”
