Industry comments on two recent US Food and Drug Administration guidance documents on accelerated approval seek clear timelines for agency feedback on confirmatory study protocols and a better understanding of how the FDA defines “due diligence” for purposes of timely study conduct.
Industry stakeholders also seek assurances that the FDA will be flexible in deciding when confirmatory studies must be underway at the time of approval.
However, consumer and academic groups say the proposed criteria for determining when a trial is underway are too vague, and that less groundbreaking drugs or those with major safety concerns should be required to have confirmatory studies at an advanced stage of recruitment before approval.
The FDA’s December draft guidance on accelerated approval highlighted the need for early sponsor/agency interactions on confirmatory trial planning. It also clarified the FDA’s interpretation of conducting trials with due diligence and discussed types of confirmatory trials.
In a January draft guidance, the FDA described considerations for determining whether a confirmatory trial is underway prior to accelerated approval.
The guidance recognized that for some rare disorders, the agency may not require an ongoing confirmatory trial at the time of accelerated approval if “appropriate justification” is provided.
However, the agency may require confirmatory trial enrollment be completed if continued enrollment and retention are likely to be especially challenging after a product receives accelerated approval.
Timely Feedback On Study Protocols
Comments on both guidances echo several themes, including sponsors’ desire for timely feedback on confirmatory study designs.
The accelerated approval draft guidance places significant emphasis on early initiation and prompt completion of confirmatory studies, the Pharmaceutical Research and Manufacturers of America said.
“To advance this objective, it is important that sponsors receive timely agency feedback on their proposed postmarketing requirements, protocols, and milestones – and in particular, that the timelines for FDA feedback enable confirmatory studies to be underway at the time of accelerated approval,” PhRMA’s comments state. “Specifically, we would recommend FDA provide feedback on confirmatory study protocols within 60 days.”
PhRMA also requests the FDA explain how the timing of discussions about protocols and milestones aligns with the PDUFA VII performance goals for communications about anticipated postmarketing requirements.
“PhRMA believes that receiving FDA’s feedback for the first time on ‘preliminary evaluation of required postmarketing studies, including the study purpose, critical study design elements including type of study and study population’ six to eight weeks prior to the application goal date per the PDUFA VII Commitment Letter will come too late to enable confirmatory studies to be underway at the time of accelerated approval,” the comments state.
The industry group asks that the FDA “be willing to grant early meetings to discuss confirmatory study design well before the application submission.”
Furthermore, it is important for the FDA to exercise flexibility in determining whether confirmatory studies must be underway at the time of approval, PhRMA said.
“In some instances, favorable readouts from Phase II trials may result in the accelerated approval pathway becoming appropriate when neither the agency nor the sponsor anticipated it,” PhRMA said. “Other times, the nature of the approval or indication statement and changes in the standard of care at or near approval should inform the most efficient and informative confirmatory study.”
“In both instances, it may be difficult for FDA and sponsors to reach alignment on the confirmatory study prior to approval, which will make it difficult or impossible for studies to be underway at the time of the approval.”
Due Diligence
PhRMA also requests the agency clarify the meaning of “due diligence” in the context of confirmatory trial conduct.
In a 1990s rulemaking, the FDA described due diligence as requiring a “good faith effort” to complete a study, but the accelerated approval draft guidance uses different terminology that could be interpreted to create a new standard, PhRMA said.
The draft guidance states that sponsors must commit sufficient resources to conducting the confirmatory trial expeditiously so that a determination of whether the drug provides the expected clinical benefit can be made as soon as possible. It also states that sponsors should take steps to facilitate high retention of participants.
“Because of the heightened challenges of rare disease drug development, it is important that this precept be implemented with flexibility, since sponsors and investigators may pursue confirmatory trials with timely rigor yet be confounded by systemic problems.”
Alexion
“The focus on ‘resources’ could suggest that there would be varying standards for due diligence based on differences in company resources,” PhRMA said. “Further, the ‘as soon as possible’ appears out of alignment with the rulemaking discussion and also with the inclusion of specific milestone dates in the approval letters for accelerated approvals.”
The trade group requests the FDA provide additional detail on the meaning of due diligence and confirm that the guidance’s concept is meant to align with the 1990s rulemaking term that Congress ratified.
Comments from the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT) request the agency clarify how much past the target due date constitutes a failure to act with due diligence. The academic group’s comments also said the FDA should initiate expedited withdrawal if progress reports indicate that the sponsor is not completing confirmatory studies with due diligence.
In comments on the underway guidance, Alexion said the due diligence requirement should be implemented flexibly for rare diseases.
“Because of the heightened challenges of rare disease drug development, it is important that this precept be implemented with flexibility, since sponsors and investigators may pursue confirmatory trials with timely rigor yet be confounded by systemic problems, such as suboptimal patient recruitment and enrollment, caused by prevailing conditions beyond their control,” Alexion’s comments state.
“We urge the agency to acknowledge the need for increased flexibility in both the design and expectations for confirmatory trials as well as in the likelihood of delays in their execution,” Alexion said.
Underway Criteria
PhRMA said the underway draft guidance sets forth an overly strict interpretation that would limit use of the accelerated approval program.
The guidance describes three criteria for determining if a trial is underway:
- The trial has a target completion date consistent with diligent and timely conduct considering the nature of the trial’s design and objectives
- The sponsor’s progress and plans for postapproval conduct provide sufficient assurance to expect timely completion
- Enrollment has been initiated.
PhRMA recommends eliminating the first two criteria because these relate more to the requirements for postapproval studies and due diligence. They also do not align with the plain meaning of underway as being in progress or happening now.
“With respect to a randomized controlled study, this term as used in the FDCA can best be understood as meaning that the clinical study has begun and is in progress, i.e., that the third criterion is met,” PhRMA’s comments state.
The group asks the FDA to clarify what inputs it intends to consider when assessing diligence and timeliness and how, if at all, these criteria would be used to determine whether a real-world evidence study is underway.
Some patient and consumer groups seek more specific criteria for determining when a trial is underway.
The National Center for Health Research says the key criteria proposed by the FDA are too vague. “The lack of specific enrollment and timeline benchmarks will result in delays that expose patients to drugs without verified clinical benefit for many years.”
The consumer group recommends the FDA replace ambiguous terms with clear, measurable criteria, including concrete benchmarks and milestones. For example, it suggests that initiation of enrollment be defined as occurring when “a substantial number of patients (such as 25 patients or 25% of patients, whichever is larger) already have been in treatment long enough to determine if adverse events or other missing data are likely to be a problem. That would better ensure that the trial is feasible as designed.”
Friends of Cancer Research says additional clarification on what constitutes meaningful trial progress, such as minimum patient enrollment thresholds or site activation requirements, “would enhance alignment between sponsors and the FDA. Clearer expectations would help mitigate regulatory uncertainty and prevent unnecessary delays in confirming clinical benefit.”
When Can Trials Start After Approval?
The Biotechnology Innovation Organization’s comments on the underway guidance ask the FDA to explicitly clarify how it will determine when potential enrollment and retention challenges dictate the need for enrollment to be completed at the time of accelerated approval.
BIO also seeks more details about how the FDA will decide, in the case of rare diseases, when confirmatory studies may not require randomization or may not need to be underway prior to approval.
“Greater detail about the FDA’s decision-making process for these exceptions would be beneficial, enabling a clearer understanding of which diseases, products, or justifications qualify under this exception,” BIO’s comments state. “Examples of what the agency believes would qualify for this exception would also be helpful.”
Alexion also seeks clarity on what constitutes appropriate justification for initiating confirmatory trials after approval for rare disease accelerated approval drugs.
“It would be greatly enabling were FDA to provide historic or clear hypothetical examples, illustrating factors such as the prevalence of the rare diseases or conditions in question, their disease heterogeneity, whether there is limited data on disease pathology and progression, or other unique factors militating against successful or timely patient enrollment for confirmatory trials,” Alexion said.
The Program On Regulation, Therapeutics And Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School requests more information about the limited circumstances under which the agency would grant accelerated approval without a confirmatory trial being underway.
“We propose that drugs not qualifying for priority review, those approved based on pivotal trials with low clinical benefit, or those with major safety concerns (such as boxed warnings) should be required to have confirmatory studies at an advanced stage of recruitment before approval,” PORTAL’s comments state. “By contrast, drugs with substantial clinical promise in pivotal trials or no major safety concerns could be approved with earlier-stage recruitment.”
EMD Serono seeks clarity on how a change in the standard-of-care or treatment landscape while a confirmatory trial is underway should be handled.
Since such a change “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,” the company’s comments state. “This pathway could enable patients to get the latest treatment options without unnecessary delay.”
