FDA revises master protocol guidance with new section on basket trials
The US Food and Drug Administration (FDA) has revised a 2023 draft guidance on master protocols for drug and biological product development, reflecting significant stakeholder feedback it has received since the original draft was proposed. Among the updates is a new section on evaluating drug effects across multiple diseases, conditions, or disease subtypes in basket trials.
The revised draft guidance, issued on 22 June, lays out design and analysis recommendations for clinical trials that are conducted under a master protocol, defined as a trial protocol with multiple substudies that may have different objectives and require coordination to evaluate several drugs simultaneously for a multitude of diseases or conditions. The agency noted that the decision to revise the guidance meets requirements in the 2022 Food and Drug Omnibus Reform Act (FDORA) to provide clarity on streamlining clinical trial logistics and efficiently collecting and analyzing data.
"FDA is issuing a revised draft guidance in response to public comments received on the original draft requesting that FDA provide additional recommendations on basket trials," said FDA. "Changes from the original draft include more detailed recommendations regarding basket trials and minor changes for clarity on topics such as randomization, choice of control, and informed consent."
Basket trials are defined as those designed to evaluate a drug for multiple diseases, conditions, or disease subtypes. Platform trials are similarly designed to evaluate multiple drugs for one or more diseases, conditions, or disease subtypes, but allow drugs to enter or leave the platform as the trial progresses.
Regulators emphasized that the revised guidance primarily focuses on master protocol randomized trials and may apply to a range of therapies.
"Well-designed and -conducted trials using master protocols can accelerate drug development by maximizing the amount of information obtained from the research effort," said FDA. “Compared with stand-alone trials under separate protocols, a master protocol may offer logistical advantages by leveraging shared protocol elements (e.g., visit schedule, measurement procedures), shared infrastructure (e.g., network of clinical sites, central facilities, central randomization system, data management systems), and shared oversight (e.g., steering committee, data review committee).
"Some master protocols may also improve efficiency by leveraging a shared control arm in evaluating multiple drugs or by leveraging information on drug effects across multiple related diseases, conditions, or disease subtypes," the agency added.
FDA noted that the complexity of master protocols means longer start-up times, potential design challenges, and requires greater coordination among parties. The agency discusses several key design and analysis issues to help sponsors address the complexities, including randomization, control group, informed consent, blinding to treatment assignment, adaptive design, comparisons between drugs, approaches for evaluating drug effects across multiple diseases, conditions, or disease subtypes, multiplicity, and safety. The guidance also aims to provide clarity on issues such as trial oversight, data sharing, information dissemination, and regulatory submissions.
In the revised draft guidance, FDA elaborates its expectations for how basket trials and platform trials with basket components should evaluate the effects of a drug in multiple diseases, conditions, or disease subtypes in different substudies.
"In some cases, the primary objective may be to evaluate the average effect of the drug in the combined population by conducting a single combined analysis of data across the individual substudy populations," said FDA. "In other cases, the primary objective may be to evaluate the effects of the drug within each disease, condition, or disease subtype."
FDA said that, given the complexities, sponsors may need to conduct separate analyses within each individual substudy population, using only data from that population, which may be the most appropriate way to minimize bias in many basket trials. Sponsors may also consider using information across related substudy populations to achieve potential efficiency gains, provided there is scientific justification. Regulators listed several approaches sponsors can use in basket and platform trials to leverage data to support their products' market entry.
"Sponsors should specify and justify a clear primary objective of the overarching trial and provide a rationale for how the design and analysis of the trial will accomplish the objective," said FDA. "This should include a justification for combining or leveraging information across substudies.
FDA also said that sponsors should prespecify and justify their statistical methods, including those used to evaluate the primary trial objective and to estimate treatment effects, with quantification of uncertainty. The agency emphasized that statistical methods lie along a continuum, depending on how clinical trial data are combined or leveraged across substudies.
Another key addition to the revised guidance is that it includes a chart in the appendix and includes clarification on FDA's expectations for how the master protocol sponsor, individual drug sponsors, and regulators should communicate while the master protocol is in effect.
Stakeholders can comment on the revised guidance on www.regulations.gov under docket no. FDA-2023-D-5259 until 22 August.
