Stakeholders seek to reshape FDA’s guidance for master protocols

Stakeholders have weighed in on new draft guidance for master protocols in clinical trials with suggestions on scope, acceptable randomization practices and informed consent.

The US Food and Drug Administration (FDA) issued draft guidance titled Master protocols for drug and biological product development guidance for industry on December 21.

The agency defined a master protocol as a “protocol designed with multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more medical products in one or more diseases or conditions within the overall study structure.”

In the guidance, the agency explained that trials with master protocols can accelerate drug development by getting more out of research efforts with greater efficiencies. (RELATED: FDA proposes master trial protocols that goes beyond COVID-19)

“FDA has summarized a complex and evolving field with clarity and provided direction on the many complicated variations of master protocols,” wrote directors at the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard (MRCT) in comments about the guidance. “The increasing interest and use of master protocols, particularly in investigational product development programs, will provide for active collaboration and learning as the experience grows.”

Questions about scope

In its comments about the guidance, the Biotechnology Innovation Organization (BIO) wrote that it is unclear if devices are included. BIO also asked that the definition of master protocol could be broadened to include testing of combination therapies.

Several commenters asked for clarity about the types of designs included. The guidance notes that there are three types of studies with master protocols:

Umbrella trial: a trial designed to evaluate multiple medical products concurrently for a single disease or condition.
Platform trial: a trial designed to evaluate multiple medical products for a disease or condition in an ongoing manner, with medical products entering or leaving the platform.
Basket trial: a trial designed to evaluate a medical product for multiple diseases, conditions, or disease subtypes.

“The primary focus of this guidance is on randomized umbrella and platform trials that are intended to contribute to a demonstration of safety and substantial evidence of effectiveness of a drug,” the guidance states. “The concepts discussed may also be useful to consider for early-phase or exploratory umbrella and platform trials as well as those conducted to satisfy post-marketing commitments or requirements.”

Although the guidance defines three types, it appears to limit its focus to randomized umbrella and platform trials, MRCT noted, adding that the title could be changed to specify randomized umbrella and platform studies to “reflect this scope more accurately and to avoid confusion.”

“Alternatively, substantive differences between randomized umbrella and platform trials and other trial types, if they exist, could be more clearly explained,” MRCT wrote.

AstraZeneca advised FDA to include basket trials, and BIO said it would like to see a section added on Bayesian trial design.

“Most Phase 1 through Phase 2b master protocols, especially platform trials, have action taken based on a series of Bayesian decision rules,” BIO wrote.

Suggestions on control arms and blinding

The draft guidance elicited many comments and concerns about blinding, randomization and control arms. The Oncology/Immuno-Oncology subteam of Innovative Design Scientific Working Group (IDSWG) wrote that the guidance includes a lot of information about fixed randomization, while not touching upon adaptive randomization used in many platform trials.

MRCT commented that the draft guidance focuses on a single control type, for example placebo or active control, but more than one type of control is preferred for some master protocols.

“Are there special considerations in multi-national master protocols in terms of protocol study design and/or conduct? For instance, the comparator control may or may not be available in all regions,” MRCT wrote. “There may be additional demographic and non-demographic differences between and among potential participants that would impact the randomization parameters.”

The Arnold Ventures philanthropy advised FDA to strengthen reliance on randomization of clinical trial participants in master protocols.

“The mission of FDA is to be responsible for protecting public health by ensuring the safety and efficacy of drugs and to get the public accurate, science-based information from adequate and well-controlled clinical trials,” Arnold Ventures wrote. “Clinical trials lack proper controls for systemic bias when trial participants are not randomly assigned. While not the only control for bias in clinical trial design, randomization improves comparability among clinical trial participants.”

The Alliance for Regenerative Medicine (ARM) noted that the guidance focuses on randomization to an internal as opposed to external control group.

“Because internal control is often infeasible or unethical for rare diseases, we request adding rare diseases as an example of an instance in which considerations may be made for use of external control,” ARM wrote.

The guidance notes that open label design is only justified in “rare circumstances.” ARM suggested that the guidance should cite ex vivo gene therapies as an example where blinding is impractical. ARM also asked for additional trial design considerations for rare disease therapeutics and for guidance on the use of biomarkers in master protocols.

Certara asked FDA to add comments and recommendations for master protocol applications involving investigations of rare diseases, particularly in pediatric populations.

Efficiencies in informed consent

Many commenters asked FDA to rethink its stance favoring use of a single informed consent form instead of a two-step process with a regimen-specific appendix for master protocol trials.

“Using a single consent form would require participants to be presented with the risks and benefits of multiple drugs and be provided with updates throughout their participation on each of these drugs,” wrote the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital.

With a single form, the study sponsor would need to update the consent form for each trial site every time the site was activated for a new substudy.

“This would slow overall enrollment in the master protocol because each time a change is made – the sites would not be able to continue to screen participants for open sub-studies until the single IRB of record reviews and approves the updated consent form,” the Healy & AMG Center wrote. “For multicenter trials with a large number of participating sites, this would add burden to sites, IRBs, master protocol sponsors, and most importantly study participants.”

Likewise, the MRCT wrote that FDA’s plan for informed consent appears “burdensome”.

“Both patients/participants and investigators generally prefer two-level consent, and we suggest that FDA further explore these concerns prior to the finalization of the guidance,” the MRCT wrote.

“One additional question is whether there are considerations specific to master protocols involving children (e.g., assent, one or two parent requirements, etc.) that should be mentioned,” the MRCT added.

Stakeholders seek to reshape FDA’s guidance for master protocols

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