FDA COVID-19 guidance lays out best practices for master protocols

To accelerate drug development targeting the pandemic, the FDA issued final guidance May 17 on master protocols for drugs intended to prevent or treat COVID-19 infections.

Although the guidance is geared toward developing COVID-19 drugs, the FDA said it expects master protocols to continue to play an important role in addressing the public health needs in future pandemics. Toward that end, the agency plans – within 60 days of the end of the current public health emergency – to revise the guidance based on comments it receives and its experience in implementing it.

The guidance primarily focuses on umbrella trials, which evaluate multiple therapies simultaneously for a single disease, and platform trials, which evaluate multiple therapies for a single disease in a perpetual manner, with therapies entering or leaving the platform based on a decision algorithm. The master protocols accelerate drug development by maximizing the information from the trials and reducing administrative costs and time, according to the FDA. They also can be updated to incorporate new scientific information as it becomes available.

While the guidance advises on the design, conduct and statistical considerations of master protocols intended to generate or contribute to the substantial evidence of effectiveness and adequate characterization of the safety of a COVID-19 drug, the principles outlined in it also may apply to master protocols intended to generate proof-of-concept or dose-ranging data. In addition, the guidance provides administrative and procedural recommendations.

Blinding is one of the best practices discussed in the guidance, with the FDA advising sponsors to “make every effort to incorporate blinding” into the protocol. In a placebo-controlled trial in which the investigational drugs have multiple routes of administration or variable dosing schedules, the guidance suggests two ways to provide blinding: a multiple-dummy design or a distinct, blinded placebo control for each drug being evaluated. When blinding is impractical, the guidance recommends use of an objective endpoint such as all-cause mortality.

The guidance also discusses a challenge unique to master protocols, stressing the importance of ensuring that the analysis and communication of results for one investigational drug does not lead to the inadvertent dissemination of information for the other drugs still being evaluated. “Knowledge of accumulating data can affect the course and conduct of a trial, and the behavior of its sponsor, investigators and participants, in ways that are difficult to predict and impossible to adjust for,” according to the guidance.

Although a master protocol includes multiple therapies for the same disease, the FDA said it doesn’t require comparisons between the drugs included in an umbrella or platform trial. However, “the comparisons may be useful for comparative-effectiveness research and informing treatment guidelines,” the agency added. Master protocol sponsors should prespecify in the statistical analysis plan if they plan on conducting such comparisons.

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