FDA: Master protocols have value in COVID-19, and beyond

Regulatory NewsRegulatory News | 15 April 2021 |  By 

An official from the US Food and Drug Administration (FDA) recommended that developers of COVID-19 drugs consider using master protocols to assess the benefits and the risks of potential COVID-19 treatments and outlined ways to ensure the integrity of the data generated from these protocols.
Gregory Levin, the deputy director of the Division of Biometrics III in the FDA’s Office of Biostatistics, described how master protocols can be leveraged to evaluate the safety and effectiveness of COVID-19 drugs at the 14 April DIA/FDA Biostatistics Industry and Regulator Forum.
Levin’s remarks drew from recent submissions of master protocols to the agency for COVID-19 treatments.
FDA’s 2018 guidance defines master protocols as “a protocol designed with multiple sub-studies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure.” (RAPS Focus 21 December 2018) These protocols have often been used to boost statistical power in trials with small sample sizes.
Master protocols have been most frequently implemented in oncology to generate evidence for multiple drugs or multiple diseases and are increasingly being used by drug developers for other types of treatments.
Levin said that master protocols have proven to be “quite valuable” for COVID-19 drugs. He said that “one of the issues with COVID-19 development, particularly in the US, is that there are a lot of small studies for many, many agents, the outcome of some were not promising. The results from these studies have been difficult to interpret due to the small sample sizes and the lack of precision and the tremendous uncertainty about important outcomes such as patient mortality.”
He said that “what a platform can do in such a setting is allocate resources to the most promising treatments.”
One of Levin’s recommendations was that the analysis of the data should only use concurrent control data “unless there is a compelling rationale to leverage non-concurrent control data.” Using concurrent control data is important because it is the only way to avoid systematic differences between the drug and the control, he added: “In the COVID-19 setting there can be very real reasons why there may be changes over time in patients such as the mortality rate in the standard of care…. There can also be changes in the virus itself which may affect the mortality rate.”
Levin also espoused the overall benefits of using platform trials, or master protocols, for in drug development plans for other therapeutics.
These protocols “can increase efficiency through shared infrastructure and a shared control arm. There can also be a value to provide some comparative benefit and risk of treatments to inform real world treatment decisions.”
Janet Woodcock, the former director of the FDA’s Center for Drug Evaluation and Research, who now heads the agency’s Operation Warp Speed program, has long advocated for the benefit of master protocols. In 2017, she co-authored a New England Journal of Medicine piece advocating for the use of platform trials for efficient generation in precision medicine to efficiently generate evidence for precision medicine in an article written for the New England Journal of Medicine in July 2017. (RELATED: FDA officials: Master protocols needed for precision medicine, Regulatory Focus 07 July 2017)
More recently, Woodcock pointed to some of the missed opportunities of investigational use of COVID-19 therapeutics during the early days of the pandemic, when early adoption of master protocols and platform trials could have allowed investigators and regulators to acquire more comprehensive and useful data. (RELATED: Woodcock: Pharma, regulators have lessons to learn from COVID, Regulatory Focus 12 November 2020)
DIA/FDA Biostatistics Industry and Regulator Forum



© 2023 Regulatory Affairs Professionals Society.

Discover more of what matters to you