FDA issues new COVID-19 master protocol guidance

Regulatory NewsRegulatory News | 17 May 2021 |  By 

A new guidance from the US Food and Drug Administration (FDA) addresses how master protocols can be used in developing drugs to treat or prevent COVID-19.

“To meet the urgent demand for effective therapies, FDA has worked with clinical trial experts to rapidly advance best practices in the design and execution of clinical trials,” said acting FDA Commissioner Janet Woodcock in announcing the new guidance. “Master protocols that are well designed and executed can accelerate drug development by maximizing the amount of information obtained from the research effort. These trials can be updated to incorporate new scientific information, as medical science advances,” she added.

The Accelerating COVID-19 Therapeutics Interventions and Vaccines (ACTIV) is a public-private initiative run under the auspices of the Foundation for the National Institutes of Health. Woodcock pointed to ACTIV as an “excellent example of master protocols being used to simultaneously study a number of promising drugs.”

The new guidance notes that both platform and stand-alone trials have strengths and weaknesses, but that master protocols have inherent efficiency that can accelerate drug development. The up-front time and effort required to set up a complex master protocol should also be considered when weighing the best approach. Sponsors should engage FDA at an early stage in the trial planning process to help work through these considerations.

Guiding principles for developers outlined in the document include a consideration for including both types of trials in a development program. Sponsors should have a clear vision of objectives to be accomplished that will help guide trials design and developers should justify intended doses to be evaluated. “In general, master protocols are not intended for first-in-human investigation,” notes the guidance.

A master protocol should have a randomized comparator arm. Giving this issue forethought can help overcome the “high potential” for confounding that exists when a trial is conducted during a public health emergency such as the COVID-19 pandemic. Some of the complexities that might contribute to confounding include the shifting considerations of which drugs are considered standard of care and might be considered for inclusion as background therapy in either arm. Additionally, some patients may not be eligible for certain drugs because of concurrent chronic medications, risk factors or comorbidities.

Despite potential challenges, developers “should make every effort to incorporate blinding into their trials,” according to the guidance. Considering multiple-dummy designs or distinct, blinded placebos as controls for each drug included in a master protocol trial are among the strategies suggested by FDA. Where blinding is impractical, FDA “strongly recommends” selecting an objective endpoint such as all-cause mortality.

Sponsors of trials investigating both novel and repurposed drugs for COVID-19 should also consider how they collect safety data. If repurposed drugs are both well-characterized and have low toxicity, however, FDA may concur that “a selective approach to safety data collection” may be appropriate. The guidance details factors to consider when considering such a selective approach, such as how selective data collection might affect the other arms of a master protocol-based development program..

Master protocols should be reviewed by a central institutional review board; sponsors should use an independent and external data monitoring committee “or other appropriate independent entity” for safety and efficacy reviews.

The guidance also outlines statistical considerations in the design and use of master protocols, such as when a Bayesian analysis might be the best statistical approach. More broadly, the FDA also advises sponsors to stick to “apples to apples” comparisons between participants when possible, while acknowledging that randomization ratios and even participation criteria may change over the course of a trial.

Woodcock, long a proponent of master protocols and platform trials in drug development, was detailed to lead the therapeutics effort for Operation Warp Speed, the COVID-19 task force set up by the Trump Administration in 2020 at the beginning of the COVID-19 public health emergency.

“Master protocols also reduce administrative costs and time associated with starting up new trial sites for each investigational drug. They can also increase data quality and efficiency through shared and reusable infrastructure,” said Woodcock. “The FDA expects master protocols to continue to play an important role in addressing the public health needs created by the pandemic and in generating clinical evidence in general.”



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