The guidance takes effect immediately and will remain in effect throughout the pandemic.
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The U.S. Food and Drug Administration (FDA) issued final guidance Monday on master protocols for evaluating prevention and treatment options for COVID-19. The guidance takes effect immediately and will remain in effect throughout the pandemic.
The document, COVID-19: Master Protocols Evaluating Drugs and Biological Products for Treatment or Prevention Guidance for Industry, brings industry best practices learned during the pandemic to bear on the design and execution of clinical trials. This new guidance focuses specifically on strategies to evaluate therapeutics to treat or prevent COVID-19.
Master protocols are designed to incorporate multiple sub-studies involving coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes, with one or more objectives, all within the same overall trial structure.
This guidance focuses on umbrella trials (which simultaneously evaluate multiple therapies for a single disease) and platform trials (which evaluate multiple therapies perpetually). It also provides administrative and procedural recommendations to sponsors of master protocols for COVID-19 drugs.
Key points in the guidance are to:
- Include an appropriate randomized comparator arm that account for changes in standard of care.
- Obtain Agency concurrence for changes when the drug is used as background therapy or as part of the control arm.
- Design protocols to prevent study participants from being randomized to drugs they are not eligible to receive.
- Incorporate blinding into trials, perhaps using a multiple-dummy design, or a distinct placebo control for each drug. If impractical, design an objective end-point.
- Design multiple intervention-specific endpoints in cases where drugs are intended to affect different aspects of the disease.
- When considering a selective approach to safety and toxicity data for repurposed drugs, work with the FDA to identify which data is necessary in these new circumstances.
In terms of statistical data collection and analysis, the guidance recommends:
- Early on, discuss with the FDA any plans to include complex adaptive or Bayesian designs.
- Base statistical analyses for a given investigational drug on comparisons against only those control arm participants who were concurrently randomized.
- When some participants are eligible for only some treatment arms in the trial, statistical analyses for a given treatment should only include eligible participants.
- If the overall randomization ratio to an investigational drug and its comparator changes during the trial, comparisons between them should be stratified by the time periods of the various randomization ratios.
- To reduce correlation errors in umbrella or platform trials, include considerations beyond the p-value from a single comparison in determining effectiveness.
- Prevent the analysis and communication of results for one investigational drug from inadvertently disseminating information regarding other drugs and thus compromising trial integrity.
The guidance also outlines administrative and procedural recommendations for working with the FDA.
“Compared with conducting separate stand-alone trials, conducting an umbrella or platform trial can increase data quality and efficiency through shared infrastructure and can reduce overall sample size through sharing of a control arm,” the guidance explained. Therefore, while it focuses on generating data regarding the effectiveness and safety of COVID-19 therapies or preventions, “the principles may also apply to master protocols generating proof of concept or dose-ranging data for drugs to treat or prevent COVID-19.”
As Janet Woodcock, M.D., the acting FDA commissioner, noted when making the announcement, “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.
“Master protocols also reduce administrative costs and time associated with starting up new trial sites for each investigational drug,” she continued. “They can also increase data quality and efficiency through shared and reusable infrastructure. These advantages are of particular importance during a public health emergency such as the current SARS-CoV-2 pandemic, where there is a critical need for efficient drug development.”
The FDA guidance is intended to complement other COVID-19 guidances from the FDA, such as COVID-19: Developing Drugs and Biological Products for Treatment or
Prevention (February 2021), Emergency Use Authorization for Vaccines to Prevent COVID-19 (February 2021) and others.
Master protocol trials are quite complex, necessitating “a high degree of up-front planning and coordination,” compared to standalone trials, the FDA pointed out.
“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,” Woodcock said.
The guidance was issued without a public comment period because of the dire nature of the COVID-19 public health emergency, but remains subject to comment and so may be refined as more is learned.
