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The agency has published multiple guidance documents and policy initiatives for updating and advancing the clinical research process.
One lesson of the COVID-19 pandemic is the importance of being able to assess potential new therapies and vaccines quickly and reliably and in ways that can adapt to changing scientific evidence and public health needs. FDA has responded to these pressures by generating multiple guidance documents and policy initiatives for updating and advancing the clinical research process, including the incorporation of master protocols in research programs to facilitate the development of safety and effectiveness information for multiple test therapies in a compressed time period.
FDA Acting Commissioner Janet Woodcock has long supported wider use of master protocols for such purposes and has worked to advance this approach in the face of greater urgency during the pandemic to ensure that a promising drug is safe and effective. Clearer FDA policies for utilizing master protocols can help advance “best practices in the design and execution of clinical trials” to better evaluate drugs for the treatment or prevention of COVID-19, Woodcock commented in announcing final guidance on this clinical research approach.
The guidance aims to overcome fairly limited use of master protocols in the United States by clarifying for sponsors FDA’s recommendations for evaluating coronavirus treatments or preventives through a coordinated research approach. The advisory describes the design, conduct, and statistical considerations of such studies, along with procedures and recommendations for sponsors to follow.
FDA explains the differences and uses of master protocols for umbrella trials (evaluate multiple products simultaneously for a single disease) and for platform trials (evaluate multiple therapies in a perpetual manner, with test products entering and leaving the study based on results). By coordinating multiple studies, this approach can address multiple scientific questions for several test therapies and help avoid confounding, which is more likely for studies conducted during a public health emergency. An important efficiency is to utilize a common randomized comparator arm.
On the downside, this more complex research approach can require more up-front planning and coordination, FDA concedes, advising research sponsors to consult agency experts early in product development to assess these considerations and study options. In some situations, both stand-alone and platform studies may be appropriate for a drug development program. And while FDA recommends subject blinding, the guidance acknowledges that blinding is not always possible or practical. Master protocols should be reviewed by a central institutional review board, and sponsors should use independent data monitoring committees to ensure objective review of safety and efficacy.
While this latest guidance specifically applies to biopharmaceutical research conducted during the current public health emergency, FDA notes that it aims to provide a basis for ongoing use of master protocols in the future. The agency says that it plans to revise the guidance going forward based on the experience gained during the pandemic.
Well-designed master protocols are important in accelerating drug development, Woodcock noted, “by maximizing the amount of information obtained from the research effort.” Such trials can be updated to incorporate new scientific information and can reduce administrative costs and time involved with starting up new study sites for each investigational therapy. And this approach can increase data quality and efficiency through shared and reusable infrastructure.
Woodcock cites the public-private initiative organized by the Foundation for the National Institutes of Health, the Accelerating COVID-19 Therapeutics Interventions and Vaccines (ACTIV) study, as an “excellent example of master protocols being used to simultaneously study a number of promising drugs.” The potential for well-designed master protocols to accelerate drug development compared to stand-alone studies signals that this research approach will “continue to play an important role in addressing the public health needs created by the pandemic and in generating clinical evidence in general,” Woodcock concluded.