COVID-19 Highlighted Master Protocol Benefits, But Challenges Remain
Master protocols, having shown their usefulness in COVID-19 and oncology research, are on the rise and expected to expand into other therapeutic areas. But even with the strong backing of regulators, challenges remain for master protocol studies to become more commonplace.
Only 2.5 percent of the 558 COVID-19 intervention trials listed with ClinicalTrials.gov as of Dec. 1, 2020, used master protocols, according to former FDA Commissioner Robert Califf, currently head of clinical policy and strategy for Verily and Google Health. That’s “not many, but if there were master protocols with a lot of sites signed up being efficient, obviously we could answer questions much more quickly,” he said.
For example, Califf pointed to eight master protocol trials in the U.S. focused on COVID-19 — specifically, the REMAP-COVID sub-platform trial, the I-SPY COVID-19 adaptive platform trial and six trials within NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program. The eight master protocol trials collectively had 229 active sites by the first week of January 2021 and were in the process of setting up 325 more. The eight studies collectively plan to have between 952 and 1,002 sites.
In contrast to a slow start in the U.S., the University of Oxford’s RECOVERY (Randomized Evaluation of COVID-19 Therapy) was able to be up and running by March 2020, while the pandemic was still in its early days. RECOVERY’s master protocol design has successfully yielded data on several possible interventions — specifically, low-dose dexamethasone, hydroxychloroquine, lopinavir-ritonavir, azithromycin, convalescent plasma, colchicine, tocilizumab, aspirin and Regeneron’s antibody cocktail of casirivimab and imdevimab. Immunoglobin was also tested in children only. RECOVERY was able to take off quickly, thanks to immediate buy-in by the UK’s nationalized health system, which immediately provided the trial with 176 sources for data.
Christian Schneider, director of the National Institute for Biological Standards and Control (NIBSC), part of the UK’s Medicines and Healthcare products Regulatory Agency (MHRA), says the agency had seen increased use of what the agency deems “complex clinical trials” over the past three years. At last week’s DIA Europe 2021 conference, Schneider said about one-third of the 29 trials approved by MHRA in 2020 were for COVID-19 indications, and most of them were either umbrella or platform master protocols. Surprisingly, one-quarter of the approved trials were in nononcology.
Adaptive trials will be covered when the International Council for Harmonization (ICH) publishes a draft version of its E20 guidelines, either later this year or in 2022. “It is happening — there will be ICH guidelines that include Bayesian elements and adaptive design,” says Frank Pétavy, head of a methodology, data analytics and methods task force with the European Medicines Agency. ICH is planning member meetings to discuss E20 in June, with final publication estimated for 2024.
Janet Woodcock, acting commissioner of the FDA, is a longtime proponent of master protocols and has made it clear that she’d like to see more such trials in the U.S. During a recent webinar, she said the U.S. would be further along in its fight against the coronavirus if the country had a better infrastructure in place for running master protocol studies.
“The studies that we should have set up should have been overpowered based on our original estimates, so that we nailed down answers that everyone could believe in,” she said.
“In the U.S., when we have a master protocol, it takes a long time to get the sites up, whereas it appears that in the RECOVERY trial it just sort of happened,” Califf said. “I’m sure it wasn’t without tremendous effort, but perhaps the buy-in of the health system and the clinical practice regime is what made the difference here. It’s worth examining the question of where our effort is going.”