No Match Found
The World Health Organization (WHO) has proposed a master protocol for companies and institutions that aim to test therapeutics against SARS-CoV-2, the novel coronavirus that causes the respiratory disease, COVID-19. The WHO’s plan, part of its COVID-19 R&D Blueprint, borrows from similar designs in oncology and other outbreaks such as Ebola.
Master protocols allow researchers to test different investigational agents against a shared control arm with a uniform set of clinical endpoints, enrollment criteria, predefined data collection and statistical methods. Institutional review board (IRB) approval is gained before the trial is started and is not needed every time a new agent is added.
Master protocols are designed to run in perpetuity, allowing different investigational agents to be added and others to leave the trial once the necessary data are collected. The investigational agents are compared individually to the control group, but not to one another.
This trial design is in contrast to traditional clinical trials, in which researchers test one investigational agent against a control group across a specified patient population and among clinical institutions for which it has obtained IRB approval.
The WHO’s COVID-19 proposed master protocol has a pilot stage and a pivotal stage. The pilot stage will have about 50 to 100 participants randomized to one of the various investigational agents or standard-of-care as the control. The WHO will use the results from the pilot phase to inform the design of the pivotal phase and identify markers of disease evolution and clinical benefits.
Once the pivotal phase is started, the investigational agents would be tested “until there is available evidence that they have a favorable benefit-risk profile or until futility is established; according to a prior established clinical and statistical criteria.”
“The trial is intended to include as many sites as possible affected by the epidemic,” the blueprint stated. The WHO issued a request for comments on the protocol, which closed on March 4. It also has issued a master protocol for vaccine development.
Master protocols have been used mainly in oncology, but the FDA also has used the tool as a more efficient way to test therapeutics in pandemic situations.
In 2015, during the Ebola outbreak in Africa, the FDA and the National Institutes for Allergy and Infectious Disease (NIAID) used a master protocol to test multiple therapeutic agents to treat patients infected with the virus. The trial, like the one proposed by the WHO, also used an adaptive design whereby Bayesian statistics, a type of probability statistics, are used to predict which treatments are likely to have a benefit based on early, limited data.
The adaptive design allows investigators to quickly identify which treatments could be beneficial, lessening the time it takes to get a potentially effective drug to patients.
While the Ebola epidemic declined before the clinical efficacy of the agents in the trial could be determined, the FDA stated in a blog post last year, that the trial design “successfully illustrated the feasibility and desirability of innovative trial designs to meet the demands of a public health crises.”
The FDA issued guidance last September about how drug sponsors and other stakeholders could work with the agency on the design of innovative trials that use master protocols and adaptive designs among other elements. A draft guidance issued in 2018, outlines considerations for the design of master protocols.
Master protocols with adaptive designs have successfully delivered results in other settings, including the Phase II I-SPY 2 neoadjuvant breast cancer study where multiple agents predicted by the study to be effective have subsequently completed confirmatory trials and been approved. Other such trials are ongoing in glioblastoma multiforme (GBM AGILE), pancreatic cancer (Precision Promise) and Alzheimer’s disease (EPAD) among others.
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