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, which is 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 end points, enrollment criteria, predefined data collection, and statistical methods. The investigational agents are compared individually to the control group but not to one another. Institutional review board/Ethics Committee (IRB/EC) approval is gained before the trial is started and is not needed every time a new agent is added.
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 clinical and statistical criteria established prior to the study start. Other arms can be added if evidence emerges that there are suitable candidate therapeutics. Conversely, in some patient populations, not all trial arms are appropriate (e.g., due to contraindications based on comorbid conditions or concomitant medication) and in some hospitals, not all treatment arms will be available (e.g., due to manufacturing and supply shortages). Also, if one or more of the active drug treatments is believed, by the attending clinician, to be contraindicated (or definitely indicated) for the specific patient, the randomization will be between fewer arms.
In already-started studies, all randomized participants are to be followed up until death, discharge from hospital or 1 month post-randomization (whichever is sooner). It is recognized that in the setting of COVID-19 trials, there may be some variability in exactly how many days post-randomization information on disease status is collected. This is acceptable and will be taken into account in the analyses and interpretation of results, the principle being that some information about post-randomization disease status is better than none.
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 were used to predict which treatments were likely to have a benefit based on early, limited data.
While the Ebola epidemic declined before the clinical efficacy of the agents in the trial could be determined, the FDA stated that the trial design “successfully illustrated the feasibility and desirability of innovative trial designs to meet the demands of a public health crises.” As a follow-up, the FDA issued guidance(1) 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.
On 16 March 2020, EMA’s Human Medicines Committee (CHMP) published a document(2) urging the EU research community to prioritize large randomized controlled studies (with a control arm without antivirals or other experimental agents) because they are most likely to generate the conclusive evidence needed to enable rapid development and approval of potential treatments for COVID-19. The statement promotes a harmonized approach to data collection and a robust methodology for COVID-19 clinical trials across the EU to make the best use of the available supply of investigational agents. It emphasizes the need to include all EU countries in these trials. The CHMP also expressed concern about the amount of planned small studies or compassionate-use programs across Europe that are unlikely to be able to generate the required level of evidence to allow clear-cut recommendations. Such studies would not be in the best interests of patients.
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- S Department of Health and Human Services Food and Drug Administration, master protocols: efficient clinical trial design strategies to expedite development of oncology drugs and biologics guidance for industry (Draft Guidance) 2018
- A call to pool EU research resources into large-scale, multi-centre, multi-arm clinical trials against COVID-19. EMA/136815/2020
