The US FDA’s formal guidance on development of COVID-19 treatments and preventative agents takes a broadly flexible approach to Phase 2 and 3 trial design, repeatedly indicating a willingness to consider varied options while urging sponsors to discuss their trials plans with the agency earlier rather than later.
“FDA is committed to supporting all scientifically sound approaches to attenuating the clinical impact of COVID-19,” the guidance declares. At the same time, however, the agency seeks rigorous clinical evaluations that meet traditional regulatory standards, ideally with placebo controls, randomization and double blinding.
The final guidance, issued on May 11, 2020, focuses on drugs and biologics for treatment or prevention of COVID-19, with two major exclusions: convalescent plasma and preventive vaccines. Development of therapies using plasma from recovered COVID-19 patients was covered by a Center for Biologics Evaluation and Research guidance released on 8 April. (Also see “US FDA Sets Convalescent Plasma Access Recommendations For Coronavirus Patients” – Pink Sheet, 16 Apr, 2020.)
Prospective vaccine manufacturers are also encouraged to contact CBER for direction.
The mechanism of action of a drug candidate influences important study design elements, ranging from population and endpoints to safety assessment and duration of follow-up, the guidance notes. The COVID-19 pipeline is notable for its variety of approaches, ranging from products attacking viral replication and entry to neutralizing antibodies to anti-inflammation agents, immunomodulators, stem cells and RNA interference. (The Pink Sheet’s COVID-19 Pipeline Tracker has information on more than 250 therapies and 100 vaccines.)
The FDA guidance recommendations are centered on development of drugs with direct antiviral activity or immunomodulatory activity, but “may be applicable” to other types of products, the agency said. “For some biological products (e.g., cellular and gene therapies and blood products) there may be additional considerations,” the guidance cautions.
CAST A WIDE NET
Trials should start with a baseline categorization of the severity of COVID-19 in patients with documented (preferably lab-confirmed) diagnoses, using criteria based on objective measures. As an example, the guidance includes an example defining SARS-CoV-2 patients as infected without symptoms or with mild, moderate, severe or critical COVID-19.
The guidance emphasizes the range of populations that should be evaluated in COVID-19 treatment trials. Trials should be conducted in settings from outpatient to hospital inpatient to ICU admission to use of mechanical ventilation. Differences in clinical environments, populations, and disease severity in turn will influence the “relevance and appropriateness” of the clinical endpoints selected for a trial.
FDA Commissioner Stephen Hahn referenced the imperative for clinical development to reflect different manifestations of the disease during a Senate HELP committee hearing on 12 May. “We want to adapt it to the clinical circumstance as well as to the type of therapy that’s put before us,” Hahn said.
“We do know that in some circumstances patients who’ve had severe COVID disease have developed thrombotic or clotting type episodes, so we’ve prioritized review of agents that we think might be beneficial,” he said. “Obviously, the clinical endpoints for those trials will be different than an agent that’s an antiviral like remdesivir where … we’re looking at time to recovery.”
Expansive enrollment criteria will be necessary for clinical development to address the scope of the public health crisis, the guidance suggests, urging sponsors to enroll complicated or fragile patients. People at high risk of complications, like the elderly and people who are immunocompromised or who have underlying cardiovascular, respiratory or kidney disease or diabetes, should be included in clinical trials, the FDA said. Indeed, the guidance suggests conducting trials in nursing homes and other elderly care facilities.
Clinical trial sites also should include “geographic locations with a higher concentration of racial and ethnic minorities to recruit a diverse study population.” At the same time, the document notes, “given the expected fluctuation in regions in the frequency of SARS-CoV-2 infection, sponsors should address the need to open new sites and potentially suspend existing sites.”
“Children should not be categorically excluded from clinical trials of investigational COVID-19 products in which there is a prospect for direct benefit,” the guidance states. The FDA pledges to “work with sponsors to reach agreement on the initial pediatric study plan and any pediatric trial protocols as quickly as possible to avoid any unnecessary delays.”
Sponsors specifically should discuss the potential to extrapolate adult efficacy data to children, the guidance suggests. “For example, if dosing recommendations for a drug are the same for adults and adolescents and there is sufficient prospect of benefit to justify the risks, then it may be appropriate to include adolescents in the initial Phase III clinical trials.”
CAUTIOUS EMBRACE OF PLATFORM DESIGNS
The FDA “strongly recommends” that sponsors conduct trials that are randomized, placebo-controlled, double-blind, and use a superiority design.
“Under certain circumstances it may be appropriate to conduct decentralized and/or platform clinical trials,” the guidance states, taking a cautious stance on the increasingly popular platform trial approach.
“FDA recognizes the potential of, and significant interest in, such approaches,” the guidance continues. The agency “may provide additional recommendations as we gain more experience regarding their use in this context.” Sponsors, as always, should discuss their plans with the agency.
The National Institutes of Health is backing platform trials in its anti-COVID-19 efforts. The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTV) consortium, launched by NIH in mid-April with 16 biopharma companies, US health agencies and the European Medicines Agency, is discussing a variety of master protocol options for different populations.
“Everyone agrees a master protocol structure where you are testing multiple therapies simultaneously is probably the only way to do this efficiently and where you can add or drop arms as they succeed or fail,” David Wooley, senior VP of research partnerships at the Foundation of the National Institutes of Health, said. FNIH is coordinating ACTV. (Also see “NIH Partnership To Pick COVID-19 Therapeutics For Clinical Trials; Results Anticipated By Summer” – Pink Sheet, 19 Apr, 2020.)
The NIH is already using an adaptive platform trial design in its first sponsored study of COVID-19 therapies, the Phase III ACTT trial, which started in February 2020 testing Gilead Sciences Inc.’s antiviral remdesivir against placebo. (Also see “COVID-19 Study Of Gilead’s Remdesivir Using Ebola-Style Adaptive Platform Trial” – Pink Sheet, 17 Mar, 2020.)
The trial is evolving rapidly: the primary endpoint was changed after a planned review of the outcome scale after 100 patients, and the NIH recently announced movement to a second stage of the trial, dubbed ACTT2, combining remdesivir with Eli Lilly & Co.’s anti-inflammatory Olumiant (baricitinib). (Also see “NIH Pushes Ahead With First COVID-19 Combo: Remdesivir Plus Lilly’s Olumiant” – Scrip, 12 May, 2020.)
The FDA guidance identifies one potential role for adaptive design: when there is “some but limited” data supporting a drug’s potential for efficacy, and the sponsor hopes to