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generate some evidence before enrolling a large number of subjects.
A trial with “the prospect of expanding from a proof-of-concept phase to a larger confirmatory trial” can incorporate “prospectively planned adaptations.” It should also include prospectively planned criteria to stop the trial for futility.
Stopping criteria are emphasized in the guidance, which encourages sponsors “to incorporate prospectively planned criteria to stop the trial for futility (lack of efficacy) or harm in any confirmatory trial.”
REACTING TO AN EVOLVING LANDSCAPE
In the fluid COVID-19 treatment landscape, “the standard of care is expected to change as additional information, such as from randomized controlled trials, emerges,” the agency observed. “FDA anticipates events that occur outside of an ongoing trial may provide important new information … and may motivate revisions to the trial design.”
“Well-motivated changes based on information external to the trial can be acceptable,” the guidance states.
When there is an established standard of care for specific populations, FDA recommends placebo-controlled superiority studies that add drug candidate or placebo to the standard of care.
When the standard of care changes, drugs that share a mechanism of action with the new standard of care can use an active-comparator controlled study design, the guidance says, “if there is sufficient preclinical and initial clinical evidence of activity.” New direct acting antiviral candidates, for example, could use an active-comparator control when a direct acting antiviral becomes the standard of care.
DIFFERENT POPULATIONS, DIFFERENT ENDPOINTS
The guidance allows for some flexibility in efficacy endpoints, advising that trials evaluate drug candidates against placebo on “clinically meaningful aspects of the disease.”
Different patient population, disease severities and clinical settings may necessitate different endpoints assessed at different time points. In general, however, “the time window should be sufficiently long to ensure capture of important events related to patient status, treatment and COVID-19 progression,” the guidance notes.
Additionally, “sponsors should address potential relapses in their endpoint definitions to ensure adequate assessment of the durability of response,” the guidance says.
The guidance lists a number of examples of important clinical outcome measures, emphasizing an overarching need for “clear definitions and specific clinical criteria.” Suggestions include measures of respiratory failure, need for mechanical ventilation or hospitalization, sustained clinical recovery (symptom resolution), and “objective measures of sustained improvement” like return to room air or baseline oxygen requirement.
The FDA guidance references the ordinal scale measuring clinical status set out in the World Health Organization’s COVID-19 R&D Blueprint, listing “clinical status at an appropriate time point assessed using an ordinal scale” as an example of an endpoint for trials in severe or critical COVID-19 patients. A suitable ordinal scale includes multiple clinical outcomes of interest “ordered by their clinical importance,” the guidance notes.
The WHO scale runs from zero (uninfected) to eight (death), and tracks measures including oxygen therapy and mechanical ventilation. It is the most common of the ordinal scales that are being used in industry- and government-sponsored Phase III. (Also see “COVID-19 Phase III Trial Design: Big Ambitions, Little Consistency” – Pink Sheet, 11 May, 2020.)
Outpatient trials might look at the proportion of patients hospitalized at set time, like 28 days, or time to sustained clinical recovery.
Virologic endpoints should not be used a primary endpoints for Phase III trial, the guidance rules, “because there is no established predictive relationship between magnitude and timing of viral reductions and the extent of clinical benefit of how a patient feels, functions or survives.” The optimal sample size, timing, and assays for clinically relevant virologic measurements are also not established.
However, virologic measures make suitable secondary endpoints in Phase III, and can be used as a primary endpoint in a Phase II trial to support a Phase III clinical endpoint study, the guidance notes. “Collection of virologic data and evaluation of antiviral resistance are important components of drug development for COVID-19.”
HURRY, THEN PAUSE
The exigencies of the pandemic have dramatically increased the pace of drug development, but they do not obviate the need for adequate safety assessment. Thus, “if enrollment is anticipated to be rapid, but additional safety data are needed before dosing a large number of subjects,” the FDA guidance suggests building an “enrollment pause” into the trial.
“In this case, enrollment would be temporarily halted,” the agency said. The trial’s data monitoring committee would “assess the data and then recommend that the trial or dosing group either terminate or resume enrollment.”
The FDA guidance also suggest the use of standardized toxicity grading scales for clinical trials in patients with severe COVID-19 or with serious comorbidities, pointing to toxicity grading scales developed by the National Institutes of Health’s Division of AIDS and the National Cancer Institute.
The final COVID-19 treatment and prevention drug development guidance was issued without a draft version because FDA concluded that “prior public participation for this guidance is not feasible or appropriate.” The guidance will be in effect for the duration of the COVID-19 public health emergency declared by the US Department of Health and Human Services on 31 January 2020.
The end of the emergency will not, however, be the end of FDA’s guidance on COVID-19. Experience with the implementation of the guidance is “expected to assist the agency more broadly in its continued efforts to assist sponsors in the clinical development of drugs for the treatment of COVID-19,” the FDA said. “Therefore, within 60 days following the termination of the public health emergency, FDA intends to revise and replace this guidance with any appropriate changes,” based on comments received and internal discussion.