US FDA Pushing Coronavirus Trial Sponsors To Include Control Groups
Executive Summary
“We still try hard to get people to have a control group,” Bob Temple says in an interview. “Not everybody always wants to have a control group. We've been trying hard to do it.”
Amid the rush of coronavirus therapeutic proposals and a drive to gather data quickly, US Food and Drug Administration officials said they continue to push for development program characteristics to ensure the information is as useful as possible.
In an interview with the Pink Sheet, Robert Temple, deputy director for clinical science in the FDA’s Center for Drug Evaluation and Research, said that effort includes encouraging controlled clinical trials for testing COVID-19 therapeutics.
“We still try hard to get people to have a control group,” Temple said. “Not everybody always wants to have a control group. We've been trying hard to do it.”
Agency officials repeatedly have called for placebo or other controls to be included in clinical trials because often they are the quickest and easiest way to determine whether a therapy is effective. (Also see "US FDA Welcomes Variety Of Phase II/III Trial Designs For COVID-19 Therapies, But With Standards" - Pink Sheet, 13 May, 2020.)
Even so, Temple acknowledged that it has been unusual for the FDA to say that a proposal cannot move forward. (See sidebar.)
However, several late-stage coronavirus trials have been limited by their lack of control arms, which is expected to complicate efforts to determine whether efficacy has been demonstrated.
A 4 May editorial in the Journal of the American Medical Association also stated that few of the studies will be powered to detect a mortality difference. (Also see "COVID-19 Phase III Trial Design: Big Ambitions, Little Consistency" - Pink Sheet, 11 May, 2020.)
An editorial published in the British Medical Journal 12 May also found many registered coronavirus trials lack control groups or randomization.
Robert Temple
FDA
Authors Paul Glasziou, professor of evidence-based medicine, Sharon Sanders, assistant professor, and Tammy Hoffmann, professor of clinical epidemiology, all of Bond University in Australia, wrote that of 145 registered trials of the anti-malarial hydroxychloroquine, 32 have planned sample of 100 patients or less, 10 have no control group, and 12 are comparative, but not randomized.
The group said that while some of the trials registered on ClinicalTrials.gov “will provide useful information, many are too small and poorly designed to be helpful, merely adding to the COVID-19 noise.”
“The massive waste in research that exists is not new but has been exacerbated by the pandemic-inspired rush to research,” they wrote.
Regulators Concerned About Underpowered Coronavirus Trials
International regulators also are concerned about the increasing number of underpowered clinical trials and observational studies.
The issue emerged during a 14 May discussion of the International Coalition of Medicines Regulatory Authorities (ICMRA) about policy and regulatory requirements during the pandemic, including clinical trial management, pharmacovigilance, and drug supply issues.
“ICMRA members stressed the need for stringent regulatory requirements for COVID-19 studies and agreed to provide further guidance on the prioritization of clinical trials and on serology in order to promote a harmonized approach,” the European Medicines Agency said in the meeting summary.
The EMA also said in a summary of the meeting that there was broad agreement that multi-center, multi-arm clinical trials should be prioritized because they are most likely to generate the robust evidence needed for quick assessment and approval of coronavirus therapies and vaccines. (Also see "EU Regulators Concerned By Mushrooming Of Small COVID-19 Trials" - Pink Sheet, 19 May, 2020.)
CDER Director Janet Woodcock moderated the ICMRA discussion. She has said that platform and similar trial designs should be employed to test multiple potential coronavirus therapeutics at the same time, because the global clinical research network likely cannot handle the demand otherwise. (Also see "Woodcock Warns Research Apparatus Could Be Overwhelmed If Coronavirus Trials Don’t Use Master Protocols" - Pink Sheet, 27 Apr, 2020.)
Woodcock has also urged adjustments to trial requirements such as informed consent in order to limit health care workers’ interactions with coronavirus patients.
Simple Trials For Coronavirus
Jacqueline Corrigan-Curay, director of the CDER Office of Medical Policy, who also participated in the interview, said there has been more interest in setting up master protocols to test as many potential new treatments as possible, and she reiterated that the design may be necessary to test all the potential therapeutics.
Corrigan-Curay added that “some of these trials are simple – really focused on the data that you need.”
Jacqueline Corrigan-Curay
FDA
Temple said the trials are collecting data on a “major endpoints,” such as time to get off the respirator or leave the hospital.
“[Simple] in the old sense,” he said. “You don't have endless eligibility criteria, because you can't get to measure those things. And you don't have large numbers of exotic endpoints. You look at the important stuff, you know, survival.”
Corrigan-Curay said many of the endpoints being used are different than trials for chronic diseases, where complex scales are necessary to measure improvement. She said the coronavirus trials often are testing treatments against doing nothing.
“We're dealing with nothing, and you're trying to just get those first therapies that can hit really what's happening,” she said. “What you're worried about is those folks who are going to hospital getting ARDS [acute respiratory distress syndrome] and dying from this disease.”