Randomized Trials Key to Determining Effectiveness of Ebola Therapies and Vaccines

US researchers and regulators continue to support the use of randomized clinical trials to test potential treatments and vaccines to combat the Ebola virus, despite objections that this approach is unethical and unfair to vulnerable populations. Anthony Fauci, director of the National Institute of Allergy & Infectious Diseases (NIAID), articulated the case for “gold-standard” randomized trials at a hearing before the House Energy & Commerce Health subcommittee last month.

Fauci explained to members of Congress that the only way to determine the safety and efficacy of a new vaccine is to conduct clinical trials where not everyone gets the same vaccine at the same time. In response to proposals from some legislators that any promising vaccine should be distributed to all comers, Fauci pointed out that if NIH had taken that route a month ago, and the Ebola outbreak then moderated, as it has done recently in Liberia, health officials would not know if the improvement was due to the vaccine, to better care methods, or to other factors.
When people are suffering, Fauci acknowledged that there’s an emotional desire to give them any available treatment. But experience tells us, he said, that a substantial number of early test therapies turn out to be ineffective, and some will be toxic.

To develop potential Ebola vaccines, NIAID is planning to enroll patients in a randomized, double-blinded Phase II trial in Liberia, beginning in January. Another trial in Sierra Leone will follow a step protocol that phases in participants based on subject response. Any participants who become sick, Fauci noted, will receive immediate treatment.

In response to concerns about assigning patients to placebo arms in therapeutic trials, NIH, FDA, academic investigators and industry sponsors are collaborating on designing a “master protocol” for an adaptive, randomized trial that would utilize a common control arm for several candidate Ebola therapies. European researchers, working with Doctors Without Borders, continue to protest that any use of a placebo or standard-of-care control is unethical. A European research group plans two clinical trials in West Africa, administering different test drugs to patients to yield comparative results.

Collaboration is important in developing Ebola vaccines and therapies, Fauci observed. NIAID has been doing research on Ebola vaccines since 2001, but was a “lone wolf,” as NIH couldn’t get industry “even slightly interested” in this area, he recalled. Only a year ago or so was NIAID able to attract as a partner a big pharma company, GlaxoSmithKline, and that is why “we have a vaccine now” for testing.

Fauci concluded his remarks at the hearing by acknowledging that the desire to do randomized clinical trials with a control arm may seem “insensitive,” but that decades of experience shows that many things can go wrong “if we don’t get the right answer.”