Clinical trial design for treatment of Ebola virus disease versus Ebola vaccine

Ebola outbreak in West Africa has brought a lot of attentions to this deadly virus. The world is so unprepared for the Ebola treatment and prevention. Now that the developed countries including US are starting to develop the drugs for treating and preventing the Ebola virus, the discussions about the Ebola drug trials are in the center stage.

First of all, there is a big distinction between developing the drugs for treating Ebola virus disease and developing the Ebola vaccine. Many people may discuss the Ebola trial without clear distinction of the treatment and prevention. In a Forbes article “FDA: Some Ebola Patients Need To Get Placebo”, the author clearly mis-interpreted the original FDA paper and blurred the distinction between drug for treating Ebola patients and the Ebola vaccine.

The ethical dilemma and debate about the randomized, controlled trial are on the issues for drug trials targeting the treatment of the Ebola patients, not the Ebola vaccine. FDA’s article in New England Journal of Medicine “Evaluating Ebola Therapies — The Case for RCTs” discussed the issues with clinical trial design for Ebola therapies (treating Ebola infected patients), not for Ebola vaccine (preventing people from Ebola infection).

So far, the majority of the clinical trials are focusing on the Ebola virus vaccine, not on the Ebola treatment. According to clinicaltrials.gov, there are 21 clinical trials registered, except for 2 trials that are conducted in ebola patients or ebola virus infested patients, all other trials are for Ebola vaccine and conducted in healthy volunteers

The immediate need is to find effective therapies for treating the Ebola virus infected patients. Down the road, developing effective vaccines to prevent the Ebola virus infection (at least prevent the similar outbreaks) is more important. Without any incentives, the drug companies may be more interested in developing the Ebola vaccine because of its much greater marketing potential.

 A Comparison of Ebola Therapy and Ebola Vaccine

	Ebola Therapy	Ebola Vaccine
Purpose	Treatment of Ebola Virus Infected patients	Prevention people from Ebola virus infection
Target population	Ebola virus infected patients	General public or population at risk for Ebola infection (such as health care workers)
Study population	Ebola virus infected patients	Healthy volunteers
Efficacy Measure	Survival rate (proportion of patients who can survive in two weeks)	the immunogeneicity (i.e., the occurrence or titer of the anti-ebola virus antibodies).
Control group	Placebo-controlled study is not feasible, but the best supportive care as control group is feasible.	Placebo control is feasible.
Study endpoint	Survival is a hard endpoint	Titer of antibodies is a surrogate, soft endpoint. The overall effectiveness is difficult to measure.
Tolerance for safety	Comparing to the vaccine, there may be more tolerance in terms of the safety.	The new drug / therapy must be extremely safe since the vaccine will be used by the healthy people

Specifically for clinical trials to find effective therapies for Ebola virus infected patients, the clinical trial design is at the center of the debate. The experts in European countries prefer the clinical trials using the historical control (i.e., without the concurrent control group) while US (FDA and NIH) prefers the traditional randomized controlled trials with the best supportive care as the control group.

• Ethical dilemma for Ebola drug trials
• Evaluating Ebola Therapies — The Case for RCTs

With very high mortality rate, it is understandable to think that a randomized, supportive care controlled or placebo controlled study is ridiculous. If there is a new experimental therapy with even a slim of hope, people will jump on it. Just as it said in the article “The Ethical Issues In Using An Experimental Ebola Drug”.

“the World Health Organization said in a statement today that it is ethical to offer unproven drugs to treat or prevent the spread of the Ebola virus

Under American law, the Food and Drug Administration can permit a drug manufacturer to provide an unapproved drug to patients if they don't have any alternatives and the consequences are severe. It's called "compassionate use" and most of these exceptions are granted when the drug is in a clinical trial testing its safety, proper dose and efficacy.
The most profound example of this comes from the 1980s, in the early days of the AIDS epidemic. There was no approved drug that had any effect, and people were dying. Dr. Anthony Fauci [director of the National Institute of Allergy and Infectious Diseases] was key to changing this approach, and expanding access to AZT outside of clinical trials. But this is different in that the drugs for the Ebola virus have not yet entered clinical trials in humans.”

Considering the high mortality rate and no proven therapy for treating the Ebola virus disease, using a historical control seems to an easy choice. With this design, all patients will be given the experimental drug(s). If the survival rate in patients treated with experimental drug(s) is lower than a fixed number (historical control), the experimental treatment would be considered as effective. However, it all depends on how reliable the historical control is and whether or not the other best supportive cares have changed over time. The study design can still be randomized and controlled. It is just the concurrent control group is another experimental drug(s).

It is generally agreed that the clinical trials for Ebola virus disease treatment should have more than one arms and should be randomized, controlled. The European countries seem to prefer a study design with multiple experimental therapies to compare each other. US (FDA and NIH) seems to prefer a study design with experimental therapy compared with the concurrent control of the best supportive care. This can be essentially viewed as an add-on study design with one group to be the best supportive care only and another group to be the best supportive care + the experimental therapy. For the purpose of demonstrating the efficacy of the experimental therapy, this seems to be the most reasonable approach.

In the end, the action is always better than debate. Let’s put aside the debate and start the clinical trials for Ebola treatment. The clinical trials for Ebola virus disease treatment (new therapies) have begun.

• Chimerix An Open-Label, Multicenter Study of the Safety and Anti Viral Activity of Brincidofovir (BCV, CMX001) for Ebola Virus Disease
• Ebola treatment trials to be fast-tracked in West Africa
• First trials for Ebola treatments to start at MSF sites in December
• Ebola trials to start in December

 “US scientists have not yet announced which treatments will be tested in clinical trials that they plan to run in the United States and, possibly, in Liberia. Doctors and researchers organizing the trials met at the US National Institutes of Health in Bethesda, Maryland, on 11 November.
"We had good discussions,” says Clifford Lane, deputy director for clinical research and special projects at the US National Institute of Allergy and Infectious Diseases in Bethesda. “We are working on refining our adaptive-design protocol with specific arms based upon those discussions.”

MSF says that the trials at its sites will test whether the interventions boost the proportion of patients who survive for two weeks. It hopes to report initial results from the trials as early as February 2015.
MSF said previously that none of the trials run at its sites will assign patients to receive standard of care treatment rather than an experimental intervention. Whether or not to use a standard of care control group in these trials is a thorny and hotly debated question. The US trials plan to use a control group, but have not made final decisions about the trial design.”

It is reported that the first Ebola treatment trial has started in January, 2015. The study lead by Dr Jake Dunning is a study without concurrent control group - there is no randomization. The Ebola virus positive patients are asked if they are willing to participate in the trial to receive the experimental treatment. if they decline the participation, the patients will receive the standard supportive care. Hopefully, they will track the at least the mortality rate in those who decline the participation.

The Ebola vaccine trials has also begun and some of the studies have reported the success (safe and generating antibody response in healthy volunteers).

• Ebola booster vaccine starts first trials in Oxford
• First human trial of NIH-GSK Ebola vaccine shows promise
• Ebola: new study is first to report vaccine success in Africa