Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease

Background: Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. Methods and Findings: A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Conclusions: The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments. Ben Cooper and colleagues model different trial designs, including a multi-stage approach that contains non-randomized and randomized elements.Background: The current outbreak of Ebola virus disease (EVD)—a frequently fatal disease that first appeared in human populations in 1976 in remote villages in central Africa—has infected more than 24,000 people and killed more than 10,000 people in Guinea, Sierra Leone, and Liberia since early 2014. Ebola virus is transmitted to people from wild animals and spreads in human populations through direct contact with the bodily fluids (including blood, saliva, and urine) or with the organs of infected people or through contact with bedding and other materials contaminated with bodily fluids. The symptoms of EVD which start 2–21 days after infection, include fever, headache, vomiting, diarrhea, and internal and external bleeding. Infected individuals are not infectious until they develop symptoms but remain infectious as long as their bodily fluids contain virus. There is no proven treatment or vaccine for EVD, but supportive care—given under strict isolation conditions to prevent the spread of the disease to other patients or to healthcare workers—improves survival. Why Was This Study Done?: Potential treatments for EVD include several antiviral drugs and injections of antibodies against Ebola virus from patients who have survived EVD. Before such therapies can be used clinically, their safety and effectiveness need to be evaluated, but experts disagree about how to undertake this evaluation. Drugs for clinical use are usually evaluated by undertaking a series of clinical trials. A phase I trial establishes the safety of the treatment and how the human body copes with it by giving several healthy volunteers the drug. Next, a phase II trial provides early indications of the drug’s efficacy by giving a few patients the drug. Finally, a large-scale multi-arm phase III randomized controlled trial (RCT) confirms the drug’s efficacy by comparing outcomes in patients randomly chosen to receive the investigational drug or standard care. This evaluation process is very lengthy. Moreover, it is hard to ethically justify undertaking an RCT in which only some patients receive a potentially life-saving drug during an Ebola epidemic. Here, the researchers evaluate a multi-stage approach (MSA) to EVD drug evaluation that comprises a single-arm phase II study followed by one or two phase III trials, one of which may be a sequential RCT (SRCT), a type of RCT that allows for multiple interim analyses, each of which may lead to study termination. What Did the Researchers Do and Find?: The researchers used analytic methods and computer simulations to compare EVD drug evaluation using the MSA, an SRCT, and a conventional RCT without interim analyses. Specifically, they estimated the probabilities of rightly or wrongly recommending the experimental treatment and the consequences for epidemic outcomes over 100 days for the three approaches. Assuming 50% survival at 14 days after symptom development in patients treated with supportive care only, all three trial designs were equally likely to identify effective treatments, but the MSA was less likely than the other designs to incorrectly recommend an ineffective treatment. Notably, the MSA led to fewer patients receiving ineffective treatments and faster roll-out of highly effective treatments. In an epidemic where 100 new cases occurred per day, for highly effective treatments, the MSA led to between 6% and 15% larger reductions in epidemic mortality over the first 100 days of the epidemic than the SRCT did. Finally, both the MSA and the SRCT led to fewer deaths than the conventional RCT if the tested interventions were either highly effective or harmful. What Do These Findings Mean?: These findings suggest that for experimental treatments that offer either no clinically significant benefit or large reductions in mortality the MSA can provide useful information about drug effectiveness faster than the other approaches tested. Thus, the MSA has the potential to reduce patient harm and the time to roll-out of an effective treatment for EVD. Although alternative evaluation designs are possible, the researchers suggest that including a non-randomized design in phase II is the quickest way to triage potential treatments and to decide how to test them further. For treatments that show strong evidence of benefit, it might even be possible to recommend the treatment without undertaking an RCT, they suggest. Moreover, for treatments that show only modest benefit in phase II, it should be easier (and more ethical) to set up RCTs to test the treatment further. Additional Information: Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001815.