Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease

Ben S. Cooper, Maciej F. Boni, Wirichada Pan-ngum, Nicholas P.J. Day, Peter W. Horby, Piero Olliaro, Trudie Lang, Nicholas J. White, Lisa J. White, John Whitehead

Research output: Contribution to journalArticle

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Abstract

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.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.Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group.The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.

Original languageEnglish (US)
Article numbere1001815
JournalPLoS medicine
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2015

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Ebola Hemorrhagic Fever
Investigational Therapies
Clinical Trials
Randomized Controlled Trials
Therapeutics
Standard of Care
Mortality
Program Evaluation
Reproducibility of Results
Sample Size
Uncertainty
Referral and Consultation

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Cooper, B. S., Boni, M. F., Pan-ngum, W., Day, N. P. J., Horby, P. W., Olliaro, P., ... Whitehead, J. (2015). Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease. PLoS medicine, 12(4), [e1001815]. https://doi.org/10.1371/journal.pmed.1001815
Cooper, Ben S. ; Boni, Maciej F. ; Pan-ngum, Wirichada ; Day, Nicholas P.J. ; Horby, Peter W. ; Olliaro, Piero ; Lang, Trudie ; White, Nicholas J. ; White, Lisa J. ; Whitehead, John. / Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease. In: PLoS medicine. 2015 ; Vol. 12, No. 4.
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abstract = "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.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.Assuming 50{\%} 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6{\%} and 15{\%} greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group.The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.",
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Cooper, BS, Boni, MF, Pan-ngum, W, Day, NPJ, Horby, PW, Olliaro, P, Lang, T, White, NJ, White, LJ & Whitehead, J 2015, 'Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease', PLoS medicine, vol. 12, no. 4, e1001815. https://doi.org/10.1371/journal.pmed.1001815

Evaluating Clinical Trial Designs for Investigational Treatments of Ebola Virus Disease. / Cooper, Ben S.; Boni, Maciej F.; Pan-ngum, Wirichada; Day, Nicholas P.J.; Horby, Peter W.; Olliaro, Piero; Lang, Trudie; White, Nicholas J.; White, Lisa J.; Whitehead, John.

In: PLoS medicine, Vol. 12, No. 4, e1001815, 01.04.2015.

Research output: Contribution to journalArticle

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AU - Cooper, Ben S.

AU - Boni, Maciej F.

AU - Pan-ngum, Wirichada

AU - Day, Nicholas P.J.

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AU - Olliaro, Piero

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