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Drug assessment in the Ebola virus disease epidemic in west Africa

2015; Elsevier BV; Volume: 15; Issue: 11 Linguagem: Inglês

10.1016/s1473-3099(15)00344-8

1474-4457

Yazdan Yazdanpanah, Peter Horby, Johan van Griensven, France Mentré, Vinh‐Kim Nguyen, Jean Marie Denis Malvy, Jake Dunning, Daouda Sissoko, Jean‐François Delfraissy, Yves Lévy,

Hepatitis B Virus Studies

In their Personal View, Simone Lanini and colleagues1Lanini S Zumla A Ioannidis JPA et al.Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?.Lancet Infect Dis. 2015; 15: 738-745Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar argued that an adaptive randomised controlled trial (RCT) is the optimum solution to assess experimental therapeutics for Ebola virus disease and that non-RCTs are "profoundly unethical". Lanini and colleagues distinguished study designs of experimental agents as randomised versus non-randomised studies, including within the latter anecdotal experiences and compassionate use. It is irrational to make no distinction between phase 2 clinical trials and compassionate treatment. Studies by our groups, which were also cited by Lanini and colleagues, are fully regulated phase 2 clinical trials with explicit study frameworks. Moreover, we studied interventions that have been approved by regulatory authorities for use in man and implemented them only following full ethical review and approval. Clinical drug trials can be legitimately done only with the consent of individuals and communities. We worked with communities to facilitate open dialogue and partnership, which shows that RCTs would not have been accepted at the time the trials were initiated. In 1990, recognising that traditional approaches to clinical trial processes were unnecessarily rigid and unsuitable for study of HIV treatments, Byar and colleagues2Byar DP Schoenfeld DA Green SB et al.Design considerations for AIDS trials.N Engl J Med. 1990; 323: 1343-1348Crossref PubMed Scopus (126) Google Scholar concluded, in their paper design considerations for AIDS trials, that non-RCTs could be considered in the following situations. First, "there must be sufficient experience to ensure that the patients not receiving therapy will have a uniformly poor prognosis". Second, "there must be no other treatment appropriate to use as a control". Third, "the therapy must not be expected to have substantial side effects". Fourth, "there must be a justifiable expectation that the potential benefit to the patient will be sufficiently large to make interpretation of a non-RCT unambiguous". Fifth, "the scientific rationale for the treatment must be sufficiently strong that a positive result would be widely accepted". The Ebola epidemic clearly fulfils the first and second criteria, since the fatality is high.3Schieffelin JS Shaffer JG Goba A et al.Clinical illness and outcomes in patients with Ebola in Sierra Leone.N Engl J Med. 2014; 371: 2092-2100Crossref PubMed Scopus (439) Google Scholar, 4Bah EI Lamah M-C Fletcher T et al.Clinical presentation of patients with Ebola virus disease in Conakry, Guinea.N Engl J Med. 2015; 372: 40-47Crossref PubMed Scopus (316) Google Scholar The third criterion was met for most of the strategies studied. Regarding criterion four, our approach was to triage treatments into those with no effect that should be discarded quickly, from those with clear benefits that should be rolled out immediately, and those with promise that needs to be assessed in a RCT, in which combination antivirals could be also studied.5Cooper BS Boni MF Pan-ngum W et al.Evaluating clinical trial designs for investigational treatments of Ebola virus disease.PLoS Med. 2015; 12: e1001815Crossref PubMed Scopus (47) Google Scholar This strategy is also more acceptable to patients, physicians, and local communities. A debate on clinical trial design during humanitarian crises is needed, but it has to be based on an accurate characterisation of the events and issues. YY reports personal fees from AbbVie, BMS, Gilead, MSD, Roche, Johnson & Johnson, ViiV Healthcare, Janssen, and Pfizer outside the submitted work. All other authors declare no competing interests. Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24 900 cases and about 10 300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled trials (RCT) for Ebola-related research might be both unethical and infeasible and that potential interventions should be assessed in non-randomised studies on the basis of compassionate use. Full-Text PDF Non-randomised Ebola trials—lessons for optimal outbreak researchPeter William Horby and colleagues1,2 contest our views about the need for randomised clinical trials (RCT)3 and the missed opportunities for an effective Europe–Africa research framework4 during the recent Ebola virus disease outbreak in west Africa. In stating their case against the need for randomised studies, the authors quote Byar and colleagues5 as supporting the use of non-randomised designs. However, Byar and colleagues in fact do strongly support randomisation, and recommend randomisation even in phase 1 trials. Full-Text PDF