WHO R&D Blueprint – Ad-hoc Expert Consultation on clinical trials for Ebola Therapeutics
Deliberations on design options for randomized controlled clinical trials to assess the safety and efficacy of investigational therapeutics for the treatment of patients with Ebola virus disease
11 October 2018
As of October 10th, 188 Ebola Virus Disease (EVD) cases (153 confirmed and 35 probable) have been reported in eastern Democratic Republic of Congo (DRC). Of those 66 EVD patients have been offered and received one of the investigational therapeutics on an emergency basis and under compassionate use protocols.
In the context of the current Ebola Zaire outbreak in eastern DRC with a high case fatality rate, individual patients are being offered investigational therapeutics on an emergency basis outside clinical trials and as part of protocols for compassionate use.1 WHO’s guidance “Managing Ethical Issues in Infectious Disease Outbreaks2” states that compassionate use of unlicensed therapeutics is only justified when clinical trials cannot be initiated immediately.
Given the size of Ebola outbreaks it is anticipated that one single epidemic may not generate conclusive evidence and therefore it is important to plan for and implement a protocol that would allow the scientific community to collect and accumulate robust evidence over a number of outbreaks over a period of time and to move away from seeing each outbreak as a discrete episode.
Also important is the need to consider the potential operational challenges with the implementation of various trial designs and, with the administration and monitoring of different investigational therapeutic agents. The anticipation of such potential challenges is critical, so appropriate mitigation measures are implemented in advance, if pertinent.
This expert consultation convened representatives from EVD-at risk countries, international partner organizations supporting affected countries in establishing Ebola treatment centers (ETCs) and providing clinical care, partners and experts in the field of randomized controlled trials (RCTs) for evaluating investigational therapeutics (in particular clinical experts, trialists, and statisticians).
The objectives of this consultation were:
- To discuss and outline potential criteria that could inform the evidence-based selection of therapeutic agents for clinical trials.
- To review and critically appraise the existing evidence regarding different investigational therapeutics agents.
- To discuss trial design options and reach consensus on the various options towards a robust study design.
- To jointly outline a framework for an efficient collaborative approach across countries and outbreaks.
To provide/update information on a candidate therapeutic agent for EVD, please use the form below and send it directly to EVDthxagents@who.int
Declaration of interests
All experts completed a declaration of interests. Eight experts reported interests. The reported interests are summarized below.
- Dr Armand Sprecher was an advisor that provided an independent analysis during a legal proceeding in an UK court, as someone with experience in the management of EVD. This was not deemed a significant conflict of interest.
- Dr Michael Jacobs has been invited to a meeting organized by Gilead to enable him to share the UK experience of using experimental therapies (of all types) for high consequence infections and discuss future access and trials. The cost of his return flight is covered by Gilead. This is not a paid advisory meeting and Dr Jacobs will not receive any remuneration personally. This was not deemed a significant conflict of interest.
- Dr Peter Horby received research grants from the Wellcome Trust and the European & Developing Countries Clinical Trials Partnership (EDCTP) for academic work related to epidemic infectious diseases, including Ebola. This was not deemed a significant conflict of interest.
- Dr Stephan Guenther received research grants (European Commission, Government of Germany and German Research Foundation) for research work related to Lassa and Ebola. These were not deemed a significant conflict of interest. Also, Dr Guenther indicated under “patents, trademarks, copyright or other intellectual property (including pending applications) a pending patent for screening assay for inhibitors of Lassa virus.
Four interests were assessed to constitute a conflict of interest.
The following interests were declared:
- Dr Cliff Lane received research grants (GSK, Merck, Gilead). The Gilead investigational therapeutic agent is to be discussed and evaluated at the consultation. Additionally, Dr Lane’s institution NIH/NIAID has a patent pending [US Application No.62/087, 087 (PCT Application No.PCT/US2015/060733) related to anti-Ebola virus antibodies and their use] for another investigational therapeutic agent to be discussed and evaluated at the consultation (mAb114).
- Profs Jean-Jacques Muyembe-Tamfum and Sabue Mulangu are listed as inventors on the patent application for mAb 114, US Application No.62/087, 087 (PCT Application No.PCT/US2015/060733) related to anti-Ebola virus antibodies and their use; While they are listed as inventors on this patent application, the invention in question is owned by the US Government; and Profs Jean-Jacques Muyembe-Tamfum and Sabue Mulangu have not received any money for this invention, and given the low commercial value of any resulting products (limited to use during Ebola Zaire outbreaks), they consider it unlikely that they will receive any income as the inventors in the future.
- Dr Nichol indicated that he was one of the co-authors of the published study “GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses”, one of the investigational therapeutic agents to be discussed and evaluated at the consultation, and this might be perceived as affecting his objectivity or independence.
Update: Ebola treatments approved for compassionate use in current outbreak
Updated 28 September 2018
On 17 May 2018, in the early stages of the outbreak of Ebola virus disease (EVD) in Equateur province in the Democratic Republic of the Congo (DRC), WHO convened a meeting of scientific experts to evaluate and update the available information and data on investigational therapeutics intended to treat EVD. The purpose of the meeting was to consider whether the available information supported the Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI) for access to investigational therapeutics on an individual patient basis for treatment of EVD during the outbreak, outside of a clinical trial.
- Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola virus disease
On 4 June, an ethics committee in DRC approved the use of five investigational therapeutics to treat Ebola, under the framework of compassionate use/expanded access.
On 27 August, in the context of a new outbreak of EVD in North Kivu province, DRC, WHO again convened a group of independent scientific experts for the purpose of updating the May 2018 statement.
Update: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions (MEURI) for Ebola virus disease - 27 August 2018
Clinicians working in the treatment centres make decisions on which drug to use as deemed helpful for their patients, and appropriate for the setting. The treatments can be used as long as informed consent is obtained from patients and protocols are followed, with close monitoring and reporting of any adverse events.
There are parallel efforts underway to establish clinical trials for the treatments as soon as possible.
On 11 September, WHO convened an expert consultation to consider the use of investigational therapeutics or investigational vaccine(s) for post-exposure prophylaxis (PEP) for frontline healthcare workers (HCWs) potentially exposed to Ebola virus (Zaire ebolavirus) during the current outbreak involving Eastern Democratic Republic of Congo (DRC).