Ebola Research Requires Flexibility by Sponsors, Regulators

The rush is on to develop new therapies and preventives to combat the lethal Ebola outbreak, a process that has been stymied by difficulties in testing compounds for deadly diseases and the reluctance of both public and private entities to invest heavily in a field with uncertain demand. Treatments for Ebola have been low on the priority lists for international and national health agencies, as efforts to combat malaria, tuberculosis, and other widespread diseases have absorbed more attention and resources.

That has changed as Ebola has sickened and killed thousands. The World Health Organization (WHO) and public and private research programs have shifted funds to preclinical and clinical trials of promising Ebola treatments and vaccines, encouraged by WHO's decision in August that it is ethical to use unproven therapies to help contain the spreading outbreak. WHO further addressed research priorities at a "consultation" with public health officials and leaders of the biomedical research community in Geneva last month. Executives from large vaccine makers and small biotech firms joined with leaders of the infectious disease research community to consider the challenges in conducting clinical trials and collecting data from ill patients.

Some 200 experts agreed to support Phase I safety studies despite limited preclinical data. The group noted the need for flexibility in requiring ethics committee reviews and in assessing risks and benefits. Harmonized data requirements are important for results from expanded access programs to be compared to support eventual registration.

A stated goal is to minimize bias in evaluating the effect of an intervention without randomized placebo controlled trials; alternative protocols may involve randomizing patients to two different experimental therapies or to offer "usual care" to individuals not willing to be randomized, who could then provide a control group. Meeting participants also agreed that a safety monitoring board should be established to evaluate data from all interventions and that protocols should address informed consent and community concerns.

Regulatory authorities are collaborating on these issues through WHO's International Coalition of Medicines Regulatory Authorities (ICMRA) and adopting flexible approaches to facilitate access to treatment. The FDA, for example, has authorized use of a not-yet-approved Ebola diagnostic in West Africa. The agency also permitted Tekmira Pharmaceuticals to treat infected patients with its experimental treatment by converting a "full clinical hold" to a "partial hold" on a Phase I trial; that allows use of the therapy for emergency care—but not by healthy volunteers due to concerns about a possibly serious side effect.

Accelerating R&D

A main goal of researchers and regulators is to facilitate the launch of human trials on treatments exhibiting safety and immune response in primate studies. GlaxoSmithKline's Okairos unit (Basel, Switzerland) recently obtained FDA approval for Phase I testing of a vaccine developed with the National Institute of Allergy & Infectious Disease (NIAID). Small trials have begun in the U.S. and are planned for the UK, Gambia, and Mali with support from a $4.6 million grant from the Wellcome Trust and UK health agencies.

FDA has also approved Phase I trials of a vaccine developed by NewLink Genetics' in Iowa, which utilizes a vaccine platform licensed from the Public Health Agency of Canada and developed with funding from the Department of Defense (DOD). Further testing is planned for North America, Europe, and Africa. Similarly, Johnson & Johnson is planning preclinical testing of an Ebola vaccine developed by its Crucell vaccines unit in collaboration with NIAID and Bavarian Nordic. This monovalent vaccine combines vaccine platforms developed by the two companies.

WHO and research sponsors also anticipate clinical trials on several broad-spectrum antivirals that indicate potential effectiveness against Ebola. The WHO consultation examined several candidates, including a small molecule injectable treatment for hemorrhagic fever viruses from BioCryst Pharmaceuticals. A promising therapy is favipiravir, an oral tablet developed by Japan's Fujifilm as an influenza treatment. Fujifilm has engaged Boston-based MediVector to conduct Phase III trials in the U.S. for that indication, and the company now plans broader testing against Ebola and other viruses.

Most discussed is the ZMapp monoclonal antibody cocktail from Mapp Biopharmaceutical, which made headlines with the recovery of two infected U.S. health workers following ZMapp administration. HHS' Biological Advanced Research and Development Authority (BARDA) recently awarded a $25 million contract to Mapp to further ZMapp testing and production.

Clinical trials on these and other therapies may be supported by a BARDA-funded network of five clinical research organizations, launched last year to design and conduct clinical studies needed to develop drugs, vaccines, and diagnostic tests to protect against public health emergencies. BARDA Centers for Innovation in Advanced Development and Manufacturing, moreover, may help provide clinical supplies for initial trials and products for broader distribution, if appropriate.