Approaches to demonstration of Ebola virus vaccine efficacy
Authors: Philip R Krause, Marco Cavaleri, Gina Coleman, Marion F Gruber
Journal: The Lancet Infectious Diseases (2015)

After rapid advancement of several promising Ebola virus disease vaccine candidates into phase 1 clinical trials, large randomised controlled trials (RCTs) that aim to show that an investigational vaccine prevents the clinical occurrence of Ebola virus disease have been initiated. The recent decline in Ebola virus disease incidence in affected regions is very welcome news from a humanitarian and public health perspective, but it might hamper direct assessment of vaccine effectiveness based on clinical Ebola virus disease endpoints. Moreover, candidate vaccines not being investigated in these trials will need to be assessed for efficacy. Therefore, although RCTs with disease endpoints are acknowledged as the most robust study design for showing vaccine efficacy, other approaches should be considered. Although an Ebola virus disease vaccine would be mainly used in west Africa and thus be subject to approval by the relevant national regulatory authorities, regulatory approval of a vaccine in North America or Europe has the potential to support regional approval. Manufacturers might also benefit if their vaccines are licensed in several countries before widespread distribution and use. Irrespective of jurisdiction, vaccines are licensed on the basis of data derived from adequate clinical trials showing that the products are safe and effective. Although all approaches to vaccine licensure require that quality and safety are shown, licensure will not necessarily require demonstration of efficacy in a clinical trial using a clinical endpoint. In the USA, products for serious or life-threatening illnesses providing meaningful benefit over existing treatments can be approved using the US Food and Drug Administration's (FDA's) accelerated approval provisions, for which approval of an Ebola vaccine would rely on adequate and well controlled clinical trials establishing an effect of the product on a surrogate endpoint (eg, immune response) that is reasonably likely to predict clinical benefit.1US Food and Drug AdministrationCode of Federal Regulations (CFR) title 21, 2014.http://www.ecfr.gov/cgi-bin/text-idx?node=pt21.7.601Google Scholar The US regulatory provision known as the animal rule can be used when human efficacy trials are not ethical or feasible1US Food and Drug AdministrationCode of Federal Regulations (CFR) title 21, 2014.http://www.ecfr.gov/cgi-bin/text-idx?node=pt21.7.601Google Scholar and when the accelerated approval provisions cannot be used. Under specific conditions supporting the conclusion that a product is reasonably likely to produce a clinical benefit, the animal rule allows adequate and well controlled studies in animals to provide evidence of effectiveness of the product. In Canada, vaccines can be approved under the extraordinary use new drug (EUND) regulations, under which efficacy is established on the basis of studies in animal species expected to have a response predictive for human beings, and any additional information showing effectiveness in human beings, if available.2Health CanadaGuidance document—submission and Information requirements for extraordinary use new drugs (EUNDs).http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/eund-dnue-eng.phpDate: 2014Google Scholar In the European Union, vaccines can be approved under conditional marketing authorisation,3European UnionREGULATION (EC) No 507/2006.Official Journal of the European Union. 2006; L92: 6-9Google Scholar subject to the requirement that the marketing authorisation is renewed annually and that the marketing authorisation holder addresses specific obligations (post-marketing studies) associated with the approval. Alternatively, approval can occur in exceptional circumstances4European UnionREGULATION (EC) No 726/2004.Official Journal of the European Union. 2004; L136: 1-33Google Scholar if a comprehensive data package cannot be provided—eg, because of ethical or feasibility issues. Irrespective of which of these approaches will be used to show vaccine efficacy in support of licensure, data showing that human immunological responses to an Ebola vaccine reach a level that is deemed reasonably likely to be associated with clinical benefit could support vaccine efficacy. The specific threshold used in these assessments could be derived from human studies (in which immune responses in protected vaccinees are compared with those in vaccinees who contract Ebola) or from non-human primate (NHP) studies (in which a similar assessment could be made in Ebola-virus-challenged animals). Preliminary data presented on Dec 12, 2014, at a US Government-sponsored workshop suggested that vaccinated human beings might achieve immune responses similar in size to those associated with protection in NHPs, suggesting the feasibility of an immunogenicity-based approval, although the thresholds associated with protection might differ for each vaccine candidate.5Krause PR Bryant P Clark T et al.Immunology of protection from Ebola virus infection.Sci Transl Med. 2015; 7: 286ps11Crossref PubMed Scopus (16) Google Scholar Thus, depending on changes in Ebola virus disease incidence (and on which vaccine is being assessed), the most efficient path to accumulation of sufficient human data to support a regulatory conclusion of Ebola vaccine efficacy might involve immunogenicity assessments of vaccinees with a primary focus on humoral immune responses. US accelerated approval or animal rule approaches, European Medicines Agency (EMA) conditional approval or approval under exceptional circumstances, and Canada's EUND approval would require post-licensure studies to be done either during the current or a future outbreak. In the case of accelerated approval, these studies would need to be adequate and well controlled, and designed to verify clinical benefit, whereas for the animal rule the post-licensure study requirement could be met with field trials that provide additional information about effectiveness and safety. For vaccines initially approved under the Canadian EUND policy, if a complete package of safety, efficacy, and quality becomes available, the vaccine can be approved under the new drug submission regulations. Vaccine effectiveness could potentially be confirmed using epidemiological observations such as case-control studies, which have been used to provide estimates of vaccine effectiveness in post-licensure settings. Further discussion of this topic by experts is warranted. A key feature common to all of these approval provisions is that the established standards for the demonstration of safety and effectiveness are maintained. From our perspective, if needed, any of these pathways to licensure could provide an alternative science-based approach to the demonstration of vaccine effectiveness against Ebola virus disease. The rapid evolution of the Ebola outbreak will need continued regulatory flexibility and adjustment to approaches used for product development and approval. By fostering a high level of communication both together and with our stakeholders, the FDA, EMA, and Health Canada will continue to employ their science-based regulatory approaches to expedite Ebola vaccine licensure and thus facilitate the availability of one or more effective Ebola vaccines. We declare no competing interests.