World Health Organization The Ebola Outbreak Lessons Learned & Pathways for Approval for Emergency Use of Medical products World Health Organization 22 April, 2017 3rd Annual Regulatory Workshop NEW DEVELOPMENTS IN DRUG REGULATION 8 - 9 September, 2015

Independent review of WHO Activities in EVD outbreak Ebola Interim Assessment Panel – Report of July 2015 WHO Response Outline – August 2015 http://www.who.int/csr/resources/publications/ebola/ebola-panel- report/en/

Three Broad Areas Identified for improvement Review and Strengthen International Health Regulations Improve co-operation with broader health and humanitarian systems Increase WHO’s emergency response capacity

Emergency Response Capacity Recommendations include: WHO should play a central convening role in acceleration of development of appropriate diagnostics, vaccines, therapeutics and medical and information technology

Ebola candidate vaccines rVSV ZEBOV (Merck/Newlink). ChAd3 ZEBOV (GSK) Ad26.ZEBOV/MVA BN Filo Prime Boost Prophylactic Ebola Vaccine Regimen (Janssen) Ebola/Makona Glycoprotein (GP) Nanoparticle Vaccine (Novavax)

WHO Involvement in Ebola vaccine R&D Facilitated the initiation of the phase I of VSV vaccine, in Europe (Hamburg and Geneva) and in Africa (Gabon and Kenya) Joint review of clinical trial protocols – collaboration between AVAREF and WHO/RSS (with the support from Health Canada, US FDA, EMA, and several member states) Sponsored VSV vaccine Phase III CT (Ring vaccination) + in parallel study involving Frontline Workers in Guinea Summits convened

From R&D to Regulation - Challenges Difficulty in obtaining efficacy data in face of declining case numbers No immunological correlate of protection established Validation of ELISA methods for measuring immunogenicity still in progress Data requirements for registration Acceleration of regulatory review

WHO Emergency Use Assessment and Listing EUAL guidance development initiated in response to Ebola outbreak Scope includes potential future outbreaks of other diseases Developed for three product streams currently in scope of WHO prequalification programme: Vaccines Pharmaceuticals In-vitro diagnostics http://www.who.int/medicines/news/public_consult_med_prods/en/

EUAL – WHY? Provides framework for review in emergency context To guide UN procurement decision-making To assist highly impacted countries in their regulatory decision-making

EUAL - ELIGIBILITY Declared Public Health Emergency of International Concern (PHEIC) by the WHO Director-General Lack of routine marketing authorization for type of product or supply shortage Manufactured in accordance with GMP standards Attestation from producer of intention to complete development and apply for WHO prequalification [for vaccines] Manufactured in a country whose NRA has been assessed as functional for vaccine regulatory oversight by WHO. WHO may consider reviewing a candidate vaccine for EUAL that does not meet all of the above requirements Manufactured in accordance with GMP standards [(not for IVDs) a functional quality management system (QMS) required]

EUAL is not Prequalification Specific procedure under circumstances of a public health emergency for time-limited approval for use. Principles of data requirements for each product type identified in the respective guidance document. Applicants are highly encouraged to contact WHO as early as possible during development to discuss specifics of their application. Abbreviated review where some emergency use authorisation granted by an NRA.

EUAL – APPLICATION CONTENT – VACCINE EXAMPLE Manufacturing Quality Data Cell and seed bank characterisation Justified methodologies and specifications Process validation Evidence of GMP compliance Stability data Programmatic characteristics not acceptable for PQ may be allowed for EUAL

EUAL – APPLICATION CONTENT – VACCINE EXAMPLE Non-clinical Data Demonstrating acceptable safety, immunogenicity, and efficacy in the most appropriate animal model If the non-clinical package is not complete at the time of submission, the applicant must submit adequate justification for the lack of complete data and a plan and timeline for submitting those data Clinical data Demonstrating acceptable safety, immunogenicity, and efficacy, if available If it is not possible to obtain efficacy data, the applicant will have to demonstrate that immunogenicity data are sufficient under the circumstances. A plan to monitor quality, safety, and efficacy in the field and to submit the new data as soon as possible to WHO.

EUAL - DECISION WHO public report will be made available on the WHO website. The validity of a listing will generally be for 12 months. Can be reviewed and extended if necessary. Can be extended beyond the PHEIC (stockpile) Decisions will also be reassessed if further data become available that could alter the original opinion.

Have products received an EUAL? In- vitro diagnostics: Altona Diagnostics GmbH RealStar® Filovirus Screen RT-PCR Kit 1.0 Corgenix Medical Corporation ReEBOV™ Antigen Rapid Test Kit

EUAL of IVDs - challenges encountered in Ebola outbreak Larger manufacturing base (but many inexperienced) Poor technical documentation and Quality System Submission before design finalisation Difficulties in clinical performance testing Lack of standard preparations Target of test kit - inadvertent detection of post-vaccine circulating antigen or nucleic acid Fraudulent claims Ebola spiked or clinical blood samples were not available for the manufacturers Testing required BSL-4 laboratories (very few dealing with VHF including Ebola) Restriction in transportation of clinical samples outside W Africa Therefore the manufacturers had no analytical or clinical performance data

Next steps - EUAL Ad hoc Advisory Committees for the Emergency Use of Products will be established where required as part of the review process for applications for EUAL Implementation of collaborative procedure between WHO PQ and regulators from affected countries: Joint review

Next steps – more broadly Develop blueprint for research preparedness for future disease preparedness Review and revision of IHR Development of global health emergency workforce

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