1. 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

2. Independent review of WHO Activities in EVD outbreak
Ebola Interim Assessment Panel – Report of July 2015
WHO Response Outline – August 2015
report/en/

3. 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

4. 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

5. 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)

6. 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

7. 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

8. 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

9. 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

10. 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]

11. 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.

12. 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

13. 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.

14. 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.

15. 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

16. 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

17. 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

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

19. Thank you