Principles for cli nical evaluation of vaccines: WHO guidelines

1. World Health Organization - WHO Principles for clinical evaluation of vaccines: WHO guidelines Dr Ivana Knezevic WHO, Immunization, Vaccines & Biologicals Quality Assurance and Safety of Biologicals

2. Vaccine development and evaluation Preclinical/ Nonclinical testing Characteri zation of candidate vaccine Licensing PMS Product development Clinical trials Monitoring performance and development of new standards/replacement of existing Development of standards and stand. of assays Establishment of WHO standards and recommendations for production and control

3. The role of NRAs at different stages of vaccine development, production and evaluation Research and Development of vaccines Production and control of vaccines Preclinical testing Clinical trials Licensing Postmarketing surveillance

4. What is the role of regulators in clinical trials? • DEFINITION OF VACCINE OF ASSURED QUALITY RELY ON THE STRONG NRA! • Regulators should play an active role from early stages of vaccine development to post-licensing by: • Establishing regulation of clinical trials (CTs) at national level • Interacting with the other bodies (e.g., ethical committee) • By providing the expert advice on quality aspect of vaccines • By establishing an early dialogue with the manufacturers since regulatory compliance is the basis for eventual approval of clinical trials • National regulation of CTs is essential component (e.g., written guidelines, mechanism to approve trial but also to terminate it)

5. Clinical Trial Approval • Clinical Trial Approval takes different forms such as Investigational New Drug Application (IND) in the United States and Clinical Trial Certificate (CTC) or Clinical Trial Exemption (CTX) in the United Kingdom. • This is in addition to ethical clearance which is required in all countries for clinical trials.

6. How WHO standards may help regulators to review clinical trials? By providing: • Measurement standards for quality control of clinical lots http://www.who.int/biologicals/IBRP/Catalogue.htm 2. Measurement standards and standardized assays for the measurement of immune response in clinical trials 3. By providing written standards for production, control and evaluation of vaccines 4. By providing technical advice when needed by using the international expertise

7. WHO standards for vaccines and biologicals: http://www.who.int/biologicals/ Global written standards Global measurement standards Recommendations, Requirements and Guidelines for production and control of vaccines: • 1) General (e.g., GMP, quality assurance for biological products) • 2) Guidelines for DNA vaccines, synthetic peptide vaccines, etc. • 3) Requirements for a number of bacterial and viral vaccines: OPV,MMR,DTP etc.)

8. WHO Guidelines for nonclinical and clinical evaluation of vaccines • Good Laboratory Practice • Good Clinical Practice (under revision) • Clinical Evaluation of Vaccines: Regulatory Expectations (TRS 924) • Nonclinical Evaluation of Vaccines (in press)

9. WHO Guidelines for Clinical Evaluation of Vaccines • To assist in evaluation of clinical trials as a part of the regulatory overview • Audience: NRAs, Vaccine Industry, but also clinical researchers and investigators • Reviewed by more than 100 experts and discussed at the global Consultations • Adopted by the Expert Committee on Biological Standardization (ECBS), 2001

10. Scope and contents of clinical guidelines • Prophylactic vaccines • Therapeutic vaccines are NOT considered

11. Contents of the clinical guidelines • Introduction • Regulation of vaccines • Scope of the document • PART A. PRECLINICAL AND LAB EVALUATION OF VACCINES • PART B. CLINICAL EVALUATION OF VACCINES • General Remarks • Methodological considerations • Statistical considerations • Ethical considerations

12. Contents cont. • Phase I studies • Phase II studies • Phase III studies • Bridging studies • Post-licensure and surveillance • Combination vaccines • Annex 1: Glossary • Annex 2: Summary protocol for vaccine evaluation • Annex 3: References

13. WHO GCP • All clinical trials should adhere to standards described in GCP • Definition of CT: A systematic study on pharmaceutical products in human subjects (including patients and other volunteers) in order to discover or verify the effects of and/or identify any adverse reaction to investigational products, and/or to study the absorption, distribution, metabolism and excretion of the products with the objective of ascertaining their efficacy and safety

14. In which circumstances clinical trials should be considered? • 1. For novel vaccines – with no prior nonclinical and clinical experience, more extensive testing than for those licensed and used for long time • 2. For new vaccines (e.g., new for the manufacturer, new adjuvant, new route of administration etc) • 3. For licensed vaccines – subsequent change in production methods or scale-up following licensure will require further product characterisation. The extent of comparability testing needed depends of tha nature of the changes implemented

15. Characterization of vaccines • Key issues: characterization and standardization during vaccine development • Comprehensive characterization of initial batches - essential for consistency; to be completed by end of phase III • If protective in clinical trials, candidate vaccine MUST be made to the same specifications as successful preparation • Following licensing, the vaccine is a subject to batch release by NRA/NCL • A clear distinction between comprehensive characterization of a vaccine during the development and selected tests for the purpose of batch release

16. Preclinical and clinical lots • Vaccine lots - adequately representative of the formulation intended for the clinical investigation • Ideally: preclinical testing should be done on the same lots as proposed for the clinical trials (at least comparable: physico-chemical data, stability, formulation etc) • At minimum, lots prepared under conditions of GMP for clinical trial material; at later stage full GMP.

17. Design of a clinical trial • Epidemiology of the pathogen or disease of interest in the intended population • Clinical spectrum of illness, definition of high risk groups (age, gender, ethnic or population group membership, geography, social characteristics or seasonality) • Laboratory values in the intended population • Sero-prevalence studies • Characteristics of a vaccine

18. Design of an efficacy study • Randomized double-blind controlled trial • Double blinding- to avoid bias in the assessment of endpoints • Randomization – to avoid bias in assignment to one of the study groups and permits statistically valid comparisons between arms • Possible approaches: prospective cohort studies and pre-exposure cohort studies in groups at risk (e.g., traveller vaccination) • The unit of randomisation: the individual, clusters or groups (school, geographic region)

19. General considerations for efficacy trials • Size of trial • Choice of control • Placebo control • Active control • Correlates of protection • Duration of protection • Safety evaluation in phase III trials • Serious adverse events

20. Methodological Considerations • Study population • Outcome measurement • Case detection/ case ascertainment/ case definition • Monitoring and reporting adverse events

21. Study population • At least the initial phase I in healthy, immunocompetent adults at low risk • In phase II and III - target population • If a vaccine is intended for children or other vulnerable populations, vaccine should be tested in small number of intended population before proceeding to larger number • Criteria for inclusion or exclusion of subjects for enrolment in the clinical trial should be established • Special considerations for HIV trials http://www.who.int/biologicals/Meeting-Reports/Doc/VHIV01mar13.pdf

22. Outcome measurement • The primary endpoint should be the most relevant for the disease in the target population • Safety – focus on adverse events and reactogenicity • Immunogenicity – outcome in phase I, II and III • Efficacy – outcome of clinical protection and/or immunological surrogate endpoints in CTs

23. Ethical considerations • WHO GCP guidelines • Ethical guidance (WHO, CIOMS, UNAIDS) • Independent ethics committee • Involvement of children • Placebo • Human challenge studies • Prevent exposure of the individual to unreasonable risk of illness; full benefit of scientific innovation to be provided • Prevent harm to the national immunization programmes • ! REGULATORS SHOULD BE INVOLVED IN THE ETHICAL COMMITTEE BY PROVIDING THE EXPERT ADVICE AND RAISING REGULATORY CONCERNS

24. StatisticalConsiderations • General principles • Trial objectives: efficacy, safety • Superiority trials • Equivalence and non-inferiority trials • Accepted difference in equivalence and non-inferiority trials • Sample size • Duration of study

25. Bridging studies • Design and extent of a clinical bridging study • When bridging studies could be required? 1. For manufacturing change – changes in the composition or in production process, site or scale after the efficacy trial or after licensing 2. For new dosing schedule – changes in the immunization schedule, dose and/or ROA 3. For new population – a concern that safety and/or efficacy profiles may differ in different population 4. For safety - specific safety concerns in the target population; power of the study sufficient to address the rates of common adverse events

26. Post licensure studies and surveillance • Safety evaluation • Vaccine effectiveness evaluation • Study design • Observational cohort studies • Case-control studies • Stepped wedge design • Outbreak interventions • Monitoring of post marketing surveillance

27. Summary protocol for vaccine evaluation • Title and summary • Brief description of the study site (s) • Investigators • Background and rationale • Preclinical and laboratory evaluation of vaccines • Summary of product characteristics • Primary and secondary objectives • Study design • Study population • Methods and procedures • Monitoring of the trial • Timetable

28. Acknowledgement • Many thanks to the experts involved in the development of WHO guidelines for: • Clinical evaluation of vaccines: Regulatory Expectations • Nonclinical evaluation of vaccines