1. Principles for clinical evaluation of vaccines: WHO guidelines
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
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
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

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. Statistical Considerations
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