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Ivana Knezevic, WHO/FCH/IVB/QSB, Jan2005 Principles for clinical evaluation of vaccines: WHO guidelines World Health Organization - WHO Dr Ivana Knezevic.

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Presentation on theme: "Ivana Knezevic, WHO/FCH/IVB/QSB, Jan2005 Principles for clinical evaluation of vaccines: WHO guidelines World Health Organization - WHO Dr Ivana Knezevic."— Presentation transcript:

1 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan2005 Principles for clinical evaluation of vaccines: WHO guidelines World Health Organization - WHO Dr Ivana Knezevic WHO, Immunization, Vaccines & Biologicals Quality Assurance and Safety of Biologicals

2 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Vaccine development and evaluation Product development Product development Licensing Characteri zation of candidate vaccine Characteri zation of candidate vaccine Preclinical/ Nonclinical testing Preclinical/ Nonclinical testing Clinical trials Clinical trials PMS Development of standards and stand. of assays Establishment of WHO standards and recommendations for production and control Monitoring performance and development of new standards/replacement of existing

3 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Production and control of vaccines The role of NRAs at different stages of vaccine development, production and evaluation Research and Development of vaccines Clinical trials Licensing Postmarketing surveillance Preclinical testing

4 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 What is the role of regulators in clinical trials? 4DEFINITION OF VACCINE OF ASSURED QUALITY RELY ON THE STRONG NRA! 4Regulators should play an active role from early stages of vaccine development to post-licensing by: l Establishing regulation of clinical trials (CTs) at national level l Interacting with the other bodies (e.g., ethical committee) l By providing the expert advice on quality aspect of vaccines l By establishing an early dialogue with the manufacturers since regulatory compliance is the basis for eventual approval of clinical trials 4National regulation of CTs is essential component (e.g., written guidelines, mechanism to approve trial but also to terminate it)

5 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Clinical Trial Approval 4Clinical 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. 4This is in addition to ethical clearance which is required in all countries for clinical trials.

6 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 How WHO standards may help regulators to review clinical trials? By providing: 1.Measurement standards for quality control of clinical lots 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 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 WHO standards for vaccines and biologicals: Recommendations, Requirements and Guidelines for production and control of vaccines: 41) General (e.g., GMP, quality assurance for biological products) 42) Guidelines for DNA vaccines, synthetic peptide vaccines, etc. 43) Requirements for a number of bacterial and viral vaccines: OPV,MMR,DTP etc.) Global written standards Global measurement standards

8 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 WHO Guidelines for nonclinical and clinical evaluation of vaccines 4Good Laboratory Practice 4Good Clinical Practice (under revision) 4Clinical Evaluation of Vaccines: Regulatory Expectations (TRS 924) 4Nonclinical Evaluation of Vaccines (in press)

9 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 WHO Guidelines for Clinical Evaluation of Vaccines 4To assist in evaluation of clinical trials as a part of the regulatory overview 4Audience: NRAs, Vaccine Industry, but also clinical researchers and investigators 4Reviewed by more than 100 experts and discussed at the global Consultations 4Adopted by the Expert Committee on Biological Standardization (ECBS), 2001

10 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Scope and contents of clinical guidelines 4Prophylactic vaccines 4Therapeutic vaccines are NOT considered

11 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Contents of the clinical guidelines 4Introduction 4Regulation of vaccines 4Scope of the document 4PART A. PRECLINICAL AND LAB EVALUATION OF VACCINES 4PART B. CLINICAL EVALUATION OF VACCINES 4General Remarks 4Methodological considerations 4Statistical considerations 4Ethical considerations

12 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Contents cont. 4Phase I studies 4Phase II studies 4Phase III studies 4Bridging studies 4Post-licensure and surveillance 4Combination vaccines 4Annex 1: Glossary 4Annex 2: Summary protocol for vaccine evaluation 4Annex 3: References

13 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 WHO GCP 4All clinical trials should adhere to standards described in GCP 4Definition 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 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 In which circumstances clinical trials should be considered? 41. For novel vaccines – with no prior nonclinical and clinical experience, more extensive testing than for those licensed and used for long time 42. For new vaccines (e.g., new for the manufacturer, new adjuvant, new route of administration etc) 43. 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 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Characterization of vaccines 4Key issues: characterization and standardization during vaccine development 4Comprehensive characterization of initial batches - essential for consistency; to be completed by end of phase III 4If protective in clinical trials, candidate vaccine MUST be made to the same specifications as successful preparation 4Following licensing, the vaccine is a subject to batch release by NRA/NCL 4A clear distinction between comprehensive characterization of a vaccine during the development and selected tests for the purpose of batch release

16 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Preclinical and clinical lots 4Vaccine lots - adequately representative of the formulation intended for the clinical investigation 4Ideally: preclinical testing should be done on the same lots as proposed for the clinical trials (at least comparable: physico- chemical data, stability, formulation etc) 4At minimum, lots prepared under conditions of GMP for clinical trial material; at later stage full GMP.

17 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Design of a clinical trial 4Epidemiology of the pathogen or disease of interest in the intended population 4Clinical spectrum of illness, definition of high risk groups (age, gender, ethnic or population group membership, geography, social characteristics or seasonality) 4Laboratory values in the intended population 4Sero-prevalence studies 4Characteristics of a vaccine

18 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Design of an efficacy study 4Randomized double-blind controlled trial 4Double blinding- to avoid bias in the assessment of endpoints 4Randomization – to avoid bias in assignment to one of the study groups and permits statistically valid comparisons between arms 4Possible approaches: prospective cohort studies and pre-exposure cohort studies in groups at risk (e.g., traveller vaccination) 4The unit of randomisation: the individual, clusters or groups (school, geographic region)

19 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 General considerations for efficacy trials 4Size of trial 4Choice of control l Placebo control l Active control l Correlates of protection 4Duration of protection 4Safety evaluation in phase III trials l Serious adverse events

20 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Methodological Considerations 4Study population 4Outcome measurement 4Case detection/ case ascertainment/ case definition 4Monitoring and reporting adverse events

21 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Study population 4At least the initial phase I in healthy, immunocompetent adults at low risk 4In phase II and III - target population 4If 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 4Criteria for inclusion or exclusion of subjects for enrolment in the clinical trial should be established 4Special considerations for HIV trials Reports/Doc/VHIV01mar13.pdf Reports/Doc/VHIV01mar13.pdf

22 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Outcome measurement 4The primary endpoint should be the most relevant for the disease in the target population 4Safety – focus on adverse events and reactogenicity 4Immunogenicity – outcome in phase I, II and III 4Efficacy – outcome of clinical protection and/or immunological surrogate endpoints in CTs

23 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Ethical considerations 4WHO GCP guidelines 4Ethical guidance (WHO, CIOMS, UNAIDS) 4Independent ethics committee 4Involvement of children 4Placebo 4Human challenge studies 4Prevent exposure of the individual to unreasonable risk of illness; full benefit of scientific innovation to be provided 4Prevent harm to the national immunization programmes 4! REGULATORS SHOULD BE INVOLVED IN THE ETHICAL COMMITTEE BY PROVIDING THE EXPERT ADVICE AND RAISING REGULATORY CONCERNS

24 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Statistical Considerations 4General principles 4Trial objectives: efficacy, safety 4Superiority trials 4Equivalence and non-inferiority trials 4Accepted difference in equivalence and non-inferiority trials 4Sample size 4Duration of study

25 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Bridging studies 4Design and extent of a clinical bridging study 4When 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 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Post licensure studies and surveillance 4Safety evaluation 4Vaccine effectiveness evaluation 4Study design l Observational cohort studies l Case-control studies l Stepped wedge design l Outbreak interventions 4Monitoring of post marketing surveillance

27 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Summary protocol for vaccine evaluation 4Title and summary 4Brief description of the study site (s) 4Investigators 4Background and rationale 4Preclinical and laboratory evaluation of vaccines 4Summary of product characteristics 4Primary and secondary objectives 4Study design 4Study population 4Methods and procedures 4Monitoring of the trial 4Timetable

28 Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005 Acknowledgement 4Many thanks to the experts involved in the development of WHO guidelines for: 1)Clinical evaluation of vaccines: Regulatory Expectations 2)Nonclinical evaluation of vaccines


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