Post on 12-Dec-2015
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan2005
Principles for clinical
evaluation of vaccines: WHO
guidelines
World Health Organization - WHO
Dr Ivana KnezevicWHO, Immunization, Vaccines & Biologicals Quality Assurance and Safety of Biologicals
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Vaccine development and evaluation
Product development
Product development
LicensingLicensing
Characterization
of candidate
vaccine
Characterization
of candidate
vaccine
Preclinical/Nonclinical
testing
Preclinical/Nonclinical
testing
Clinical trials
Clinical trials
PMSPMS
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
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
Research and Development of vaccines
The role of the National RegulatoryAuthorities in vaccine evaluation
4 Based on National Regulation
4 Diff erent in diff erent countries4 Clinical trial approval4 Review of the manufacturer dossier
as a part of licensing procedure
4 Lot release4 Surveillance of vaccine field
performance
4 Regular inspections for GMP
The role of the National RegulatoryAuthorities in vaccine evaluation
4 Based on National Regulation
4 Diff erent in diff erent countries4 Clinical trial approval4 Review of the manufacturer dossier
as a part of licensing procedure
4 Lot release4 Surveillance of vaccine field
performance
4 Regular inspections for GMP
Clinical trials
Licensing
Postmarketing surveillance
Preclinical testing
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
What is the role of regulators in clinical trials?
4 DEFINITION OF VACCINE OF ASSURED QUALITY RELY ON THE STRONG NRA!
4 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
4 National regulation of CTs is essential component (e.g., written guidelines, mechanism to approve trial but also to terminate it)
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Clinical Trial Approval
4 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.
4 This is in addition to ethical clearance which is required in all countries for clinical trials.
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 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
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
WHO standards for vaccines and biologicals:
http://www.who.int/biologicals/
Recommendations, Requirements and Guidelines for production and control of vaccines: 4 1) General (e.g., GMP, quality assurance for biological products)4 2) Guidelines for DNA vaccines, synthetic peptide vaccines, etc.4 3) Requirements for a number of bacterial and viral vaccines: OPV,MMR,DTP etc.)
Global written standardsGlobal written standards Global measurement standardsGlobal measurement standards
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
WHO Guidelines for nonclinical and clinical evaluation of
vaccines
4 Good Laboratory Practice
4 Good Clinical Practice (under
revision)
4 Clinical Evaluation of Vaccines:
Regulatory Expectations (TRS 924)
4 Nonclinical Evaluation of Vaccines
(in press)
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
WHO Guidelines for Clinical Evaluation of Vaccines
4 To assist in evaluation of clinical trials as a part of the regulatory overview
4 Audience: NRAs, Vaccine Industry, but also clinical researchers and investigators
4 Reviewed by more than 100 experts and discussed at the global Consultations
4 Adopted by the Expert Committee on Biological Standardization (ECBS), 2001
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Scope and contents of clinical guidelines
4Prophylactic vaccines
4Therapeutic vaccines are NOT
considered
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Contents of the clinical guidelines
4 Introduction4 Regulation of vaccines4 Scope of the document
4 PART A. PRECLINICAL AND LAB EVALUATION OF VACCINES
4 PART B. CLINICAL EVALUATION OF VACCINES4 General Remarks4 Methodological considerations4 Statistical considerations4 Ethical considerations
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Contents cont.
4 Phase I studies4 Phase II studies4 Phase III studies4 Bridging studies4 Post-licensure and surveillance4 Combination vaccines4 Annex 1: Glossary4 Annex 2: Summary protocol for vaccine
evaluation4 Annex 3: References
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
WHO GCP
4 All clinical trials should adhere to standards described in GCP
4 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
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
In which circumstances clinical trials should be considered?
4 1. For novel vaccines – with no prior nonclinical and clinical experience, more extensive testing than for those licensed and used for long time
4 2. For new vaccines (e.g., new for the manufacturer, new adjuvant, new route of administration etc)
4 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
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Characterization of vaccines
4 Key issues: characterization and standardization during vaccine development
4 Comprehensive characterization of initial batches - essential for consistency; to be completed by end of phase III
4 If protective in clinical trials, candidate vaccine MUST be made to the same specifications as successful preparation
4 Following licensing, the vaccine is a subject to batch release by NRA/NCL
4 A clear distinction between comprehensive characterization of a vaccine during the development and selected tests for the purpose of batch release
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Preclinical and clinical lots4 Vaccine lots - adequately representative of
the formulation intended for the clinical investigation
4 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)
4 At minimum, lots prepared under conditions of GMP for clinical trial material; at later stage full GMP.
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Design of a clinical trial
4 Epidemiology of the pathogen or disease of interest in the intended population
4 Clinical spectrum of illness, definition of high risk groups (age, gender, ethnic or population group membership, geography, social characteristics or seasonality)
4 Laboratory values in the intended population
4 Sero-prevalence studies4 Characteristics of a vaccine
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Design of an efficacy study
4 Randomized double-blind controlled trial4 Double blinding- to avoid bias in the
assessment of endpoints4 Randomization – to avoid bias in assignment to
one of the study groups and permits statistically valid comparisons between arms
4 Possible approaches: prospective cohort studies and pre-exposure cohort studies in groups at risk (e.g., traveller vaccination)
4 The unit of randomisation: the individual, clusters or groups (school, geographic region)
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
General considerations for efficacy trials
4 Size of trial4 Choice of control
Placebo control Active control Correlates of protection
4 Duration of protection4 Safety evaluation in phase III trials
Serious adverse events
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Methodological Considerations
4Study population4Outcome measurement4Case detection/ case
ascertainment/ case definition4Monitoring and reporting
adverse events
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Study population
4 At least the initial phase I in healthy, immunocompetent adults at low risk
4 In phase II and III - target population 4 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
4 Criteria for inclusion or exclusion of subjects for enrolment in the clinical trial should be established
4 Special considerations for HIV trials http://www.who.int/biologicals/Meeting-Reports/Doc/VHIV01mar13.pdf
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Outcome measurement
4 The primary endpoint should be the most relevant for the disease in the target population
4 Safety – focus on adverse events and reactogenicity
4 Immunogenicity – outcome in phase I, II and III
4 Efficacy – outcome of clinical protection and/or immunological surrogate endpoints in CTs
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Ethical considerations4 WHO GCP guidelines4 Ethical guidance (WHO, CIOMS, UNAIDS)4 Independent ethics committee4 Involvement of children4 Placebo4 Human challenge studies4 Prevent exposure of the individual to unreasonable risk
of illness; full benefit of scientific innovation to be provided
4 Prevent harm to the national immunization programmes
4 ! REGULATORS SHOULD BE INVOLVED IN THE ETHICAL COMMITTEE BY PROVIDING THE EXPERT ADVICE AND RAISING REGULATORY CONCERNS
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Statistical Considerations
4 General principles4 Trial objectives: efficacy, safety4 Superiority trials4 Equivalence and non-inferiority trials4 Accepted difference in equivalence
and non-inferiority trials4 Sample size4 Duration of study
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Bridging studies
4 Design and extent of a clinical bridging study4 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
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Post licensure studies and surveillance
4 Safety evaluation4 Vaccine effectiveness evaluation4 Study design
Observational cohort studies Case-control studies Stepped wedge design Outbreak interventions
4 Monitoring of post marketing surveillance
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Summary protocol for vaccine evaluation
4 Title and summary4 Brief description of the study site (s)4 Investigators4 Background and rationale4 Preclinical and laboratory evaluation of
vaccines4 Summary of product characteristics4 Primary and secondary objectives4 Study design4 Study population4 Methods and procedures4 Monitoring of the trial4 Timetable
Ivana Knezevic, WHO/FCH/IVB/QSB, Jan 2005
Acknowledgement
4 Many thanks to the experts involved in the development of WHO guidelines for:
1) Clinical evaluation of vaccines: Regulatory Expectations
2) Nonclinical evaluation of vaccines