General considerations for clinical trials of vaccines Ming-Hsiao Chan, MD,MPH Researcher/Team Leader, Division of Clinical Sciences, Center for Drug Evaluation, Taiwan

Disclaimer The views expressed in this presentation are those of the speaker, and are not necessarily those of CDE and/or Department of Health (DOH) in Taiwan.

Introduction References: 1.國內法規 2. Guidelines or guidance of WHO, FDA, 臨床試驗報告之格式及內容基準(92年2月08日) 藥品臨床試驗計畫書主要審查事項(93年2月18日) 藥品優良臨床試驗準則(94年1月6日) 2. Guidelines or guidance of WHO, FDA, and EMA 3. Medical journals 4. Review experiences from cases at CDE

Introduction Note: Vaccines are a heterogeneous class of agents, and the evaluation will need to be adapted for each individual product. Therapeutic vaccines (e.g. viral-vector-based gene therapy, tumor vaccines) are not considered here.

Introduction 1. Phase I : safety Phases of clinical development (I,II,III) 1. Phase I : safety 2. Phase II : preliminary information about vaccine’s effect and its general safety 3. Phase III: fully assess the efficacy and safety

Safety is always primary CDE’s primary objectives in reviewing an IND are to assure the safety and rights of subjects.

Outlines Background, rationale and expected value Assure rights of subjects Study population Inclusion and exclusion criteria Dose, route of administration, and vaccination schedule Safety evaluations Concomitant medication Efficacy endpoints and design of clinical trial Other studies (Lot-to-lot consistency study)

Background, rationale and expected value Mechanism Epidemiology of target disease Licensed vaccine available? Unmet medical need Prognosis and clinical presentation of target disease

Background, rationale and expected value Preclinical studies a. Toxicity and safety testing b. Potency and immunogenicity Early phase clinical studies

Background, rationale and expected value Preclinical studies a. Potency: - Ideally, the potency assay should mimic the clinically expected function of the vaccine in humans - Examples: challenge models (intracerebral mouse test for rabies vaccine)

Background, rationale and expected value Preclinical studies b. Immunogenicity - Help in the selection the doses, schedules and routes of administration to be evaluated in clinical trials - Assess relevant immune response, e.g. seroconversion rates, geometric mean Ab titers, cell-mediated immunity - What’s the primary concern in interpreting the data

Background, rationale and expected value Before phase I studies: a. Appropriate animal challenging model b. Other approaches providing proof of concept

Background, rationale and expected value Plans for development of the candidate vaccine and clarify requirements for carrying out clinical trials Expected clinical benefits of the candidate vaccine

Assure rights of subjects Is there a need for controlled trials? Depending on the developmental stage Do we need a controlled trial in phase I study ? Choice of control: Placebo control a. What’s the potential harm to the controlled group without the vaccination? Is it reversible or curable? b. Inert placebo or vaccine without protection on target disease c. May not be necessary for already-licensed vaccine

Assure rights of subjects Choice of control Active control a. A comparator vaccine indicated for the same disease b. A different formulation (e.g. liquid vs lyophilized; adjuvant change; changed excipient or preservative; changed Ag dose) c. A new method of administration d. A placebo control arm for internal validation should sometimes be considered

Study population Study population Phase I study: - Healthy, immunocompetent adults - Low risk of infection or complication Phase II, III study: - Trial population could represent the target population

Study population Study population Care should be taken to identify the correct target population (demographic, epidemiological, socioeconomic factors of the population) Consideration for vaccines intended for children or vulnerable population - tested in a small number of subjects first

Inclusion and exclusion criteria Again, safety is the primary concern Subjects should be excluded if they do not meet the medical or other eligibility criteria, for example: a. Chronic illness (e.g. cardiac or renal failure) b. Progressive neurological disease c. Uncontrolled epilepsy d. Receiving long-term antibiotics treatment

Inclusion and exclusion criteria Subjects should be excluded if they do not meet the medical or other eligibility criteria, for example: e. Immune status (e.g. immunodeficiency, immunosuppression and/or prematurity) f. Allergic history g. Recent vaccinations

Dose, route of administration, and vaccination schedule Determination should be based on scientific justification: Preclinical studies Clinical studies a. Dose-response data from dose-finding studies (especially important for novel antigens) b. Dose-finding studies may also incorporate exploration of schedules Dose-response data should be explored as early as possible

Dose, route of administration, and vaccination schedule To identify appropriate schedules: a. Nature of antigens b. Target population c. Kinetic profile of the vaccine-induced antibody response Specific patients group with impaired immune function (e.g. premature infants, the immunosuppressed and haemodialysis patients)

Dose, route of administration, and vaccination schedule Phase I: Clinical tolerance, safety, and preliminary information on immunogenicity The dose and method of administration should also be assessed with respect to these parameters. Phase II: Define the optimal dose, initial schedule and safety profile before the phase III study

Safety evaluations Safety evaluations Include all subjects who receive at least one dose of vaccine Safety surveillance should begin from the start of enrollment Safety issues identified during preclinical studies and early phase clinical studies should be provided

Safety evaluations Monitoring and reporting adverse events An AE in a vaccine trial is any untoward medical occurrence in a clinical trial A specific monitoring plan with timetable and methods Methods for collection of safety data (e.g. diary cards, questionnaire, telephone contact) Intervals for collection of the data (e.g. daily or weekly)

Safety evaluations Monitoring and reporting adverse events The safety report should include evaluation of injection-site reactions and systemic events at baseline, at pre-specified vaccination times and following vaccination. Total duration of follow-up: In principle, all vaccines under development need a long-term evaluation plan. In most confirmatory clinical trials, a follow-up period of at least 6 months subsequent to the last vaccination is needed.

Safety evaluations Monitoring and reporting adverse events Total duration of follow-up Different follow-up periods should be considered on a case-by-case basis. Consider following factors: - Disease incidence - The characteristic of immune response of the candidate vaccines - The expected safety profile

Safety evaluations Safety evaluations Randomized studies in Phase III trials: a. To provide reliable rates of common adverse events (>1/100 and <1/10) b. To detect less common adverse events (<1/10,000)

Safety evaluations Reporting adverse events (including SAEs) All AEs should be well documented a. Type of adverse events b. How long after the vaccination c. Actions taken d. Patient characteristics e. Course of the adverse event

Safety evaluations Causality assessment of the AEs: (NDA) Attributing causality is sometimes difficult (e.g. SIDS in infant population) Additional clinical safety studies may be needed

Safety evaluations Post-marketing surveillance Uncommon AEs (long-term or acute) Active or passive processes Passive surveillance Voluntary reporting Effective in detecting severe or lethal events and unusual clinical response

Concomitant medication Less restriction, in general no concern regarding drug interaction Usually restrict the use of immune modifying drugs (e.g. systemic steroids, cytotoxic drugs) Exclude the subjects administered with blood products or immunoglobulins recently Should have instructions for concomitant use of other vaccines All concomitant medication use during the study should be recorded

Efficacy endpoints and design of clinical trial In phases II and III, clinical protection outcome may be measured Performed in areas where an appropriate impact of active immunization can be expected, and where a controlled trial is feasible Vaccine efficacy and/or vaccine effectiveness Immunogenicity studies may be sufficient to demonstrate clinical efficacy for vaccines containing a known antigen for which the level of protective antibody is well established. (e.g. diphtheria, tetanus)

Efficacy endpoints and design of clinical trial Outcome measurement: Vaccine efficacy: The reduction of chance of developing disease after vaccination relative to the chance when unvaccinated. Vaccine efficacy measures direct protection. VE = {(Iu-Iv)/Iu} × 100 % - Iu: incidence in unvaccinated population - Iv: incidence in vaccinated population

Efficacy endpoints and design of clinical trial Outcome measurement: Vaccine effectiveness The protection rate conferred by vaccination in a specified population. It measures both direct (vaccine induced) and indirect protection (population related )during routine use.

Efficacy endpoints and design of clinical trial Vaccine efficacy Randomized, double-blind, controlled trials (the most effective) Other approaches: secondary attack rate study, observational cohort study, case-control study Vaccine efficacy could be measured as outcome of clinical protection and/or as an immunological surrogate end-point based on immunological response.

Efficacy endpoints and design of clinical trial Clinical endpoints If an organism is able to cause a range of infections (e.g. from life-threatening invasive infection to otitis media), the primary endpoint should be selected in accordance with the proposed indication. Alternative primary endpoints: Clinical manifestations of latent infection (e.g. vaccine intended to prevent herpes zoster ) Laboratory evidence that a candidate vaccine reduces primary infection rates (e.g. candidate vaccine against hepatitis C) Other markers that predict progression to clinically apparent disease (e.g. HPV vaccine)

Efficacy endpoints and design of clinical trial Clinical endpoints Case definition Well-validated methods - Clinically apparent disease - Clinically non-apparent infections Case detection The same methodology applied For clinically non-apparent disease - Monitored at regular intervals

Efficacy endpoints and design of clinical trial Surrogate endpoints Feasibility Validity Justify the use of surrogate endpoint

Other studies (Lot-to-lot consistency study) Considered on a case by case basis Inherent and unavoidable variability in the final formulation of the vaccine Show consistency of manufacturing and performance of the final product Ideally, adequately tested during the confirmatory studies of immunogenicity and, if feasible, in protective efficacy studies Determining the number of lots to be compared

Other studies (Lot-to-lot consistency study) Pre-defined criteria for concluding comparability between lots (usually based on immunological parameters) Comparison of safety data is also important Important consideration: Which immunological parameters are the most valid and clinically relevant How large a difference between lots might be clinically significant

Other studies (Lot-to-lot consistency study) Example: Seasonal influenza inactivated vaccines 3 consecutively manufactured final formulated bulk lots of vaccine HI antibody assay Ratio of GMTs for each viral strain contained in the three vaccine lots as the primary endpoint A pair-wise comparison The two-sided 95% CI on the GMT ratio: 0.6-1.5

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