Clinical Evaluation of Preventive Vaccines: Use of Bridging Studies

1. Clinical Evaluation of Preventive Vaccines: Use of Bridging Studies Marion F. Gruber, Ph.D. 2006 FDA/Industry Statistics Workshop Washington D.C., September 29, 2006

2. Objectives • Approval Process for Preventive Vaccines • Applicable laws & regulations • Clinical endpoint efficacy studies • Correlates of Protection • Bridging studies, e.g., • New population • Foreign trials • Age Group • Comparison of two products • Considerations for successful bridging studies

3. Acts & Regulations Pertinent to Vaccine Development • PHS Act (42 USC 262-63) Section 351 • FD & C Act (21 USC 301-392) • FDAMA, November 12, 1997 • 21 CFR • 21 CFR 600-680 Biological Product Standards • 21 CFR 314.126 Adequate and well-controlled trials • 21 CFR 312 Investigational New Drug Application • 21 CFR 210-211 Good Manufacturing Practices • 21 CFR 58 Good Laboratory Practices • 21 CFR 56 Institutional Review Boards • 21 CFR 50 Protection of Human Subjects • 21 CFR 25 Environmental Impact Considerations

4. Stages of Review and Regulation Phase 4 Inspection Safety Efficacy Lot Release Clinical Investigational Plan IND BLA Data to support approval; Inspection Phase 1 Safety Immuno-genicity Phase 2 Safety Immuno-genicity Dose Ranging Phase 3 Safety Efficacy Immuno-genicity BLA Supplement Post-approval Changes: New Indications Dosing Manufacture Equip./Facilities IND =Investigational New Drug Application; BLA=Biologics License Application

5. Clinical Endpoint Efficacy Studies • Clinical trials demonstrating preventive efficacy for clinical endpoints provide the greatest scientific rigor for evaluating vaccines • Prospective, controlled, randomized • Primary endpoint: prevention of disease • Necessary in situations when • Vaccine is novel • First of its kind administered to target population • No accepted immune response correlate of protection • Example: NCKP efficacy trial of the heptavalent pneumococcal conjugate vaccine: ~ 38,000 infants • Prevention of invasive pneumococcal disease

6. Correlate of Protection • Generally, a laboratory parameter that has been shown to be associated with protection from clinical disease • Adequate and well-controlled trials • An immunological correlate of protection is most useful if clear qualitative and quantitative relationships can be determined

7. Correlate of Protection (cont.) May also be suggested by other sources: • Population-based studies of vaccines • Trials using • Specific immune globulins • Immune globulin with specific Ab • e.g. polio • Animal challenge/protection studies • Phase 2 clinical data • Protection thought to be conferred to infants by maternal antibody

8. Correlate of Protection (cont.) • Example of licensed vaccines with an identified correlate of protection: • Hep B • However, identification of correlate not a requirement for licensure • Examples of licensed vaccines without an identified immune correlate of protection: • Acellular pertussis, Typhoid, Tuberculosis (BCG) • Immune correlate(s) useful for interpreting trials with immune response endpoints, • E.g., “bridging studies”

9. Bridging Studies • A clinical trial in which a parameter of interest for a product - e.g., manufacturing process, formulation, dosing schedule – is directly compared with a changed version of that parameter with respect to the effect of the change on the product’s clinical performance. • Purpose: To determine effect of change(s) on product’s clinical performance • e.g., immune response for vaccines

10. Types of Bridging Studies To address: • New population (foreign studies) • Age group • New product to standard of care • New schedule • Manufacturing changes • If immune response/safety profile are similar, then efficacy can be inferred

11. Population Bridging Studies • Clinical endpoint efficacy trial not possible in certain regions • Disease endemic in limited areas • Existing vaccines in some countries • Approach: conduct clinical efficacy trial where disease rate is high, then “bridge” to US population with single-arm study in US

12. Population Bridging Studies (cont.) • Not possible to randomize region, ethnic group • Thus, not randomized but controlled • Compare immune/safety endpoints in region where clinical efficacy shown to those endpoints observed in US bridging study • Try to keep comparison group similar • Demographic factors, e.g., age, gender • Medical practice, e.g., concomitant vaccines, schedule & ROA, • Conduct of trial, e.g., inclusion/exclusion criteria, surveillance for AEs, timing of blood draws, etc.

13. Population Bridging Study (cont.) Design: • Comparison of immune responses is often the primary objective • Percent responders achieving an immune response above threshold considered protective • Ratio of geometric mean concentration or titer of antibodies

14. Population Bridging Study (cont.) Design: • Prospective statistical analysis plan • Studies designed to have sufficient power to rule out important difference in parameters of immune response • Provide confidence limits on differences between comparison groups for immune response parameters • e.g., seroconversion rates and geometric mean titers • Safety outcomes also measured – rates of common AEs, SAEs

15. Statistical Evaluation:Non-inferiority criteria (Current) Percent responders or sero-protected: UL of 2-sided 95% CI for difference (efficacy pop -target pop) <5-10% GMTs/GMCs: UL of 2-sided 95% CI for ratio (or 1-sided 97.5% CI) (GMC efficacy pop./GMC target pop.) <1.5-2.0 Other immunologic parameters Opsonophagocytic activity

16. Foreign Trials of Preventive Vaccines • Examples where foreign field trials may play an important role in vaccine development in the future (U.S.) • Vaccines where epidemiology precludes or limits efficacy trials in U.S. e.g., • Malaria, ETEC, Cholera • Past examples where foreign field trials played an important role in vaccine development • E.g., DTaP, oral polio, typhoid Vi PS, Hep A

17. Considerations for Foreign Trials • Efficacy (and Immunogenicity) differences between populations may result from differences in factors such as genetics, nutritional status, & background infections • e.g., OPV in developed vs. developing countries • Obtain safety and immunogenicity data using candidate vaccine in specific population in which efficacy trial will be performed • Case definition • Adequate sample size • Schedule (changes)

18. Considerations for Successful “Bridging” • Validated immune response assays (vaccines) • Foreign clinical data should meet standards of the new region • Study design, conduct & regulatory requirements (ICH E5) • Determine vaccine’s sensitivity to ethnic factors (ICH E5) • Study should meet local and international standards • ICH E6: Good Clinical Practices • ICH E8: General Considerations for Clinical Trials • Other Documents (CFR, etc.) • Generous banking of sera from efficacy trial • SOPP for storing sera

19. Population Bridging StudyForeign Trial/New Age Group • Boostrix: Tetanus Toxoid, reduced Diphtheria Toxoid and Acellular Pertussis Vaccine adsorbed (Tdap) • Active immunization against tetanus, diphtheria and pertussis as a single dose in individuals 10 through 18 years of age

20. Boostrix: Basis for Licensure • Demonstration of safety • Demonstration of non-inferiority of anti-tetanus and anti-diphtheria seroprotection and booster response vs. Td • Demonstration of booster response to pertussis antigens • Demonstration of serologic bridge to pertussis efficacy

21. Boostrix™ formulation per 0.5mL/dose comparison with Infanrix®

22. Serologic Bridge to Clinical Efficacy Study • German Household Contact Study (Infanrix®) • 3-dose series at 3, 4, and 5 months of age • Efficacy 89% (95% CI: 77- 95%) against WHO-defined pertussis • > 21 days of paroxysmal cough with positive culture and/or serologic testing • Serologic bridge • Non-inferiority to Infanrix®, administered as a 3-dose primary series • GMCs one month post Boostrix (single dose) compared to GMCs one month after completing infant series with Infanrix®

23. Serologic bridge: Testing of Study Samples • German household Contact Study • Subjects who had serologic data for at least one pertussis antigen • Majority had anti-PT toxoid serological data only • Serologic assays performed in 1994 • Boostrix Immunogenicity study • Serologic assays performed in 2003 • Used same assays and same laboratory

24. Endpoints for Serologic Bridge

25. Ratios of GMCs between Boostrix™ and Infanrix® one month post-vaccination (TVC) * ELISA units / mL ** pre-specified non-inferiority criteria met

26. Bridging Study: Age GroupHuman Papillomavirus (Types 6, 11, 16, 18) vaccine • Indication: prevention of HPV 6, 11, 16, 18 related cervical cancer, cervical dysplasia, vulvar or vaginal dysplasias, or genital warts • Children & adolescents 9-17 yrs and women 18-26 yrs • CIN 2/3 and AIS served as surrogate markers for prevention of cervical cancer in efficacy trials conducted in females 16 – 26 years of age

27. Bridging Study: Age groupHuman Papillomavirus (Types 6, 11, 16, 18) vaccine • Efficacy assessed in 4 placebo controlled, double blind, randomized Phase II and III clinical trials (n = 20,541 females (16 - 26 yrs)) • Phase II*: n = 2391 • Phase II: n = 551 • Phase III: n = 5,442 • Phase III: n = 12, 157 • VE for HPV 16/18-related disease: • CIN3 or AIS: 100% (95% CI: 87.9%, 100.0%) • VIN 2/3/ or VaIN 2/3: 100% (95% CI: 55.5%, 100.0%) *HPV 16 component of Gardasil only

28. Statistical Analysis of Non-Inferiority of HPV GMTsComparing 10-15 yr old females to 16 -23 yr old females

29. Analysis of non-inferiority comparing seroconversion rates in 10-15 yr old females with 16-23 yr old females

30. Immunogenicity Bridging between 9-15 year old females, adolescents and 16-26 year old adult women

31. Bridging study: Comparison of 2 ProductsMenactra and Menomune • Indication: Prevention of invasive meningococcal disease caused by N. meningitidis (A, C, Y and W-135) • Menomune (another meningococcal vaccine licensed and available in the US) • Comparison to Menomune • Inferred efficacy • Immune correlate: serum bactericidal antibody • Other parameters: SBA GMT, seroconversion rate, IgG (ELISA) • Non-inferiority to Menomune

32. Comparison of SBA responses to Menactra & Menomune 28 days after vaccination for participants (11-18 yrs)

33. Concluding Remarks • Preventive vaccines have unique considerations for product & clinical development • Overall planning and coordination: • Accumulate sufficient safety, immunogenicity & efficacy data during development • Anticipate the need for clinical bridging studies • Utilize available FDA documents & resources

34. Concluding Remarks • Similar study design • Evaluation of similar endpoints appropriate for assessment of treatment • Validated immune response assays (vaccines) • Prospective statistical analysis • Study/population to meet regulatory requirements in new region

35. CBER Guidance • Web:www.fda.gov/cber/reading.htm • Email:OCTMA@CBER.FDA.GOV • Fax: 1-888-CBER-FAX • Phone • DVRPA: 301- 827-3070 • OCTMA: 301- 827- 1800 or 800-835-4709

36. Acknowledgments • Karen Farizo, M.D. • Theresa Finn, Ph.D. • Antonia Geber, M.D. • Karen Goldenthal, M.D. • Amelia D. Horne, Dr.P.H. • Lucia Lee, M.D. • Nancy Miller, M.D. • Douglas Pratt, M.D.