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

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Presentation on theme: "Clinical Evaluation of Preventive Vaccines: Use of Bridging Studies Marion F. Gruber, Ph.D. 2006 FDA/Industry Statistics Workshop Washington D.C., September."— Presentation transcript:

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

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

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

4 Stages of Review and Regulation Clinical Investigational Plan Phase 1 Safety Immuno- genicity Phase 2 Safety Immuno- genicity Dose Ranging Phase 3 Safety Efficacy Immuno- genicity BLA Data to support approval; Inspection Phase 4 Inspection Safety Efficacy Lot Release BLA Supplement Post-approval Changes: New Indications Dosing Manufacture Equip./Facilities IND 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 Clinical trials demonstrating preventive efficacy for clinical endpoints provide the greatest scientific rigor for evaluating vaccines Prospective, controlled, randomized Prospective, controlled, randomized Primary endpoint: prevention of disease Primary endpoint: prevention of disease Necessary in situations when Necessary in situations when Vaccine is novel Vaccine is novel First of its kind administered to target population First of its kind administered to target population No accepted immune response correlate of protection No accepted immune response correlate of protection Example: NCKP efficacy trial of the heptavalent pneumococcal conjugate vaccine: ~ 38,000 infants Example: NCKP efficacy trial of the heptavalent pneumococcal conjugate vaccine: ~ 38,000 infants Prevention of invasive pneumococcal disease 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 Generally, a laboratory parameter that has been shown to be associated with protection from clinical disease Adequate and well-controlled trials Adequate and well-controlled trials An immunological correlate of protection is most useful if clear qualitative and quantitative relationships can be determined 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 Population-based studies of vaccines Trials using Trials using Specific immune globulins Specific immune globulins Immune globulin with specific Ab Immune globulin with specific Ab e.g. polio e.g. polio Animal challenge/protection studies Animal challenge/protection studies Phase 2 clinical data Phase 2 clinical data Protection thought to be conferred to infants by maternal antibody 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: Example of licensed vaccines with an identified correlate of protection: Hep B Hep B However, identification of correlate not a requirement for licensure However, identification of correlate not a requirement for licensure Examples of licensed vaccines without an identified immune correlate of protection: Examples of licensed vaccines without an identified immune correlate of protection: Acellular pertussis, Typhoid, Tuberculosis (BCG) Acellular pertussis, Typhoid, Tuberculosis (BCG) Immune correlate(s) useful for interpreting trials with immune response endpoints, Immune correlate(s) useful for interpreting trials with immune response endpoints, E.g., bridging studies 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 products clinical performance. 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 products clinical performance. Purpose: To determine effect of change(s) on products clinical performance Purpose: To determine effect of change(s) on products clinical performance e.g., immune response for vaccines e.g., immune response for vaccines

10 Types of Bridging Studies Types of Bridging Studies To address: New population (foreign studies) New population (foreign studies) Age group Age group New product to standard of care New product to standard of care New schedule New schedule Manufacturing changes Manufacturing changes If immune response/safety profile are similar, then efficacy can be inferred 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 Clinical endpoint efficacy trial not possible in certain regions Disease endemic in limited areas Disease endemic in limited areas Existing vaccines in some countries 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 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 Not possible to randomize region, ethnic group Thus, not randomized but controlled Thus, not randomized but controlled Compare immune/safety endpoints in region where clinical efficacy shown to those endpoints observed in US bridging study Compare immune/safety endpoints in region where clinical efficacy shown to those endpoints observed in US bridging study Try to keep comparison group similar Try to keep comparison group similar Demographic factors, e.g., age, gender Demographic factors, e.g., age, gender Medical practice, e.g., concomitant vaccines, schedule & ROA, Medical practice, e.g., concomitant vaccines, schedule & ROA, Conduct of trial, e.g., inclusion/exclusion criteria, surveillance for AEs, timing of blood draws, etc. 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 Comparison of immune responses is often the primary objective Percent responders achieving an immune response above threshold considered protective Percent responders achieving an immune response above threshold considered protective Ratio of geometric mean concentration or titer of antibodies Ratio of geometric mean concentration or titer of antibodies

14 Population Bridging Study (cont.) Design: Prospective statistical analysis plan Prospective statistical analysis plan Studies designed to have sufficient power to rule out important difference in parameters of immune response 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 Provide confidence limits on differences between comparison groups for immune response parameters e.g., seroconversion rates and geometric mean titers e.g., seroconversion rates and geometric mean titers Safety outcomes also measured – rates of common AEs, SAEs 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.) < 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.) 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., Vaccines where epidemiology precludes or limits efficacy trials in U.S. e.g., Malaria, ETEC, Cholera Malaria, ETEC, Cholera Past examples where foreign field trials played an important role in vaccine development Past examples where foreign field trials played an important role in vaccine development E.g., DTaP, oral polio, typhoid Vi PS, Hep A 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 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 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 Obtain safety and immunogenicity data using candidate vaccine in specific population in which efficacy trial will be performed Case definition Case definition Adequate sample size Adequate sample size Schedule (changes) Schedule (changes)

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

19 Population Bridging Study Foreign Trial/New Age Group Boostrix: Tetanus Toxoid, reduced Diphtheria Toxoid and Acellular Pertussis Vaccine adsorbed (Tdap) 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 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 safety Demonstration of non-inferiority of anti-tetanus and anti-diphtheria seroprotection and booster response vs. Td 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 booster response to pertussis antigens Demonstration of serologic bridge to pertussis efficacy Demonstration of serologic bridge to pertussis efficacy

21 Boostrix formulation per 0.5mL/dose comparison with Infanrix® COMPONENTBOOSTRIXINFANRIX® Tetanus Toxoid Diphtheria Toxoid Pertussis Toxoid (PT) Filamentous Hemagglutinin (FHA) Pertactin (PRN) AluminumPreservative 5.0 Lf 2.5 Lf 8.0 µg 2.5 µg 0.3 mg (as AlOH 3 ) None 10 Lf 25 Lf 25 µg 8.0 µg < mg (as AlOH 3 ) 2.5 mg 2-PE

22 Serologic Bridge to Clinical Efficacy Study German Household Contact Study (Infanrix®) German Household Contact Study (Infanrix®) 3-dose series at 3, 4, and 5 months of age 3-dose series at 3, 4, and 5 months of age Efficacy 89% (95% CI: %) against WHO-defined pertussis Efficacy 89% (95% CI: %) against WHO-defined pertussis > 21 days of paroxysmal cough with positive culture and/or serologic testing > 21 days of paroxysmal cough with positive culture and/or serologic testing Serologic bridge Serologic bridge Non-inferiority to Infanrix®, administered as a 3-dose primary series 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® 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 German household Contact Study Subjects who had serologic data for at least one pertussis antigen Subjects who had serologic data for at least one pertussis antigen Majority had anti-PT toxoid serological data only Majority had anti-PT toxoid serological data only Serologic assays performed in 1994 Serologic assays performed in 1994 Boostrix Immunogenicity study Boostrix Immunogenicity study Serologic assays performed in 2003 Serologic assays performed in 2003 Used same assays and same laboratory Used same assays and same laboratory

24 Endpoints for Serologic Bridge Pertussis antigens Endpoint(EU/mL)Ratio Infanrix®/Boostrix Infanrix®/Boostrix anti-PTGMC UL 95% CI < 1.5 anti-FHAGMC anti-PRNGMC

25 Ratios of GMCs between Boostrix and Infanrix® one month post-vaccination (TVC) AntigenInfanrix® Boostrix Infanrix®/ ** Boostrix NGMC*NGMC* Ratio (95% CI) anti-PT (0.50,0.55) anti-FHA (0.13,0.15) anti-PRN (0.21,0.27) * ELISA units / mL ** pre-specified non-inferiority criteria met

26 Bridging Study: Age Group Human 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 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 yrs Children & adolescents 9-17 yrs and women 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 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 group Human 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 ( yrs)) Efficacy assessed in 4 placebo controlled, double blind, randomized Phase II and III clinical trials (n = 20,541 females ( yrs)) Phase II*: n = 2391 Phase II*: n = 2391 Phase II: n = 551 Phase II: n = 551 Phase III: n = 5,442 Phase III: n = 5,442 Phase III: n = 12, 157 Phase III: n = 12, 157 VE for HPV 16/18-related disease: VE for HPV 16/18-related disease: CIN3 or AIS: 100% (95% CI: 87.9%, 100.0%) CIN3 or AIS: 100% (95% CI: 87.9%, 100.0%) VIN 2/3/ or VaIN 2/3: 100% (95% CI: 55.5%, 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 GMTs Comparing yr old females to yr old females Assay yr old females Comparison grp A N = yr old females Comparison grp B N = 511 Estimated fold difference Grp A/B (95% CI) N Estimated GMT (mmU/ml)N (mmU/ml) Anti HPV (1.46,1.91) Anti HPV (1.50,2.00) Anti HPV (1.55, 2.21) Anti HPV (1.72, 2.39)

29 Analysis of non-inferiority comparing seroconversion rates in yr old females with yr old females Assay yr old females Comparison grp A N = yr old females Comparison grp B N = 511 Estimated percentage Point difference Grp A-B (95% CI) N Estimated response (%)N Estimated GMT (mmU/ml) Anti HPV % (-0.9,1.3) Anti HPV % (-0.9,1.3) Anti HPV % %0.0(-0.9,1.3) Anti HPV % (-0.2, 2.5)

30 Immunogenicity Bridging between 9-15 year old females, adolescents and year old adult women 9-15 year old female adolescents year old adult women Assay (cLIA) nGMTmMU/mL 95% CI nGMTmMU/mL Anti-HPV , , Anti-HPV , , Anti-HPV , , Anti-HPV , , 478.3

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

32 Comparison of SBA responses to Menactra & Menomune 28 days after vaccination for participants (11-18 yrs) Menactra (n = 423) Menomune Serogroup (95% CI) (95% CI) A % = 4 fold rise GMT GMT (89.8, 95.0) (4920,6111) (89.5, 94.8) (2910,3620) C % = 4 fold rise GMT GMT (88.7, 94.2) (1662, 2228) (85.2, 91.5) (1406, 1911) Y % = 4 fold rise GMT GMT (77.8, 85.4) (1162, 1505) (76.0, 83.8) (1088, 1386) W-135 % = 4 fold rise GMT GMT (94.5, 98.2) (1232, 1607) (92.8, 97.1) (1384, 1725)

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

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

35 CBER Guidance Web: Web: Fax: CBER-FAX Fax: CBER-FAX Phone Phone DVRPA: DVRPA: OCTMA: or OCTMA: or

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


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