Clinical Evaluation of Preventive Clinical Evaluation of Preventive Vaccines: Use of Bridging StudiesVaccines: Use of Bridging Studies

Marion F. Gruber, Ph.D.Marion F. Gruber, Ph.D.2006 FDA/Industry Statistics Workshop2006 FDA/Industry Statistics Workshop

Washington D.C., September 29, 2006Washington D.C., September 29, 2006

ObjectivesObjectives

Approval Process for Preventive VaccinesApproval Process for Preventive Vaccines Applicable laws & regulationsApplicable laws & regulations

Clinical endpoint efficacy studiesClinical endpoint efficacy studies Correlates of ProtectionCorrelates of Protection Bridging studies, e.g., Bridging studies, e.g.,

New population New population Foreign trialsForeign trials

Age GroupAge Group Comparison of two productsComparison of two products Considerations for successful bridging studiesConsiderations for successful bridging studies

Acts & Regulations Pertinent to Acts & Regulations Pertinent to Vaccine DevelopmentVaccine Development

PHS Act (42 USC 262-63) Section 351PHS Act (42 USC 262-63) Section 351 FD & C Act (21 USC 301-392)FD & C Act (21 USC 301-392) FDAMA, November 12, 1997FDAMA, November 12, 1997 21 CFR21 CFR

21 CFR 600-680 Biological Product Standards21 CFR 600-680 Biological Product Standards

21 CFR 314.126 Adequate and well-controlled trials21 CFR 314.126 Adequate and well-controlled trials

21 CFR 312 Investigational New Drug Application21 CFR 312 Investigational New Drug Application

21 CFR 210-211 Good Manufacturing Practices21 CFR 210-211 Good Manufacturing Practices

21 CFR 58 Good Laboratory Practices21 CFR 58 Good Laboratory Practices

21 CFR 56 Institutional Review Boards21 CFR 56 Institutional Review Boards

21 CFR 50 Protection of Human Subjects21 CFR 50 Protection of Human Subjects

21 CFR 25 Environmental Impact Considerations21 CFR 25 Environmental Impact Considerations

Stages of Review and Regulation

Clinical Investigational Plan

Phase 1SafetyImmuno-genicity

Phase 2SafetyImmuno-genicityDose Ranging

Phase 3SafetyEfficacyImmuno-genicity

BLA Data to support approval;Inspection

Phase 4InspectionSafetyEfficacyLot ReleaseBLA

SupplementPost-approvalChanges:New IndicationsDosingManufactureEquip./Facilities

IND

IND =Investigational New Drug Application; BLA=Biologics License Application

Clinical Endpoint Efficacy StudiesClinical Endpoint Efficacy Studies

Clinical trials demonstrating preventive efficacy for clinical Clinical trials demonstrating preventive efficacy for clinical endpoints provide the greatest scientific rigor for evaluating endpoints provide the greatest scientific rigor for evaluating vaccinesvaccines

Prospective, controlled, randomizedProspective, controlled, randomized Primary endpoint: prevention of diseasePrimary endpoint: prevention of disease Necessary in situations when Necessary in situations when

Vaccine is novelVaccine is novel First of its kind administered to target populationFirst of its kind administered to target population No accepted immune response correlate of protectionNo accepted immune response correlate of protection

Example:Example: NCKP efficacy trial of the heptavalent pneumococcal NCKP efficacy trial of the heptavalent pneumococcal conjugate vaccine: conjugate vaccine: ~ ~ 38,000 infants38,000 infants Prevention of invasive pneumococcal diseasePrevention of invasive pneumococcal disease

Correlate of ProtectionCorrelate of Protection

Generally, a laboratory parameter that has been Generally, a laboratory parameter that has been shown to be associated with protection from clinical shown to be associated with protection from clinical diseasedisease Adequate and well-controlled trialsAdequate and well-controlled trials

An immunological correlate of protection is most An immunological correlate of protection is most useful if clear qualitative and quantitative useful if clear qualitative and quantitative relationships can be determinedrelationships can be determined

Correlate of Protection (cont.)Correlate of Protection (cont.)

May also be May also be suggestedsuggested by other sources: by other sources: Population-based studies of vaccinesPopulation-based studies of vaccines Trials using Trials using

Specific immune globulinsSpecific immune globulins Immune globulin with specific AbImmune globulin with specific Ab

e.g. polioe.g. polio Animal challenge/protection studiesAnimal challenge/protection studies Phase 2 clinical dataPhase 2 clinical data Protection thought to be conferred to infants by Protection thought to be conferred to infants by

maternal antibodymaternal antibody

Correlate of Protection (cont.)Correlate of Protection (cont.)

Example of licensed vaccines with an identified Example of licensed vaccines with an identified correlate of protection:correlate of protection: Hep BHep B

However, identification of correlate not a However, identification of correlate not a requirement for licensurerequirement for licensure

Examples of licensed vaccines Examples of licensed vaccines withoutwithout an identified an identified immune correlate of protection:immune correlate of protection: Acellular pertussis, Typhoid, Tuberculosis (BCG)Acellular pertussis, Typhoid, Tuberculosis (BCG)

Immune correlate(s) useful for interpreting trials Immune correlate(s) useful for interpreting trials with immune response endpoints, with immune response endpoints, E.g., “bridging studies”E.g., “bridging studies”

Bridging StudiesBridging Studies

A clinical trial in which a parameter of A clinical trial in which a parameter of interest for a product - e.g., manufacturing interest for a product - e.g., manufacturing process, formulation, dosing schedule – is process, formulation, dosing schedule – is directly compared with a directly compared with a changedchanged version of version of that parameter with respect to the effect of that parameter with respect to the effect of the the changechange on the product’s clinical on the product’s clinical performance.performance.

Purpose: To determine effect of change(s) Purpose: To determine effect of change(s) on product’s clinical performanceon product’s clinical performance e.g., immune response for vaccinese.g., immune response for vaccines

Types of Bridging StudiesTypes of Bridging Studies

To address:To address: New population (foreign studies)New population (foreign studies) Age group Age group New product to standard of careNew product to standard of care New scheduleNew schedule Manufacturing changesManufacturing changes

If immune response/safety profile are similar, then If immune response/safety profile are similar, then efficacy can be inferredefficacy can be inferred

Population Bridging StudiesPopulation Bridging Studies

Clinical endpoint efficacy trial not possible in Clinical endpoint efficacy trial not possible in certain regionscertain regions Disease endemic in limited areasDisease endemic in limited areas Existing vaccines in some countriesExisting vaccines in some countries

Approach: conduct clinical efficacy trial Approach: conduct clinical efficacy trial where disease rate is high, then “bridge” to where disease rate is high, then “bridge” to US population with single-arm study in USUS population with single-arm study in US

Population Bridging Studies (cont.)Population Bridging Studies (cont.)

Not possible to randomize region, ethnic groupNot possible to randomize region, ethnic group Thus, not randomized but controlledThus, not randomized but controlled

Compare immune/safety endpoints in region where clinical Compare immune/safety endpoints in region where clinical efficacy shown to those endpoints observed in US bridging efficacy shown to those endpoints observed in US bridging studystudy

Try to keep comparison group similarTry to keep comparison group similar Demographic factors, e.g., age, genderDemographic 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 Conduct of trial, e.g., inclusion/exclusion criteria, surveillance

for AEs, timing of blood draws, etc.for AEs, timing of blood draws, etc.

Population Bridging Study (cont.)Population Bridging Study (cont.)

DesignDesign:: Comparison of immune responses is often the Comparison of immune responses is often the

primary objectiveprimary objective Percent responders achieving an immune Percent responders achieving an immune

response above threshold considered response above threshold considered protective protective

Ratio of geometric mean concentration or titer Ratio of geometric mean concentration or titer of antibodiesof antibodies

Population Bridging Study (cont.)Population Bridging Study (cont.)

DesignDesign:: Prospective statistical analysis planProspective statistical analysis plan Studies designed to have sufficient power to rule out Studies designed to have sufficient power to rule out

important difference in parameters of immune important difference in parameters of immune responseresponse

Provide confidence limits on differences between Provide confidence limits on differences between comparison groups for immune response parameterscomparison groups for immune response parameters e.g., seroconversion rates and geometric mean e.g., seroconversion rates and geometric mean

titerstiters Safety outcomes also measured – rates of common Safety outcomes also measured – rates of common

AEs, SAEsAEs, SAEs

Statistical Evaluation:Statistical Evaluation:Non-inferiority criteria (Current)Non-inferiority criteria (Current)

Percent responders or sero-protectedPercent responders or sero-protected::UL of 2-sided 95% CI for difference UL of 2-sided 95% CI for difference (efficacy pop -target pop) <5-10%(efficacy pop -target pop) <5-10%

GMTs/GMCsGMTs/GMCs::UL of 2-sided 95% CI for ratioUL of 2-sided 95% CI for ratio(or 1-sided 97.5% CI)(or 1-sided 97.5% CI)(GMC efficacy pop./GMC target pop.) <1.5-2.0(GMC efficacy pop./GMC target pop.) <1.5-2.0

Other immunologic parametersOther immunologic parametersOpsonophagocytic activityOpsonophagocytic activity

Foreign Trials of Preventive VaccinesForeign Trials of Preventive Vaccines

Examples where foreign field trials may play an Examples where foreign field trials may play an important role in vaccine development in the future important role in vaccine development in the future (U.S.)(U.S.)

Vaccines where epidemiology precludes or limits Vaccines where epidemiology precludes or limits efficacy trials in U.S. e.g., efficacy trials in U.S. e.g.,

Malaria, ETEC, CholeraMalaria, ETEC, Cholera Past examples where foreign field trials played an Past examples where foreign field trials played an

important role in vaccine development important role in vaccine development E.g., DTaP, oral polio, typhoid Vi PS, Hep AE.g., DTaP, oral polio, typhoid Vi PS, Hep A

Considerations for Foreign TrialsConsiderations for Foreign Trials

Efficacy (and Immunogenicity) differences between Efficacy (and Immunogenicity) differences between populations may result from differences in factors populations may result from differences in factors such as genetics, nutritional status, & background such as genetics, nutritional status, & background infectionsinfections e.g., OPV in developed vs. developing countriese.g., OPV in developed vs. developing countries

Obtain safety and immunogenicity data using Obtain safety and immunogenicity data using candidate vaccine in specific population in which candidate vaccine in specific population in which efficacy trial will be performed efficacy trial will be performed

Case definitionCase definition Adequate sample sizeAdequate sample size Schedule (changes)Schedule (changes)

Considerations for Successful “Bridging”Considerations for Successful “Bridging”

Validated immune response assays (vaccines)Validated immune response assays (vaccines) Foreign clinical data should meet standards of the new Foreign clinical data should meet standards of the new

regionregion Study design, conduct & regulatory requirements (ICH Study design, conduct & regulatory requirements (ICH

E5)E5) Determine vaccine’s sensitivity to ethnic factors (ICH Determine vaccine’s sensitivity to ethnic factors (ICH

E5)E5) Study should meet local and international standardsStudy should meet local and international standards

ICH E6: Good Clinical PracticesICH E6: Good Clinical Practices ICH E8: General Considerations for Clinical TrialsICH E8: General Considerations for Clinical Trials Other Documents (CFR, etc.)Other Documents (CFR, etc.)

Generous banking of sera from efficacy trialGenerous banking of sera from efficacy trial SOPP for storing seraSOPP for storing sera

Population Bridging StudyPopulation Bridging StudyForeign Trial/New Age GroupForeign Trial/New Age Group

BoostrixBoostrix: Tetanus Toxoid, reduced Diphtheria : Tetanus Toxoid, reduced Diphtheria Toxoid and Acellular Pertussis Vaccine adsorbed Toxoid and Acellular Pertussis Vaccine adsorbed (Tdap)(Tdap)

Active immunization against tetanus, diphtheria and Active immunization against tetanus, diphtheria and pertussis as a single dose in individuals 10 through pertussis as a single dose in individuals 10 through 18 years of age18 years of age

Boostrix:Boostrix: Basis for Licensure Basis for Licensure

Demonstration of safety Demonstration of safety Demonstration of non-inferiority of anti-tetanus and Demonstration of non-inferiority of anti-tetanus and

anti-diphtheria seroprotection and booster response anti-diphtheria seroprotection and booster response vs. Tdvs. Td

Demonstration of booster response to pertussis Demonstration of booster response to pertussis antigensantigens

Demonstration of serologic bridge to pertussis Demonstration of serologic bridge to pertussis efficacyefficacy

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

COMPONENTCOMPONENT BOOSTRIX™BOOSTRIX™ INFANRIX®INFANRIX®

Tetanus ToxoidTetanus ToxoidDiphtheria ToxoidDiphtheria Toxoid

Pertussis Toxoid (PT)Pertussis Toxoid (PT)Filamentous Filamentous Hemagglutinin (FHA)Hemagglutinin (FHA)Pertactin (PRN)Pertactin (PRN)

AluminumAluminum

PreservativePreservative

5.0 Lf5.0 Lf2.5 Lf2.5 Lf

8.0 µg8.0 µg

8.0 µg8.0 µg2.5 µg2.5 µg

0.3 mg 0.3 mg (as AlOH(as AlOH33))

NoneNone

10 Lf10 Lf25 Lf25 Lf

25 µg25 µg

25 µg25 µg8.0 µg8.0 µg

<< 0.625 mg (as AlOH 0.625 mg (as AlOH33))

2.5 mg 2-PE2.5 mg 2-PE

Serologic Bridge to Clinical Efficacy StudySerologic Bridge to Clinical Efficacy Study

German Household Contact Study (InfanrixGerman Household Contact Study (Infanrix®)®) 3-dose series at 3, 4, and 5 months of age3-dose series at 3, 4, and 5 months of age Efficacy 89% (95% CI: 77- 95%) against WHO-defined Efficacy 89% (95% CI: 77- 95%) against WHO-defined

pertussispertussis >> 21 days of paroxysmal cough with positive culture and/or 21 days of paroxysmal cough with positive culture and/or

serologic testingserologic testing

Serologic bridgeSerologic bridge Non-inferiority to InfanrixNon-inferiority to Infanrix®®,, administered as a 3-dose administered as a 3-dose

primary seriesprimary series

GMCs one month post Boostrix (single dose) GMCs one month post Boostrix (single dose) compared to GMCs one month after completing compared to GMCs one month after completing infant series with Infanrixinfant series with Infanrix®®

Serologic bridge: Testing of Study SamplesSerologic bridge: Testing of Study Samples

German household Contact Study German household Contact Study Subjects who had serologic data for at least one Subjects who had serologic data for at least one

pertussis antigenpertussis antigen Majority had anti-PT toxoid serological data onlyMajority had anti-PT toxoid serological data only Serologic assays performed in 1994Serologic assays performed in 1994

Boostrix Immunogenicity studyBoostrix Immunogenicity study Serologic assays performed in 2003Serologic assays performed in 2003 Used same assays and same laboratoryUsed same assays and same laboratory

Endpoints for Serologic BridgeEndpoints for Serologic Bridge

Pertussis Pertussis antigensantigens

EndpointEndpoint (EU/mL)(EU/mL)

RatioRatio InfanrixInfanrix®®/Boostrix/Boostrix™™

anti-PTanti-PT GMCGMC UL 95% CI < 1.5UL 95% CI < 1.5

anti-FHAanti-FHA GMCGMC UL 95% CI < 1.5UL 95% CI < 1.5

anti-PRNanti-PRN GMCGMC UL 95% CI < 1.5UL 95% CI < 1.5

Ratios of GMCs between Boostrix™ and Infanrix® Ratios of GMCs between Boostrix™ and Infanrix® one month post-vaccination (TVC)one month post-vaccination (TVC)

AntigenAntigen Infanrix®Infanrix® BoostrixBoostrix™™ Infanrix®/ Infanrix®/ ** ** Boostrix™Boostrix™

NN GMC*GMC* NN GMC*GMC* Ratio (95% CI)Ratio (95% CI)

anti-PTanti-PT 28842884 45.745.7 29412941 86.986.9 0.53 (0.50,0.55)0.53 (0.50,0.55)

anti-FHAanti-FHA 685685 83.683.6 29792979 614.8614.8 0.14 (0.13,0.15)0.14 (0.13,0.15)

anti-PRNanti-PRN 631631 112.3112.3 29782978 470.7470.7 0.24 (0.21,0.27)0.24 (0.21,0.27)

* ELISA units / mL* ELISA units / mL

** pre-specified non-inferiority criteria met** pre-specified non-inferiority criteria met

Bridging Study: Age GroupBridging Study: Age GroupHuman Papillomavirus (Types 6, 11, 16, 18) vaccineHuman Papillomavirus (Types 6, 11, 16, 18) vaccine

Indication: prevention of HPV 6, 11, 16, 18 related Indication: prevention of HPV 6, 11, 16, 18 related cervical cancer, cervical dysplasia, vulvar or vaginal cervical cancer, cervical dysplasia, vulvar or vaginal dysplasias, or genital wartsdysplasias, or genital warts

Children & adolescents 9-17 yrs and women 18-26 yrsChildren & adolescents 9-17 yrs and women 18-26 yrs CIN 2/3 and AIS served as surrogate markers for CIN 2/3 and AIS served as surrogate markers for

prevention of cervical cancer in efficacy trials prevention of cervical cancer in efficacy trials conducted in females 16 – 26 years of ageconducted in females 16 – 26 years of age

Bridging Study: Age groupBridging Study: Age groupHuman Papillomavirus (Types 6, 11, 16, 18) vaccineHuman Papillomavirus (Types 6, 11, 16, 18) vaccine

Efficacy assessed in 4 placebo controlled, Efficacy assessed in 4 placebo controlled, double blind, randomized Phase II and III double blind, randomized Phase II and III clinical trials (n = 20,541 females (16 - 26 yrs))clinical trials (n = 20,541 females (16 - 26 yrs)) Phase II*: Phase II*: n = 2391n = 2391 Phase II: Phase II: n = 551 n = 551 Phase III: Phase III: n = 5,442n = 5,442 Phase III: Phase III: n = 12, 157n = 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 *HPV 16 component of Gardasil onlyonly

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

AssayAssay

10-15 yr old females10-15 yr old females

Comparison grp AComparison grp A

N = 506N = 506

16-23 yr old females16-23 yr old females

Comparison grp BComparison grp B

N = 511N = 511

Estimated Estimated fold fold

differencedifference

Grp A/BGrp A/B

(95% CI)(95% CI)NN

Estimated Estimated GMTGMT

(mmU/ml)(mmU/ml)NN

Estimated Estimated GMTGMT

(mmU/ml)(mmU/ml)

Anti HPV 6Anti HPV 6 426426 960.0960.0 320320 574.9574.9 1.671.67 (1.46,1.91)(1.46,1.91)

Anti HPV 11Anti HPV 11 426426 1224.81224.8 320320 705.9705.9 1.74 1.74 (1.50,2.00)(1.50,2.00)

Anti HPV 16Anti HPV 16 427427 4713.34713.3 306306 2548.02548.0 1.85 1.85

(1.55, 2.21)(1.55, 2.21)

Anti HPV 18Anti HPV 18 429429 918.4918.4 340340 452.9452.9 2.032.03

(1.72, 2.39)(1.72, 2.39)

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

AssayAssay

10-15 yr old females10-15 yr old females

Comparison grp AComparison grp A

N = 508N = 508

16-23 yr old females16-23 yr old females

Comparison grp BComparison grp B

N = 511N = 511

Estimated Estimated percentagepercentage

Point Point differencedifference

Grp A-BGrp A-B

(95% CI)(95% CI)

NN

Estimated Estimated responseresponse

(%)(%)NN

Estimated Estimated GMTGMT

(mmU/ml)(mmU/ml)

Anti HPV 6Anti HPV 6 426426 100 %100 % 320320 100 %100 % 0.00.0

(-0.9,1.3)(-0.9,1.3)

Anti HPV 11Anti HPV 11 426426 100 %100 % 320320 100 %100 % 0.00.0

(-0.9,1.3)(-0.9,1.3)

Anti HPV 16Anti HPV 16 427427 100 %100 % 306306 100%100% 0.00.0

(-0.9,1.3)(-0.9,1.3)

Anti HPV 18Anti HPV 18 429429 100 %100 % 340340 100 %100 % 0.80.8

(-0.2, 2.5)(-0.2, 2.5)

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

9-15 year old female 9-15 year old female adolescentsadolescents

16-26 year old adult women 16-26 year old adult women

Assay Assay (cLIA)(cLIA)

nn GMTGMT

mMU/mLmMU/mL

95% CI95% CI nn GMTGMT

mMU/mLmMU/mL

95% CI95% CI

Anti-HPV Anti-HPV

66927927 931.3931.3 876.9, 876.9,

989.2989.228272827 542.4542.4 526.6, 526.6,

558.7558.7

Anti-HPV Anti-HPV 1111

927927 1305.71305.7 1226.2, 1226.2, 1390.41390.4

28272827 766.1766.1 740.5, 740.5, 792.6792.6

Anti-HPV Anti-HPV 1616

929929 4944.94944.9 4538.5, 4538.5, 5334.85334.8

27072707 2313.82313.8 2206.2, 2206.2, 2426.72426.7

Anti-HPV Anti-HPV 1818

932932 1046.01046.0 971.2, 971.2, 1126.51126.5

30403040 460.7460.7 443.8, 443.8, 478.3478.3

Bridging study: Comparison of 2 ProductsBridging study: Comparison of 2 ProductsMenactra and MenomuneMenactra and Menomune

Indication: Prevention of invasive Indication: Prevention of invasive meningococcal disease caused by meningococcal disease caused by N. N. meningitidismeningitidis (A, C, Y and W-135) (A, C, Y and W-135)

Menomune (another meningococcal vaccine Menomune (another meningococcal vaccine licensed and available in the US) licensed and available in the US)

Comparison to MenomuneComparison to MenomuneInferred efficacyInferred efficacy

Immune correlate: serum bactericidal antibodyImmune correlate: serum bactericidal antibody Other parameters: SBA GMT, seroconversion Other parameters: SBA GMT, seroconversion

rate, IgG (ELISA)rate, IgG (ELISA)Non-inferiority to MenomuneNon-inferiority to Menomune

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

Menactra Menactra (n = 423)(n = 423)

Menomune Menomune (n = 423)(n = 423)

SerogroupSerogroup (95% CI)(95% CI) (95% CI)(95% CI)

AA % = 4 fold rise% = 4 fold rise

GMTGMT

92.792.7

54835483

((89.8, 95.0)89.8, 95.0)

(4920,6111)(4920,6111)

92.492.4

32463246

((89.5, 94.8)89.5, 94.8)

(2910,3620)(2910,3620)

CC % = 4 fold rise% = 4 fold rise

GMTGMT

91.791.7

19241924

((88.7, 94.2)88.7, 94.2)

(1662, 2228)(1662, 2228)

88.788.7

16391639

((85.2, 91.5)85.2, 91.5)

(1406, 1911)(1406, 1911)

YY % = 4 fold rise% = 4 fold rise

GMTGMT

81.881.8

13221322

((77.8, 85.4)77.8, 85.4)

(1162, 1505)(1162, 1505)

80.180.1

12281228

((76.0, 83.8)76.0, 83.8)

(1088, 1386)(1088, 1386)

W-135W-135 % = 4 fold rise% = 4 fold rise

GMTGMT

96.796.7

14071407

((94.5, 98.2)94.5, 98.2)

(1232, 1607)(1232, 1607)

95.395.3

15451545

((92.8, 97.1)92.8, 97.1)

(1384, 1725)(1384, 1725)

Concluding RemarksConcluding Remarks

Preventive vaccines have unique considerations Preventive vaccines have unique considerations for product & clinical developmentfor product & clinical development

Overall planning and coordination: Overall planning and coordination: Accumulate sufficient safety, immunogenicity Accumulate sufficient safety, immunogenicity

& efficacy data during development & efficacy data during development Anticipate the need for clinical bridging Anticipate the need for clinical bridging

studiesstudies Utilize available FDA documents & resourcesUtilize available FDA documents & resources

Concluding RemarksConcluding Remarks

Similar study designSimilar study designEvaluation of similar endpoints Evaluation of similar endpoints

appropriate for assessment of treatmentappropriate for assessment of treatmentValidated immune response assays Validated immune response assays

(vaccines)(vaccines)Prospective statistical analysisProspective statistical analysisStudy/population to meet regulatory Study/population to meet regulatory

requirements in new regionrequirements in new region

CBER GuidanceCBER Guidance

Web:Web: www.fda.gov/cber/reading.htmwww.fda.gov/cber/reading.htm Email:Email: OCTMA@CBER.FDA.GOVOCTMA@CBER.FDA.GOV Fax: 1-888-CBER-FAXFax: 1-888-CBER-FAX PhonePhone

DVRPA: 301- 827-3070DVRPA: 301- 827-3070 OCTMA: 301- 827- 1800 or 800-835-4709OCTMA: 301- 827- 1800 or 800-835-4709

AcknowledgmentsAcknowledgments

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.