# Presentation: 151947

##  GardasilTM : Quadrivalent Human Papillomavirus 6, 11, 16, 18 L1 VLP VaccineApplicant: Merck & Co., Inc.

**Vaccines and Related Biological Products Advisory Committee Meeting**
**May 18, 2006**
**Nancy B. Miller, M.D.**
**CBER, FDA**

**Notes:**

Good morning.
My name is Dr. Miller and I will presenting the FDA review of the Gardasil License Application.

## Review Team

**Chairperson:****	****	****	****Gopa Raychaudhuri, Ph.D.**
**Regulatory Coordinator:****	****	****Julienne Vaillancourt, R.Ph., M.P.H.**
**Clinical:****	****	****	****	****Nancy Miller, M.D.**
**                                               ****	****	****Joseph Toerner, M.D., M.P.H.**
**                                               ****	****	****Karen Goldenthal, M.D.**
**                                               ****	****	****Antonia Geber, M.D.**
**                                               ****	****	****Douglas Pratt, M.D., M.P.H**
**Statistical:****	****	****	****Henry Hsu, Ph.D., M.P.H.**
**                                               ****	****	****Lev Sirota, Ph.D.**
**                                               ****	****	****A. Dale Horne, Dr.Ph.**
**Product:****	****	****	****	****Robin Levis, Ph.D.**
**                                               ****	****	****Rolf Taffs, Ph.D.**
**	****	****	****               ****	****	****Gennady Rezapkin, Ph.D.**
**	****	****	****               ****	****	****Loris McVittie, Ph.D.**
**                                                ****	****Jerry Weir, Ph.D.**
**Non-Clinical:****	****	****	****Sally Hargus, Ph.D.**
**                                              ****	****	****Marion Gruber, Ph.D.**
**Pharmacovigilance:            ****	****	****Hector Izurieta, M.D.**
**	****	****	****	****	****Robert Ball, M.D., M.P.H.**
**Bioresearch Monitoring:****	****	****Robert Wesley****	**
**Facility:             ****	****	****	****Susan Yu, Ph.D.**
**	****	****	****             ****	****         ****	****Laurie Norwood, Ph.D.**
**Advertising/Promotional Labeling:      Maryann Gallagher**

**Notes:**
I would like to acknowledge the review team for their excellent work in the review of this complicated application on a priority basis.

## Gardasil: Description

- Each 0.5 mL dose contains
- 20 mcg HPV 6 L1 VLP
- 40 mcg HPV 11 L1 VLP
- 40 mcg HPV 16 L1 VLP
- 20 mcg HPV 18 L1 VLP
- Adjuvant: 225 mcg aluminum
- Administered 0, 2, and 6 months IM

**Notes:**
The candidate vaccine, Gardasil  is prepared from purified virus like particles of the major capsid (L1) protein of HPV types 6, 11, 16, and 18.
The L1 proteins are produced by fermentations in recombinant Saccharyomyces cerevesiae and self-assembled into virus like particles.
The VLPs are purified and adsorbed onto aluminum.

Each 0.5 mL dose contains 20 mcg HPV 6, 40 mcg HPV 11, 40 mcg HPV 16, and 20 mcg HPV 18  L1 VLPs with 225 mcg aluminum.
The vaccine is administered IM in a 3-dose regimen at 0, 2, and 6 months.

## Gardasil:Applicant’s Proposed Indications (1)

**Prevention of HPV 16/18 related:**
**Cervical cancer**
**Cervical AIS**
**CIN 2 and CIN 3**
**Vulvar and vaginal cancer**
**VIN 2 and VIN 3**
**VaIN 2 and VaIN 3**
**Prevention of HPV 6/11/16/18 related:**
**CIN grade 1**
**Genital warts (condyloma acuminata)**
**VIN grade 1 and VaIN grade 1**
**HPV infection**

**AIS = Adenocarcinoma in situ; CIN = Cervical Intraepithelial Neoplasia; **
**VIN = Vulvar Intraepthelial Neoplasia; VaIN = Vaginal Intraepithelial Neoplasia**

**Notes:**
The applicant’s proposed indications for Gardasil include the following:
Prevention of HPV 16/18 related:
Cervical cancer, cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grades 2 and 3, vulvar and vaginal cancer, vulvar intraepithelial neoplasia (VIN) grades 2 and 3, and vaginal intraepithelial neoplasia (VaIN) grades 2 and 3.

In addition, the applicant’s indication include: 
Prevention of HPV 6/11/16/18 related:CIN grade 1, cervical warts (or condyloma acuminata), VIN grade 1 and VaIN grade 1, and HPV infection.

## Gardasil:Applicant’s Proposed Indications (2)

- Children and adolescents 9 through 17 years of age and women 18 through 26 years of age.

**Notes:**
The sponsor’s proposed population and age indication is for preadolescents and adolescents age 9-17 years of age and women 18 through 26 years of age.

## Gardasil:FDA Proposed Indications

- FDA considers the data submitted in the BLA to be supportive of use of Gardasil in preadolescent and adolescent _females 9-17 years of age_ and females _18-26 years of age_.

**Notes:**
FDA considered the data submitted in the BLA to be supportive of use of Gardasil in preadolescent and adolescent females 9-17 years of age and 18-26 years of age.

## Regulatory History

**1997:**  Submission of IND for monovalent HPV 11 L1
- VLP vaccine (Other INDs for monovalent HPV 16 and 18)
**2000:**  Submission of IND for quadrivalent HPV 6, 11, 16, 18 L1 VLP vaccine
**2001 (November):**  VRBPAC discussion of endpoints for Phase 3 development
**2002:**  Product development program granted fast track status; Initiation of Phase 3 trials
**2005 (May):**  Pre-BLA meeting, agreement to allow rolling BLA and Priority Review
**2005 (August):**  Start of rolling BLA submisssion
**2005 (December):**  Last section of rolling BLA received including Phase 3 study data; 6 month priority review

**Notes:**
The first IND for monovalent HPV 11 vaccine was submitted in 1997, and the INDs for monovalent HPV 16 and 18 followed.
In 2000, the IND for the quadrivalent vaccine was submitted.
In 11/01, there was an important VRBPAC meeting to discuss potential preventive HPV vaccine endpoints.
In 2002, the product program development was granted fast track status, and Phase 3 trials were initiated. 
In 5/05, the pre-BLA meeting was held, and there was agreement to allow rolling BLA and priority review.
In 8/05, the first piece of the BLA was submitted, and in 12/05, the last part of the rolling BLA was received, including Phase 3 study data.  (This was the start of the 6 month priority review clock).

## Efficacy Endpoint for Preventive HPV Vaccines (Cervical Cancer)

- November 2001 VRBPAC:
-    CIN 2/3 histology, AIS, or worse with virology.

**Notes:**
The endpoints for a preventive HPV vaccine were discussed at the 11/01 VRBPAC, and the majority of members of the Advisory Committee concluded that, because CIN 2/3 is an immediate and obligate precursor to squamous cervical cancer and AIS is an immediate and obligate precursor to adenocarcinoma, that CIN 2/3 histology, AIS  or worse with virology (detection of HPV) would be an appropriate endpoint for Phase 3 trials of a preventive HPV vaccine.  Cervical cancer was not feasible as an endpoint (long period of time, standard of care is to treat CIN 2/3).  
Endpoints for External Genital Lesion endpoints were not discussed at that VRBPAC meeting.   

(Additional information:  CIN 2/3 and AIS are Figo Stage 0 cervical cancer.
VaIN 1 may be caused by low risk and high risk types, rx watchful waiting.
VaIN 2/3 associated with high risk types, rx is ablation and excision)

## Phase I/II Safety and Immunogenicity Studies

**001:****  **HPV 11 L1 VLP Vaccine
**002:****  **HPV 16 L1 VLP Vaccine
**004:****  **HPV 16 L1 VLP Vaccine
**006:****  **HPV 18 L1 VLP Vaccine

**Notes:**
There were 4 Phase I/II trials to test the safety and immunogeniicty of monovalent HPV 11, 16 and 18 L1 VLP vaccines.
HPV 6 was not tested individually (HPV 6 has app. 92% homology with HPV 11).

## Gardasil BLA:  Protocols Contributing to Combined Efficacy Analysis

**005:**  “Proof of Concept” Phase II Efficacy 	    Trial (HPV 16)
**007:**  Quadrivalent Dose-Ranging and 	  	    Efficacy Study
**013:**  CIN/Warts Efficacy Study
**015:**  CIN 2/3 Efficacy Study

**Notes:**
The Phase 3 studies which contributed to assessment of efficacy included the following:
Protocol 005, was a Phase 2 “Proof of concept” efficacy study for monovalent HPV 16 (persistent infection)

Protocol 007, was a phase 2b study to assess the dose for the quadrivalent HPV vaccine to go forward into Phase 3 trials, and to assess efficacy for prevention of infection caused by the 4 HPV types included in the vaccine.

Protocol 013, was a Phase 3 study to asses quadrivalent vaccine efficacy against CIN and warts associated with the vaccine HPV types

Protocol 015, was a Phase 3 study to assess quadrivalent vaccine efficacy against CIN 2/3 associated with HPV 16 and/or 18.
Protocol 015 also included a consistency lot substudy, nonserious adverse event substudy, and a registry substudy.

## Gardasil:Protocol 013 Substudies

**011:**  Hepatitis B Concomitant 	     Use Substudy
**012:**  HPV 16 Bridging Substudy

**Notes:**
Protocol 013 included 2 substudies:
Protocol 011, a study to assess concomitant administration of Hepatitis B vaccine and Gardasil.

Protocol 012, a study to assess bridging of monovalent HPV 16 vaccine (from Protocol 005) with the HPV 16 component of the quadrivalent HPV 16 vaccine.

## Immunogenicity and Safety Studies in Adolescents

**016:**  Adolescent/Adult Bridging and 	     End-Expiry Study
**018:**  Adolescent Immunogenicity and 	     Safety Study

**Notes:**
Protocol 016 was designed to evaluate the safety and immunogenicity of the vaccine in preadolescents 10-15 years of age, with comparison of the immune response between the younger age group of subjects and women 16-23 years of age.  In addition, this  protocol included a substudy to assess the immunogenicity of partial formulations. 

Protocol 018 provided additional safety and immunogenicity data for the preadolescent/adolescent age group, with comparison to a saline placebo

## Comparison of Study Design:Protocols That Contribute to Combined Analysis

| Features | Protocol 005 | Protocol 007 | Protocol 013 | Protocol 015 |
| --- | --- | --- | --- | --- |
| Sites | US | US, International | US, International | US, International |
| Design | DB, R, PC | DB, R, PC | DB, R, PC | DB, R, PC |
| Vaccine  | HPV 16 | Gardasil | Gardasil* | Gardasil |

***384 subjects received HPV 16 to bridge to Protocol 005**
**DB = Double blind; R=Randomized; PC = Placebo controlled**
**From Table 1, HPV L1 VLP Vaccine Combined Efficacy (Interim Analysis)**

**Notes:**
Cases of HPV 16 and/or 18 related CIN 2/3  were pooled from Protocols 005, 007, 013, and 015 in an overall analysis of efficacy.

These studies were very similar in design.
.  
The studies were DB, R, PC, multicenter trials, and except for Protocol 005, which was conducted in the US, were conducted internationally.  

Visits were generally every 6 months, except for Protocol 015, in which the subjects were seen every year (except for the first year).

## Comparison of Study Design:Baseline Characteristics of Subjects

| Subjects | Protocol 005 | Protocol 007 | Protocol 013 | Protocol 015 |
| --- | --- | --- | --- | --- |
| Inclusion Criteria |  |  |  |  |
| Age
Gender | 16-23 years
female | 16-23 years
female | 16-23 years
female | 16-26 years*
female |
| Lifetime Partners | 0-5 | 0-4 | 0-4 | 0-4 |
| Exclusion Criteria |  |  |  |  |
| Previous abnormal Pap | Not allowed | Not allowed  | Not allowed | Not allowed |

***23 years except for 26 years in Singapore**
**Source: Table 1, HPV L1 VLP Vaccine Combined Efficacy (Interim Analysis Report) **

**Notes:**
The efficacy trials were conducted in females 16-23 years of age, except for Protocol 015, where the upper age limit was 26 years to accommodate subjects in Singapore.

Subjects in the protocols were to have < 5 sexual partners in their lifetime.

Subjects with a history of abnormal Pap tests before study entry were excluded from the study.
However, subjects with an abnormal Pap test at the first Pap test (Day 1) were not excluded from the study. abnormal Pap test.

## Comparison of Study Design:Pap Tests and Referral for Colposcopy

| Features | Protocol 005 | Protocol 007 | Protocol 013 | Protocol 015 |
| --- | --- | --- | --- | --- |
| Pap interval | 6 months | 6 months | 6 months  | 12 months |
| Pap test | ThinPrepTM | ThinPrepTM | ThinPrepTM | ThinPrepTM |
| Pap reading | 5 regional labs | DCL Lab, Indianapolis | DCL Lab,
Indianapolis | DCL Lab, Indianapolis |
| Minimal Pap Referral | ASC-US | ASC-US
HPV (+) HC-II | ASC-US
HPV (+) HC-II | ASC-US
HPV (+) HC-II |
| Screening Triage | Voluntary | Voluntary | Mandatory | Mandatory |
| Exit Colposcopy | Yes | Yes | No | No |

**Source: Interim Analysis, Table 1**

**Notes:**
The Pap testing interval was 6 months for the trials except for Protocol 015 after the first year.

The minimal Pap test for referral to colposcopy was AS-CUS (with HPV HC II testing in Protocols 007, 013, and 015).

There was a mandatory colposcopy algorithm for Protocols 013 and 015.

## Comparison of Study Design:Triage Abnormal Pap Tests for Colposcopy

| ThinPrepTM Pap Result | Protocol 005 | Protocols 007
and 013 | Protocol 015 |
| --- | --- | --- | --- |
| ASC-US | Reflex HPV test on residual ThinPrepTM  material; if probe positive, referred for colposcopy; if probe negative, Pap at routine interval | Reflex HPV test on residual ThinPrepTM  material; if at least one probe positive, referred for colposcopy; if both probes negative, Pap at routine interval | Repeat ThinPrepTM  Pap in 6 months |
| LSIL | Referred for colposcopy | Referred for colposcopy | Repeat ThinPrepTM  Pap in 6 months |

**Source: Table 2.7.3-cervix cancer: 5**

**Notes:**
This slide details the differences in the colposcopy algorithms for the 4 trials.  
It is noted that the protocols had a well-defined triage scheme for referral to colposcopy and ascertainment of abnormal Pap tests.

(007 and 013: similar, aggressive)
(005 and 015: similar, conservative)

## Comparison of Study Design:Laboratory Tests, Pathology Panel

| Features | Protocol 005 | Protocol 007 | Protocol 013 | Protocol 015 |
| --- | --- | --- | --- | --- |
| Laboratory Processing | DCL Lab, Indianapolis | DCL Lab, Indianapolis | DCL Lab, Indianapolis | DCL Lab, Indianapolis |
| Pathology Panel Reading (Endpoints)* | Kurman
Ronette
Stoler
Ferenczy^ | Kurman
Ronette
Stoler
Ferenczy | Kurman
Ronette
Stoler
Ferenczy | Kurman
Ronette
Stoler
Ferenczy |
| HPV Causality Assessment | Merck HPV PCR assay frozen biopsy | Merck HPV PCR assay paraffin | Merck HPV PCR assay paraffin | Merck HPV PCR assay paraffin |

***All biopsies in 4 studies read by one of several pathologists in central Lab for patient management.  Biopsies also independently read by panel of expert pathologists for final diagnosis for study purposes (endpoints). Panel blinded to group, HPV testing, dx at DCL.**
**^Until 10/2000, pathologists were Kurman/Sherman/Stoler/Ferenczy**
**Source: Interim Analysis, Table 1**

**Notes:**
The cases were determined based on the reading of an expert pathology panel (who were blinded to PCR status, central lab diagnoses, and other path panel diagnosis at the time of reading), in conjunction with identification of  vaccine type HPV by PCR in tissue adjacent to the histopathological tissue.  

The PCR assay was performed in frozen biopsy material for Protocol 005, and in paraffin block material in the other 3 trials.

Because of the similarity of the 4 studies, FDA concluded that it was appropriate to allow for a combined efficacy analysis across trials.

## Comparison of Study Design: Number of Subjects, Median Age, and Duration of Follow-up In Efficacy Population

| Subjects | Protocol 005 | Protocol 007 | Protocol 013 | Protocol
015 |
| --- | --- | --- | --- | --- |
| N
# Vaccine
# Placebo | 2391
1193
1198 | 551
276
275 | 5442
2717
2725 | 12157
6082
6075 |
| Median Age
(Range) | 20 yr.
(16-25) | 20 yr.
(13-24) | 20 yr.
(16-24) | 20 yr.
(15-26) |
| Mean duration of follow-up | 3.1 years | 2.4 years | 1.7 years | 1.4 years |

**Total number of subjects with data for cervical disease efficacy = 20541**
**Sources: CSR 007, Table 7-2 and 2.7.3–cervix cancer Table 2.7.3:8**

**Notes:**
The median age of the subjects was 20 years for all studies.
The number of subjects who received at least one dose of vaccine or placebo in each trial are noted on this slide.
Protocol 015 was the largest trial, with Protocol 013 next largest.  In Protocol 013, and additional 304 subjects received the monovalent HPV 16 vaccine in bridging to Protocol 005.
The mean duration of post-month 7 follow-up at the time of the BLA submission was 3.1 years for Protocol 005, 2.4 years for Protocol 007, 1.7 years for Protocol 013, and 1.4 years for Protocol 015.

## Number of Subjects Enrolled:Distribution by Protocol and Region(Efficacy Population)

| Subjects | Protocol 005 | Protocol 007 | Protocol 013 | Protocol 015 | Total |
| --- | --- | --- | --- | --- | --- |
| North America | 2391
(100%) | 251
(45.6%) | 1713
(29.8%) | 913
(7.5%) | 5268 |
| Latin America | 0 | 187 
(33.9%) | 2278
(39.8%) | 3191
(26.2%) | 5606 |
| Europe | 0 | 113
(20.5%) | 1189
(20.7%) | 7872 
(64.8%) | 9174 |
| Asia-Pacific | 0 | 0 | 566
(9.9%) | 181
(1.5%) | 747 |

**Source: Table 2.7.3-cervix cancer: 9**

**Notes:**
This slide shows the distribution of subjects in the 4 geographical regions for the efficacy analysis.
The majority of subjects (65%) in Protocol 015 were from Europe, and the majority of subjects (40%) in Protocol 013 were from Latin America.   

## Subjects Excluded from Efficacy AnalysisBecause of Baseline HPV Status

|  | Gardasil | Placebo | Total |
| --- | --- | --- | --- |
| Number of Subjects Enrolled | 10291 | 10292 | 20583 |
| Received > 1 injection | 10268 | 10273 | 20541 |
| Excluded from PPE analysis
HPV 16
HPV 18 | 
2818
1626 | 
3008
1692 | 
5826
3318 |
| Sero and/or PCR+ HPV 16*
At Day 1
At/before Month 7 | 
1654
1770 | 
1679
2029 | 
3333
3799 |
| Sero and/or PCR+ HPV 18*
At Day 1
At/before Month 7  | 
574
656 | 
572
773 | 
1146
1428 |

***Day 1 includes Sero+ and/or PCR+. Post Day 1 includes PCR+ only.**
**Source: Interim Analysis Report, Table 2**

**Notes:**
Some subjects were excluded from the PPE analysis for HPV 16 and/or HPV 18 because of baseline HPV status.

## Role of Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analyses	

| Baseline HPV Status | HPV 6- related | HPV 11- related | HPV 16-related | HPV 18- related |
| --- | --- | --- | --- | --- |
| Naïve to all 4 vaccine HPV types | Yes | Yes | Yes | Yes |
| Positive HPV 6 or 11, Naïve 16/18 | No | No | Yes | Yes |
| Positive HPV 16, Naïve for 6/11/18 | Yes | Yes | No | Yes |
| Positive HPV 18, Naïve 6/11/16 | Yes | Yes | Yes | No |

**Naïve:  Subjects seronegative Day 1 and PCR negative Day 1 through Month 7.**
**Source: Merck Briefing Document**

**Notes:**
How a case was counted for the specific per protocol analysis is important to understand.

If a subject was naïve (that is, did not have evidence of previous exposure to all 4 of the vaccine HPV types [was seronegative at baseline and PCR negative for that type Day 1 through Month 7), that subject would be eligible for the per protocol population for each of the types.

## Role of Baseline HPV Status and Endpoint Counting for Prophylactic Vaccine Efficacy Analyses	

| Baseline HPV Status | HPV 6- related | HPV 11- related | HPV 16-related | HPV 18- related |
| --- | --- | --- | --- | --- |
| Naïve to all 4 vaccine HPV types | Yes | Yes | Yes | Yes |
| Positive HPV 6 or 11, Naïve 16/18 | No | No | Yes | Yes |
| Positive HPV 16, Naïve for 6/11/18 | Yes | Yes | No | Yes |
| Positive HPV 18, Naïve 6/11/16 | Yes | Yes | Yes | No |

**Source: Merck Briefing Document**
**Note:  Non-HPV 6, 11, 16, 18 related disease not included in analyses.**

**Notes:**
If a subject was naïve to HPV 6, 11,and 18 (that is, did not have evidence of prior exposure to HPV 6, 11, and 18 by virtue of serongativity and PCR negativity through Month 7), but had evidence of prior exposure to HPV 16 (that is, the subject was seropositive at Day 1 and/or PCR positive for HPV 16 Day 1 through Month 7) , that subject would be eligible for the per protocol populations for HPV 6, 11, and 18, but not for HPV 16.

It is noted that HPV related disease not caused by vaccine types were not included in the analyses.

## Efficacy Analysis Populations (1)

**Per Protocol Population for Efficacy (PPE):**  **Received all 3 vaccinations, naïve to relevant vaccine HPV type through Month 7, did not deviate from protocol; cases counted after Month 7.**
**Modified Intent to Treat -1 Population (MITT-1):**  **Same as PPE, but included protocol violators**
**Modified Intent to Treat-2 Population (MITT-2):** **Received at least 1 vaccination, naïve to relevant vaccine HPV type at Day 1, and had any follow-up visit after the first vaccination; cases counted from 30 days after dose 1.**

**Notes:**
It is important to understand the definitions of the efficacy populations presented.
The PP population received all 3 vaccinations, was naïve to the relevant vaccine HPV type through Month 7 [seronegative at day 1 and PCR negative through Month 7], and did not deviate from protocol.  Cases were counted starting after Month 7.

The Modified Intent to Treat Population 1 was like the PP population, but included protocol violators.  In general, analyses in this population gave similar results to the per protocol population.

The Modified Intent to Treat Population 2 was similar to the PP population, but subjects received 1 vaccination, and cases were counted 30 days after dose 1. In general, there were several cases in the vaccine group who developed infection early  in the vaccination phase.

## Efficacy Analysis Populations (2)

**Restricted MITT-2 Population (RMITT-2):****  **Seronegative and PCR negative to all four vaccine HPV types at Day 1 and a normal Pap test at Day 1; cases counted 30 days after dose 1.
**All MITT-1 Population:****  **Naïve to all four vaccine HPV types through Month 7, and cases counted starting after Month 7.

**Notes:**
The Restricted MITT-2 population were naïve for all 4 vaccine HPV types at Day 1, had a normal Pap test,  and cases were counted starting 30 days after Dose 1. 

The All-MITT 1 population was added to assess efficacy in a population who were naïve to all 4 vaccine HPV types and received all 3 vaccinations and cases were counted after Month 7.  The results of analyses conducted in this population were similar to the PP population.  

## Efficacy Analysis Populations (3)

**Modified Intent to Treat-3 Population (MITT-3):**  Received at least one vaccination and had any follow-up visit one month after dose 1.  Cases were counted from 30 days after dose 1.  Subjects were included regardless of baseline HPV status.

**Notes:**
The Modified Intent to Treat 3 population included all subjects who received at least 1 vaccination, regardless of baseline HPV status, and cases were counted 30 days after dose 1.  This population was considered important because it allowed an assessment of all vaccinated subjects.  The results of these analyses were generally lower than in the PP population because not all subjects were naïve to the vaccine HPV types.

## Baseline Characteristicsof Subjects in Efficacy Population (Protocols 005, 007, 013, and 015)

- Squamous intraepithelial lesion (SIL) present at baseline: **12%**
- PCR positive and/or 	seropositive to a vaccine HPV type: **27%**

**Notes:**
It was noted that 12% of the subjects in the efficacy population overall had an abnormal baseline Pap test with squamous intraepithelial lesion.  The majority of these were low grade SIL and atypical squamous cells of undetermined significance (ASC-US).

In addition, 27% of these subjects had been previously exposed to one or more of the vaccine HPV types (sero+ and/or PCR+).
App. 11% were SP for HPV 16 (and 4% were also PCR + also HPV 16);
App. 8% were SP for HPV 6 (and were also PCR + for HPV 6); 
App. 3.7% were SP for HPV 18 (and 0.9% were also PCR + for HPV 18); 
App. 2% were SP for HPV 11 (and 0.2% were also PCR + for HPV 11).

## Endpoints from Efficacy Protocols(Protocols 005, 007, 013, and 015)

- Primary Endpoints:
- HPV 16/18 related CIN 2/3 or worse [015, combined analysis]
- HPV 6/11/16/18 related CIN [013]
- HPV 6/11/16/18 related External Genital Lesions (EGLs) [013]

**Notes:**
Efficacy endpoints included HPV 16/18 related CIN 2/3 or worse (the primary analysis for Protocol 015 and across trials0, HPV 6/11/16/18 related CIN (co-primary endpoint for Protocol 013), and HPV 6/11/16/18 related EGLs (primary endpoint for Protocol 013).

## Other Endpoints 

- Other Endpoints of Interest:
- HPV 16/18 related EGLs
- CIN 2/3 due to any HPV type and non-vaccine HPV types
- EGL due to any HPV type and non-vaccine HPV types

**Notes:**
Other efficacy endpoints included HPV 16/18 related EGLs, HPV 6/11/16/18 related persistent infection, CIN 2/3 due to any HPV type and non-vaccine HPV types, and EGL due to any HPV type and non-vaccine HPV types.

**Efficacy Against HPV 16/18 CIN 2/3 or Worse**

**Notes:**
First, I will discuss the efficacy against HPV 16/18 CIN 2/3 or worse.

## Analysis of Efficacy AgainstHPV 16/18 Related CIN 2/3 or Worse (Protocol 015)

|  | Gardasil
N=6082 |  |  | Placebo
N=6075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population | N | No. of cases | Incidence | N | No. of cases | Incidence | Efficacy
(95% CI) |
| PPE | 5301 | 0 | 0.0 | 5258 | 21 | 0.3 | 100%
(75.8, 100%) |
| MITT-3 | 5947 | 67 | 0.6 | 5973 | 111 | 1.0 | 39.2%
(16.9, 55.8%) |

**Incidence Rate:  Calculated per 100 person years at risk.**
**PPE:  Naïve to relevant HPV type, received three doses of vaccine, cases counted**
**after Month 7. **
**MITT-3:  Included regardless of baseline HPV status; received at least one dose **
**of vaccine,  cases counted 30 days post-dose 1.    Sources: Table 7-2, p. 229; Table 7-5, p. 236, CSR 015v2**

**Notes:**
Please note that the incidence rate for the slides included in this talk was calculated per 100 person years at risk.

In Protocol 015, the primary analysis was vaccine efficacy in the prevention of HPV 16 and/or 18 related CIN 2/3, there was 100% efficacy in the PP population.  

This is in contrast to the analysis conducted in all subjects with data after 1 dose, who may or may not be naïve to the vaccine HPV types, where a 39% vaccine efficacy against HPV 16 and/or 18 CIN 2/3 was noted.   

## Analysis of Efficacy AgainstHPV 16/18 Related CIN 2/3 or Worse (Protocols 005, 007, 013, 015)

|  | HPV L1 VLP Vaccine
N=10268 |  |  | Placebo
N=10273 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population | N | No. of Cases | Incidence | N | No. of Cases | Incidence | Efficacy
(95% CI) |
| PPE | 8487 | 0 | 0 | 8460 | 53 | 0.4 | 100%
(92.9, 100%) |
| MITT-3 | 9831 | 122 | 0.6 | 9896 | 201 | 0.9 | 39.0%
(23.3, 51.7%) |

**Source: Table 2.7.3-cervixcancer: 29, p. 127-8**

**Notes:**
The combined analysis for trials 005, 007, 013 and 015 was comparable to the analysis in Protocol 015, where for subjects naïve for the relevant vaccine HPV type(s), the vaccine efficacy against HPV 16 and/or 18 related CIN 2/3 or worse is 100%, and for the all comers population, the vaccine efficacy is 39%.

## Analysis of Efficacy of Against HPV 16/18 RelatedCIN 2/3 or Worse by HPV Type – MITT 3 Analysis (Protocols 005, 007, 013, 015)

|  | Gardasil
N=10268 |  |  | Placebo
N=10273 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| HPV Type | N | No. of cases | Incidence | N | No.  of cases | Incidence | Efficacy
(95% CI) |
| HPV-16 | 9831 | 115 | 0.5 | 9896 | 184 | 0.9 | 37.2% 
(20.3, 50.7%) |
| HPV-18 | 8814 | 7 | 0.04 | 8846 | 33 | 0.2 | 78.7%
(51.0, 92.0%) |

**Source: Table 2.7.3-cervixcancer:31, p. 131**

**Notes:**
In the analyses of the combined trials for vaccine efficacy against the specific HPV type, in the MITT-3 population, there is better efficacy against HPV 18 related CIN 2/3 (77%) as compared to HPV 16 related CIN 2/3 (37%).  An almost identical result was noted in the same analysis in Protocol 015.

HPV 16 has been noted to have a higher risk for progression than other types.  In addition, there is a higher incidence of HPV 16 positivity as compared to HPV 18 positivity.  FDA asked Merck to comment on the median time to development of CIN 2/3 related to HPV 16 and 18, and there was no apparent difference in this interval to account for the better efficacy. It is not clear that higher prevalence of HPV 16 alone is the cause for the lower efficacy for HPV 16 related CIN 2/3.

**Efficacy Against**
**HPV 6/11/16/18 CIN**

**Notes:**
The next endpoint was efficacy against HPV 6/11/16/18 related CIN.   

## Analysis of Efficacy AgainstHPV 6/11/16/18 Related CIN (Protocol 013)

|  | Gardasil 
N=2717 |  |  | Placebo
N=2725 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| 
Population | N | No. of cases | Incidence | N | No. of cases | Incidence | Efficacy
(95% CI) |
| PPE | 2240 | 0 | 0 | 2258 | 37 | 1.0 | 100%
(87.4, 100%) |
| MITT-3 | 2607 | 65 | 1.2 | 2611 | 113 | 2.0 | 42.9%
(21.9, 58.6%) |

**Source: Table 7-3, CSR 013v1, p. 240, Table 7-8. p 250.**

**Notes:**
This was a primary endpoint in Protocol 013.  The vaccine efficacy in the per protocol population was again 100%, whereas in the MITT-3 population (all comers), the vaccine efficacy was 43%.

## Analysis of Efficacy AgainstHPV 6/11/16/18 Related CIN (Protocols 007, 013, 015)

|  | Gardasil
N=9075 |  |  | Placebo
N=9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population | N | No. of cases | Incidence | N | No. of cases | Incidence | Efficacy
(95% CI) |
| PPE
Combined | 7858 | 4 | 0.03 | 7861 | 83 | 0.7 | 95.2% 
(87.2, 98.7%) |
| MITT-3 Combined | 8814 | 170 | 1.0 | 8846 | 317 | 1.8 | 46.4% 
(35.2, 55.7%) |

**Source: Table2.7.3-cervixcancer: 26, p. 121-2**

**Notes:**
Similar results were noted in the analysis of protocols 007, 013, and 015.  
There were 4 cases that occurred in Gardasil recipients in the PP population.  

## Cases of HPV 6/11/16/18Related CIN in PPE Population

**Four cases occurred in the Gardasil group for the PP analysis (Protocol 015).****  **
**All four cases had HPV 16 related **_**CIN 1**_** at Month 12-13.**
** **
**One subject had anti-HPV 16 level just below level of detection and LSIL at Day 1 and HSIL at Mo 7, and possibly had prior exposure to HPV 16; also non-naïve to HPV 18 at Day 1 and colposcopy triggered by the HSIL at Mo 7, led to a diagnosis of HPV 18 related CIN 3 at Mo 9.**
**Three other subjects developed LSIL at Mo 7 and **
**    ****Mo 12, which led to colposcopies with the resulting diagnoses.  One had anti-HPV 16 level at Mo 7 higher than GMT seen in Per Protocol Immunogenicity (PPI) population.**

**Notes:**
All 4 had HPV 16 related CIN 1 at Month 12-13. One of the subjects had an anti-HPV 16 level just below the level of detection and LSIL at Day 1 and HSIL at Month 7, and possibly had prior exposure to HPV 16.   She also was non-naïve to HPV 18 at day 1 and a colposcopy triggered by the HSIL at Month 9 led to a diagnosis of HPV 18 related CIN 3 at Month 9. 

The other 3 subjects developed LSIL at Month 7 and Month 12, which led to the colposcopies with the resulting diagnoses.  One of these subjects had an anti-HPV 16 level at Month 7 that was higher than the GMT seen in the PPI population.

## Analysis of Efficacy Against HPV 6/11/16/18Related CIN by HPV Type – MITT-3(Protocols 005, 007, 013, 015)

|  | Gardasil
N=10572 |  |  | Placebo
N= 10273 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| HPV Type | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| HPV 6/11 | 8814 | 16 | 0.1 | 8846 | 61 | 0.3 | 73.7%
(53.8, 85.8%) |
| HPV 16 | 10121 | 155 | 0.7 | 9896 | 278 | 1.3 | 45.6%
(33.6, 55.6%) |
| HPV 18 | 8814 | 19 | 0.1 | 8846 | 63 | 0.4 | 69.7%
(48.8, 82.9%) |

**Source: Table 2.7.3-cervixcancer:28, p. 126 **

**Notes:**
When Vaccine efficacy against vaccine HPV type related CIN is assessed in combined trials,  the vaccine efficacy against HPV 18 related CIN lesions (70%) is higher than compared to vaccine efficacy against HPV 16 related CIN  (46%) in the MITT-3 population.  VE against HPV 6/11 related CIN is app. 74%.

## Efficacy Against HPV 6/11/16/18 Related CIN 2/3 or Worse and AIS (Protocols 005, 007, 013, and 015) 

|  | Gardasil |  |  | Placebo |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Day 1 Status | N | No. cases | Incidence | N | No. of cases | Incidence | Efficacy
95% CI |
| MITT-3 | 9831 | 122 | 0.7 | 9896 | 201 | 0.9 | 39.0%
(23.3, 51.7%) |
| PCR (-)
Sero (-) | 9342 | 1 | 0.6 | 9400 | 81 | 0.4 | 98.8%
(92.9, 100.0%) |
| PCR (-)
Sero (+) | 853 | 0 | 0.0 | 910 | 4 | 0.2 | 100%
(-63.6, 100.0%) |
| PCR (+)
Sero (-) | 661 | 42 | 3.2 | 626 | 57 | 4.6 | 31.2%
(-4.5, 54.9%) |
| PCR (+)
Sero (+) | 473 | 79
[121]* | 9.1 | 499 | 69
[130]* | 7.3 | -25.8%
(-76.4, 10.1%) |

*** Total number of cases in subjects who were sero+ and/or PCR+ at baseline for the relevant HPV type which was associated with disease.**
**Source: Table 1-1, Additional efficacy analysis requested by CBER**

**Notes:**
One area of potential concern identified by the review team was the apparent increased incidence of CIN 2/3 or AIS related to the vaccine type with which a subject was originally infected in Gardasil recipients who were PCR positive and seropositive for that HPV type as compared to placebo recipients.  This reversal was not seen in other non-naïve subgroups (i.e., those who were seropositive, PCR negative and those who were seronegative and PCR positive). In addition, the total number of non-naïve subjects who developed CIN 2/3 or AIS was somewhat higher in the placebo group (130) as compared to the Gardasil group (121).  

## Selected Characteristics for Subgroup of Vaccine Related HPV PCR Positive and Seropositive Subjects at Day 1(Protocol 013)

|  | Gardasil | Placebo |
| --- | --- | --- |
| Subgroup Population | 156 | 137 |
| History of cervicovaginal infection or STD | 35.9% | 32.1% |
| Pap test with HSIL | 6.5% | 3.7% |

**Source: Table 2a-2, Response to CBER questions from 3/1/06.**

**Notes:**
The above observation may be due to an imbalance in the baseline characteristics in the Gardasil and placebo groups for this subgroup.  Additional information was provided and demonstrated that in those who were seropositive and PCR positive at  baseline, the Gardasil recipients (in protocol 013) had a higher incidence of HSIL in their baseline Pap test as compared to those in the placebo group for this particular subgroup.  There was a lesser imbalance noted in Protocol 015.

In addition, subgroup analyses need to be interpreted with care.  

FDA concluded that there was a reasonable explanation for the results, and are not likely indicative of enhancement of disease.

**Notes:**
The next analyses concern efficacy against any HPV type and non-vaccine HPV related CIN.

## Overall Impact on CIN 2/3 or WorseDue to Any HPV Type (Protocols 007, 013, and 015)

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| MITT-3 | 8814 | 287 | 1.6 | 8846 | 328 | 1.9 | 12.2%
(-3.2, 25.3%) |

**Source: Table 5.3.5.3.2:17, p. 78-9, Integrated Summary of Efficacy**

**Notes:**
In the MITT-3 population in protocols 007, 013, and 015, the vaccine efficacy against CIN 2/3 due to any HPV type is app. 12 %.

## Analysis of Efficacy Against Non-HPV 6/11/16/18 Related CIN 2 or CIN 3 Among Subjects in All MITT-1 Population (Protocols 007, 013, 015)

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| CIN 2 | 5993 | 59 | 0.7 | 5766 | 49 | 0.6 | -16.1%
(-73.2, 21.8%) |
| CIN 3 | 5993 | 36 | 0.4 | 5766 | 27 | 0.3 | -28.5%
(-120.1, 24.1%) |

**All MITT-1 Population:  Naïve to all four vaccine HPV types through Month 7, received three doses of vaccine.**
**Source: Table 3-4, Additional Efficacy Analyses Requested by CBER**

**Notes:**
The data for specific non-vaccine HPV types has not yet been provided to the BLA.  
This slide demonstrates that subjects who are naïve to all 4 types through Month 7 may develop disease related to non-vaccine HPV types, and there is a slightly higher incidence of these events in the vaccine group as compared to the placebo group.  

**Efficacy Against HPV 6/11/16/18**
**Related External Genital Lesions (EGLs)**

**Notes:**
The next analyses concern efficacy against HPV 6/11/16/18 related EGL.  

## Analysis of Efficacy AgainstHPV 6/11/16/18 EGL (Protocol 013)

|  | Gardasil 
N=2717 |  |  | Placebo
N=2725 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population | N | No. of cases | Incidence | N | No. of cases | Incidence | Efficacy
(95% CI) |
| PPE | 2261 | 0 | 0.0 | 2279 | 40 | 1.0 | 100%
(88.4, 100%) |
| MITT-3 | 2671 | 26 | 0.5 | 2668 | 80 | 1.4 | 67.8%
(49.3, 80.1%) |

**Source: Table 7-3, CSR 013v1, p. 240 and Table 7-18, p. 271**

**Notes:**
In Protocol 013, a co-primary endpoint was HPV 6/11/16/18 related EGLs.
The vaccine efficacy is again 100% in the PP population.
The vaccine efficacy in the MITT-3 group is also quite good (app. 68%).  
The better vaccine efficacy against EGLs in MITT-3 population is most likely due to the fact that subjects were excluded from participation if they had a prior history of EGLs, and they would be more likely to be aware of such a diagnosis because the lesions are readily noticeable. There was likely less prevalent disease in the EGL efficacy population compared to the CIN efficacy population.  In addition, there may have been a shorter incubation period for HPV 6 and 11.

## Analysis of Efficacy AgainstHPV 6/11/16/18 Related EGLs(Protocols 007, 013, 015) 

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| PPE  | 7987 | 1 | 0.01 | 7899 | 113 | 0.9 | 99.1%
(95.0, 100.0%) |
| RMITT-2 | 5742 | 6 | 0.1 | 5775 | 127 | 1.1 | 95.3%
(89.4, 98.3%) |
| MITT-3 | 8954 | 68 | 0.4 | 8962 | 229 | 1.3 | 70.4% 
(61.0, 77.7%) |

**Source: Table2.7.3-exgenlesions: 6, p. 39-40**
**Table 4-1, Additional Efficacy Analyses Requested by CBER**

**Notes:**
In similar analysis in combined trials, the same high efficacy is noted for the PP population, the MITT-3 population, and the RMITT-2 population.  

This high efficacy is maintained across lesions of different severity (not shown here).  

## Analysis of Efficacy Against HPV 6/11/16/18Related EGLs by HPV Type (Protocols 007, 013, 015)

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| MITT-3 
HPV 6/11 | 8954 | 59 | 0.3 | 8962 | 194 | 1.1 | 69.6%
(59.2, 77.7%) |
| MITT-3 HPV 16 | 8954 | 11 | 0.1 | 8962 | 55 | 1.1 | 80.0%
(61.3, 90.5%) |
| MITT-3 HPV 18 | 8954 | 2 | 0.01 | 8962 | 20 | 0.1 | 90.0%
(58.7, 98.9%) |

**Source: Appendix 2.7.3-exgenlesions:9,  p. 64**

**Notes:**
99-100% efficacy is maintained for all vaccine HPV types for both the PP population and the MITT-3 population in combined trials.  

## Analysis of Efficacy Against HPV 16/18 Related EGLs (Protocols 007, 013, 015) 

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population - EGL type | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| PPE - Condyloma, VIN 1 or VaIN 1) | 7769 | 0 | 0.0 | 7741 | 24 | 0.2 | 100.0%
(83.4, 100.0%) |
| PPE - VIN 2/3 or VaIN 2/3 or worse) | 7769 | 0 | 0.0 | 7741 | 10 | 0.1 | 100.0%
(55.5, 100.0%) |
| MITT-3 - Condyloma, VIN 1 or VaIN 1) | 8954 | 7 | 0.04 | 8962 | 51 | 0.3 | 86.2%
(69.6, 94.7%) |
| MITT-3 – 
VIN 2/3 or VaIN 2/3 or worse) | 8954 | 8 | 0.05 | 8962 | 26 | 0.1 | 69.1%
(29.8, 87.9%) |

**Source: Table 2.7.3-exgenlesions:7, p. 41**

**Notes:**
The vaccine efficacy against HPV 16/18 related EGLs (both condylomas, VIN 1, and VaIN 1, as well as VIN 2/3 and VaIN 2/3 is also high.  There is evidence of efficacy in the MITT-3 population of nearly 70% for the more advanced lesions.

(The efficacy against HPV 16/18 related VIN 2/3 or VaIN 2/3 or worse is much better than the VE against HPV 16/18 related CIN 2/3 or worse (app. 70 % compared to 39%). 

FDA requested that vaccine efficacy be broken down for each different lesion type for each protocol and for combined protocols 007, 013, and 015.  

## Analysis of Efficacy Against HPV 6/11/16/18 Related EGL by Severity of Disease –PPE Population (Protocols 007, 013, 015)

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population - EGL type | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| PPE - Condyloma | 7897 | 1 | 0.0 | 7899 | 91 | 0.8 | 98.9%
(93.7, 100.0%) |
| PPE – VIN 1 | 7897 | 0 | 0.0 | 7899 | 10 | 0.1 | 100.0%
(55.4, 100.0%) |
| PPE-VIN 2/3 | 7897 | 0 | 0.0 | 7899 | 8 | 0.1 | 100.0%
(41.4, 100.0%) |
| PPE-VaIN 2/3 | 7897 | 0 | 0.0 | 7899 | 5 | 0.04 | 100.0%
(<0.0, 100.0%) |

**Source: Table 1-1, Response to CBER request 5/1/06.**

**Notes:**
FDA had requested that the EGL endpoints be broken down by specific type, with analyses in Protocols 013, 015, and combined for 007, 013, and 015.  In the combined protocols for the PP population, there was high efficacy against condylomas and each of the specific lesions, although the number of cases was smaller for VIN and VaIN lesions.

In Protocol 013, VE was similar for each of the lesions noted above in the PPE, although the numbers were small.  [The LB for the condylomas was 86.4% with 100% efficacy; the LB for VIN 2/3 and VaIN 2/3 was < 0.0%).   

## Analysis of Efficacy Against HPV 6/11/16/18 Related EGL by Severity of Disease –MITT-3 population (Protocols 007, 013, 015)

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Population - EGL type | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| MITT-3 Condyloma | 8954 | 58 | 0.3 | 8962 | 184 | 1.0 | 68.5%
(57.5, 77.0%) |
| MITT-3
VIN 1 | 8954 | 8 | 0.05 | 8962 | 19 | 0.1 | 57.8%
(<0.0, 84.0%) |
| MITT-3
VIN 2/3 | 8954 | 7 | 0.04 | 8962 | 22 | 0.1 | 68.1%
(22.7, 88.5%) |
| MITT-3
VaIN 2/3 | 8954 | 2 | 0.01 | 8962 | 9 | 0.1 | 77.7%
(<0.0, 97.7%) |

**Source:  Table 1-3, CBER Additional Request for analyses, 5/1/06**

**Notes:**
In the MITT-3 population, there was also evidence of benefit (although the LB of the 95% CIs were < 0.0 for VIN 1 and VaIN 2/3 in this population).

In Protocol 013, the efficacy for the condylomas was similar (with similar LBs), and for VIN 2/3 VE was app. 43% (95% CI:  <0.0, 87.8) and for VaIN 2/3 was 100% (95% CI <0.0, 100%).  

## Efficacy Against HPV 6/11/16/18 Related EGLs (Protocols 007, 013, and 015)

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Day 1 Status | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| Sero (-) PCR (+) | 810 | 44 | 2.9 | 782 | 41 | 2.8 | -4.0%
(-63.2, 33.6%) |
| Sero (+) PCR (-) | 1270 | 0 | 0.0 | 1301 | 4 | 0.2 | 100.0%
(-56.2, 100.0%) |
| Sero (+) PCR (+)  | 336 | 5
[49]* | 1.0 | 331 | 5
[50]* | 1.0 | 2.4%
(-324.3, 77.5%) |

*** Total number of cases in subjects who were  sero+ and/or PCR + at baseline for the **
**relevant HPV type which was associated with disease.**
**Source: Table 2.7.3-exgenlesions:8, p. 43 and Table 7-1, Additional Efficacy Analyses **
**Requested by CBER**

**Notes:**
When comparing the incidence of HPV 6/11/16/18 related EGLs in  the subgroup who were PCR positive and seropositive at baseline (Gardasil vs.placebo), there is little or no difference.   For the non-naïve group, there were 50 cases of HPV 6/11/16/18 related EGLs as compared to 49 in the vaccine group, and 5 in each group who were initially sero+ and PCR+.

## Impact of Gardasil on Incidence of EGLs Dueto Any HPV Type by Severity of Disease (Protocols 007, 013, 015)

|  | Gardasil
N=9075 |  |  | Placebo
N= 9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | No. of cases | Incidence | N | No. of 
cases | Incidence | Efficacy
(95% CI) |
| RMITT 2 condylomata, VIN 1 or VaIN 1 | 5734 | 52 | 0.5 | 5769 | 151 | 1.3 | 65.4%
(52.3, 75.3%) |
| RMITT 2- VIN 2/3 or VaIN 2/3 or worse | 5734 | 5 | 0.04 | 5769 | 27 | 0.2 | 81.3%
(50.8, 94.4%) |
| MITT-3 – condylomata, VIN 1 or VaIN 1 | 8954 | 169 | 1.0 | 8962 | 284 | 1.6 | 40.5%
(27.8, 51.1%) |
| MITT-3 – VIN 2/3 or VaIN 2/3 or worse | 8954 | 22 | 0.1 | 8962 | 43 | 0.2 | 48.7%
(12.3, 70.8%) |

**Source: Table 2.7.3-exgenlesions: 9, p. 46**

**Notes:**
Also of interest is the vaccine efficacy in the reduction of EGLs due to any HPV type (which includes vaccine and non-vaccine HPV types).  Efficacy is still noted to the RMITT-2 population (naïve to all 4 vaccine types with negative Pap at day 1) with 65% efficacy against warts and low grade VIN 1 and VIN 2, and 81% efficacy against the higher grade lesions.  For these same groups, there was 41% and 49% vaccine efficacy, respectively, in the MITT-3 population.  

As compared to efficacy against CIN due to any HPV type, the efficacy is higher for the EGLs in these two populations, although < 100%.

## Efficacy Against Non-HPV 6/11/16/18Related EGL in All MITT-1 Population (Protocols 007, 013, 015)

|  | Gardasil
N=9075 |  |  | Placebo
N=9075 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | No. of cases | Incidence | N | No. of cases | Incidence | Efficacy
(95% CI) |
| EGL not related to HPV 6/11/16/18 | 5999 | 52 | 0.6 | 5773 | 49 | 0.6 | -2.1%
(-54.1, 32.2%) |
| Condyloma, VIN 1, VaIN 1 | 5999 | 46 | 0.5 | 5773 | 49 | 0.6 | 9.7%
(-37.9, 40.9%) |
| VIN 2/3 or VaIN 2/3 | 5999 | 5 | 0.1 | 5773 | 6 | 0.1 | 19.8%
(-215.3, 80.6%) |
| Vulvar or vaginal cancer | 5999 | 1 | 0.01 | 5773 | 0 | 0.0 | NA |

**Source: Table 6-2, Additional Efficacy Analyses Requested by CBER**

**Notes:**
Of interest is assessment of vaccine efficacy against non-vaccine HPV types, and there is little or none noted.  The incidence rates in both the Gardasil and placebo groups are quite similar.

There was one case of anogenital cancer diagnosed in a subject in Protocol 013 who developed an external genital lesion (posterior introitus) at app. Month 24.  No vaccine type HPV PCR was identified in the pathological material. This subject had an immune response to all 4 vaccine types, and had normal Pap tests throughout the study.

## Safety

- Safety Population
- Safety Surveillance
- Deaths
- SAEs
- Pregnancies/Lactation

**Notes:**
I will now review the safety results for the Phase 3 trials.

## Safety Population:Detailed and General

| Safety Population | Gardasil | Placebo |
| --- | --- | --- |
| Detailed Safety Population | 6160 | 4064 |
| General Safety Population | 11778 | 9686 |

**Source: Tables 2.7.4: 4 and 5, p. 29-30, Summary of Clinical Safety 3/8/06**

**Notes:**
This slide provides a breakdown of the number of subjects overall in the Detailed safety population (with VRCs) and the General safety population (with  or without VRCs).
FDA review looked at the Detailed Safety population but considered all SAEs rergardless of the population.

## Vaccine Exposure in 9-15 Year OldFemale Subjects  (Protocols 016 and 018)

| Age | Females
Gardasil |
| --- | --- |
| 9 | 85 |
| 10 | 158 |
| 11 | 196 |
| 12 | 165 |
| 13 | 190 |
| 14 | 192 |
| 15 | 137 |
| Total | 1123 |

**Source: Applicant’s response to additional CBER questions**

**Notes:**
This slide shows the vaccine exposure for females between the ages of 9-15 years of age.  It is noted that 1123 girls received the vaccine. 

## Safety Surveillance(Detailed Safety Cohort)

- Vaccine Report Cards for 14 days after each vaccination (Protocols 005, 007, 013 + NSAE 015)
- Solicited local AEs:  Pain, tenderness, redness for 5 days after vaccination
- Temperatures for 5 days after vaccination
- 	_>_ 100° F oral
- Solicited  and unsolicited systemic AEs:  Sore muscle, sore joints, headache, rash, diarrhea for 14 days after vaccination

**Notes:**
Briefly, for a majority of subjects, a Vaccine Report card was used to record solicited AEs in the 5 days after vaccination (including pain, tenderness, and swelling); oral temperatures were recorded for 5 days after each vaccination; and solicited and unsolicited systemic AEs were recorded for 14 days after each vaccination (including sore muscles, sore joints, headaches, rash, and diarrhea).

## Serious Adverse Event Reporting

- Any SAE for day of consent to 14 days postdose 1, and 14 days postdose 2 and 3 regardless of attribution
- Any death or SAE which resulted in study discontinuation
- Any SAE throughout study which was possibly vaccine or procedure related or whose relationship was unclear
- Pregnancy related SAEs throughout study

**Source: Applicant’s Response to CBER question**

## Reporting New MedicalConditions

- Pre-vaccination
- Study period through Month 7
- Study period after Month 7

**Notes:**
In addition, all new medical conditions for the pre-vaccination period, for the vaccination period through Month 7, and for the entire study period after Month 7 were provided to the BLA.

## Pregnancy and Lactation Reporting 

- All pregnancies were to be followed to outcome
- SAEs were reported for mothers and infants
- Lactation outcomes were followed

**Notes:**
All pregnancies were to be followed to outcome, as well as lactation outcomes.
All SAEs were reported for mothers and infants.

**Safety Results**

**Notes:**
These are the safety results.

## Deaths(Protocols 007, 013, 015, 016, 018)

|  | Gardasil (N=11, 0.9%) | Placebo (N=7, 0.7%) |
| --- | --- | --- |
| Trauma | 5 | 3 |
| DVT/PE | 1 | 1 |
| Sepsis, DIC | 1 |  |
| Sepsis, pneumonia | 1 |  |
| Arrythmia | 1 |  |
| Pancreatic Cancer | 1 |  |
| Convulsion, drug use | 1 |  |
| Suicide |  | 2 |
| Asphyxiation
post-C-section |  | 1 |

**Source: Summary of Clinical Safety (3/8/06), Table 2.7.4:20, p. 56-61.**

**Notes:**
There were 11 deaths in the Gardasil group (0.9%) and 7 in the placebo group (0.7%).  There was no pattern identified.

## Serious Adverse Events (Protocols 007, 013, 015, 016, 018)

| SAE (Organ system) | Gardasil N=11778 | Placebo N=9680 |
| --- | --- | --- |
| Gyn or Obstetrical | 42 | 41 |
| GI | 11 | 6 |
| Appendicitis | 4 | 1 |
| Injury | 6 | 6 |
| Neurological | 4 | 7 |
| Immune mediated | 2 | 4 |
| Coagulation/DVT | 2 | 1 |
| Pulmonary | 2 | 5 |
| GU | 6 | 5 |
| Endocrine | 1 | 0 |
| Injection site reaction | 1 | 0 |
| Psychiatric | 5 | 2 |
| Cardiovascular | 1 | 1 |
| Musculoskeletal | 1 | 1 |
| ENT | 1 | 0 |
| Administration of excess study vaccine | 16 | 20 |
| Total | 101  (0.9%) | 97 (1.0%) |

**Source: Summary of Clinical Efficacy (3/8/06) Table 2.7.4:21, p. 63-102.**

**Notes:**
There were 101 SAEs identified in the Gardasil group (0.9%)  and 97 idenitifed in the placebo group (1.0%).

No pattern or signal of concern was identified.  

Upon review of the datasets by FDA, no significant discrepancy was identified in the number or type of SAEs as reported by the sponsor. 

## New Medical Conditions (Number and Percent) During Vaccination Period (through Month 7) and after Month 7 for Selected Organ Systems(Protocols 007, 013, 015, 016, 018)

| Organ System | During Vaccination Period |  | Post Month 7 |  |
| --- | --- | --- | --- | --- |
|  | Gardasil
N=11778 | Placebo
N=9868 | Gardasil
N=10452 | Placebo
N=9385 |
| Cardiac | 11 (0.1%) | 12 (0.1%) | 21 (0.2%) | 13 (0.1%) |
| Endocrine | 20 (0.2%) | 17 (0.2%) | 40 (0.4%) | 33 (0.4%) |
| GI | 711 (6.0%) | 638 (6.6%) | 7272 (7.0%) | 595 (6.3%) |
| Immune | 150 (1.3%) | 112 (1.2%) | 105 (1.0%) | 88 (0.9%) |
| Musculoskeletal | 387 (3.3%) | 256 (2.6%) | 320 (3.1%) | 242 (2.6%) |
| Neoplasms | 68 (0.6%) | 50 (0.5%) | 105 (1.0%) | 67 (0.7%) |
| Nervous system | 684 (5.8%) | 495 (5.1%) | 333 (3.2%) | 217 (2.3%) |
| Psychiatric | 168 (1.4%) | 162 (1.7%) | 212 (2.2%) | 203 (2.2%) |
| Surgical | 384 (3.3%) | 296 (3.1%) | 477 (4.6%) | 495 (5.3%) |
| Appendectomy | 19 (0.2%) | 4 (<0.1%) | 17 (0.2%) | 26 (0.3%) |

**Source: Summary of Clinical Efficacy (3/8/06): Appendices 2.7.4: 31, 33, 34, 36**

**Notes:**
This slide shows the new medical conditions in the 7 month vaccination period as compared to the new medical conditions in the period after the 7 month vaccination period.  The rates were fairly comparable between the Gardasil and placebo groups.  

## Pregnancy Outcome Summary (Protocols 013, 015, 016, 018)

|  | Gardasil (N=10418) | Placebo (N=9120) |
| --- | --- | --- |
| Subjects with pregnancies | 1115 (10.7%) | 1151 (12.6%) |
| Number of pregnancies | 1244 | 1272 |
| Number of fetuses/infants with known outcomes | 996 | 1018 |
| Number of pregnancies with unknown outcomes | 258 | 263 |
| Live Births | 621 (62.3%) | 611 (60.0%) |
| Spontaneous miscarriage | 249 (25%)* | 257 (25.2%)* |
| Late fetal deaths | 11 (1.2%) | 8 (0.9%) |

***Percentage calculated with number of known outcomes**
**Source: Summary of Clinical Safety (3/8/06), Table 2.7.4:24, p. 126-8.**

**Notes:**
Regarding pregnancy outcomes, for the pregnancies with known outcomes, the proportion of live births and spontaneous miscarriages appear comparable between the vaccine and placebo groups.

## Distribution of Congenital Anomalies by Estimated Dates of Conception (EDCn) Timing in Relation to Vaccination (Protocols 013, 015, 016, 018)

|  | Gardasil | Placebo |
| --- | --- | --- |
| Congenital Anomalies | 15 | 16 |
| EDCn within 30 days of study vaccine | 5** | 0 |
| Live birth reported in neonatal period | 5 | 0 |
| EDCn beyond 30 days of study vaccine | 10 | 16 |
| Live birth reported in neonatal period | 8 | 12 |
| Live birth reported beyond neonatal period | 1 | 1 |
|    Fetal Loss | 0 | 2 |
|    Intra-uterine diagnosis | 1 | 1 |

****Diagnoses included hip dysplasia, ankyloglossia and pyloric stenosis, congenital**
**hydronephrosis, club foot, and congenital megacolon**
**Source: Table 2.7.4:26, p. 135, safety update 3/8/06**

**Notes:**
The total number of congenital anomalies were similar in the 2 treatment groups (16 for placebo and 15 for Gardasil group).  
One item of note was the number of infants with congenital anomalies that were born to mothers who received vaccine within 5 days of the estimated date of conception in the Gardasil group (5) as compared to none in the placebo group.  The 5 infants had anomalies which were not developmentally related, and included hip dysplasia, ankyloglossia and pyloric stenosis, congenital hydronephrosis, club foot, and congenital megacolon.  

## Adverse Events in Pregnancy/Lactation (1)(Protocols 013, 015, 016, 018)

- A similar pattern and occurrence of SAEs and AEs in pregnancy were reported in women who were vaccinated with Gardasil (N=40, 4.2%) or placebo (N=41, 4.3%).
- These events included conditions leading to C-section, premature labor, and conditions associated with pregnancy.

**Notes:**
There was a similar pattern and occurrence of SAEs and AEs in women who were vaccinated with Gardasil (N=40, 4.2%) or placebo (N=41, 4.3%). These events included conditions leading to C-section, premature labor, and conditions associated with pregnancy (e.g., pre-eclampsia).

## Adverse Events in Pregnancy/Lactation (2)(Protocols 013, 015, 016)

- Higher proportion of children with SAEs in women who received Gardasil while breastfeeding in the vaccination period (Gardasil N=17, 3.4%; placebo N=9, 1.8%);  the events were of similar nature in both groups.
- In both the vaccine and placebo groups, these included respiratory infections, gastroenteritis, and asthma.

**Notes:**
There was a higher proportion of children with SAEs in women who received Gardasil while breastfeeding in the vaccination period.  The events were of similar nature, and included respiratory infections, gastroenteritis, and asthma.  Others in the Gardasil group included bronchial obstruction, head injury, dehydration, and identification of a congenital anomaly.

## Adverse Events in Infants/Lactation(3)(Protocols 013, 015, 016)

| Event | Gardasil
N=500 | Placebo
N=495 |
| --- | --- | --- |
| Respiratory Infections | 12  | 4 |
| Gastroenteritis/Diarrhea | 5 | 2 |
| Asthma | 1 | 1 |
| Bronchial Obstruction | 1 | 0 |
| Cellulitis | 1 | 0 |
| Dehydration | 1 | 0 |
| Head Injury | 1 | 0 |
| Anomalous pulmonary venous return | 1 | 0 |
| Unspecified Viral Infection | 0 | 1 |
| Febrile Convulsion | 0 | 1 |

**Source: Summary of Clinical Safety, Page 181-182 and Appendix 2.7.4:195, Pages 1076-1079**

**Notes:**
The events were of similar nature, and included respiratory infections, gastroenteritis, and asthma.  Others in the Gardasil group included bronchial obstruction, head injury, dehydration, and identification of a congenital anomaly.

The interval between vaccination of the mother and the respiratory events in the infants varied from 12-231 days in the 17 infants whose mothers received Gardasil while breastfeeding.  AEs in infants whose mothers received placebo while breastfeeding ranged from 3-145 days after vaccination.  The numbers are small, and it is unclear that we can draw any strong conclusions.
Neither Gardasil nor anti-HPV antibody excretion in milk was specifically studied. 

## FDA Safety Conclusion (1)

- Although no obvious safety signal was identified, post-marketing pharmacovigilance activities will continue to collect AEs that occur post-vaccination in a larger population.

## FDA Safety Conclusion (2)

- An imbalance was noted regarding the EDCn of infants who had congenital anomalies (five cases for mothers who received Gardasil vs. none for mothers who received placebo).  However, there did not appear to be a pattern among the congenital anomalies.

## Immunogenicity

- Bridging immune response in adolescent girls to adult women
- Duration of immune response
- Co-administration with Hepatitis B vaccine

**Notes:**
Lastly, I will discuss immunogenicity data.
The assay for the anti-HPV antibodies was an ELISA assay.

It is noted that no immune correlate of protection was identified.

## Bridging Immune Response from Females 16-26 Years toFemales 9-15 Years of Age

- Females naïve to the four vaccine HPV types are expected to benefit most from the vaccine.
- Efficacy studies cannot be conducted in preadolescent girls.

**Notes:**
Bridging of the immune response from females 16-26 years of age to females 9-15 years of age was conducted rather than efficacy studies in young females.

For one, females naïve to the four vaccine HPV types are expected to most benefit from the vaccine.

Second, efficacy studies cannot be conducted in preadolescent girls.

## Month 7 HPV 6 GMTs and 95% CI by Age at Enrollment - 9 to 26 Year Old Female Recipients of Gardasil  (PPI)

**Source: Figure 5.3.5.3.3:3, Integrated Summary of Immunogenicity**

**Notes:**
This figure demonstrates that the GMTs are highest at the youngest age groups, and decrease as the age increases. 

This pattern of decreasing immune response with increasing age is commonly noted for other antigens.  

## Immunogenicity Bridging Between 9-15 Year Old Females in the Immunogenicity Studies to 16-26 Year Old Females in the Efficacy Studies (PPI)

|  | 9-15 Year Old Females in Protocols 016 and 018 |  |  | 16-23 Year Old subjects in Protocols 013 and 015 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Assay (cLIA) | n | GMT
mMU/mL | 95% CI | n | GMT
mMU/mL | 95% CI |
| Anti-HPV 6 | 927 | 931.3 | 876.9, 989.2 | 2827 | 542.4 | 526.6, 558.7 |
| Anti-HPV 11 | 927 | 1305.7 | 1226.2, 1390.4 | 2827 | 766.1 | 740.5, 792.6 |
| Anti-HPV 16 | 929 | 4944.9 | 4538.5, 5334.8 | 2707 | 2313.8 | 2206.2, 2426.7 |
| Anti-HPV 18 | 932 | 1046.0 | 971.2, 1126.5 | 3040 | 460.7 | 443.8, 478.3 |

**Source: Table 5.3.5.3.3:29, p. 85, Integrated Summary of Immunogenicity**

**Notes:**
The sponsor compared the GMTs in girls participating in Protocols 016 and 018 to the GMTs in subjects who participated in the pivotal efficacy trials, Protocol 013 and Protocol 015.  The GMTs were higher in girls who received Gardasil as compared to adult women who participated in the efficacy trials.

**Duration of Immune Response**

**Notes:**
As to duration of immune response,  

## Persistence of Anti-HPV 18 Immune Responses in 18 to 26 Year Old Female Recipients of Gardasil (Seronegative at Day 1 and PCR Negative Through Month 7) Versus Placebo Recipients (Seropositive and PCR Negative at Day 1)

**Source: Figure 5.3.5.3.3:16, p. 69, Integrated Summary of Immunogenicity**

**Notes:**
This next figure demonstrates the persistence of anti-HPV 18 immune responses in adult women who were seronegative for HPV 18 at baseline and received Gardasil as compared to women who received placebo and were non-naïve to HPV 18 at baseline.  It can be seen that the level of anti-HPV 18 is slightly higher in women who were vaccinated out to Month 24 as compared to non-naïve placebo recipients, and the pattern is similar to that seen for the other vaccine HPV types.  However, data for immune response past this point has not been submitted to the BLA.  

## Seropositivity Rates for Anti-HPV 6, 11, 16, and 18 at Month 24 (Vaccinated Women 18-26 years) with Serology Data at All Time Points (N=2818)

| HPV type | Seropositivity rate at Month 24 (95% CI) |
| --- | --- |
| Anti-HPV 6 | 95.7%
(94.5, 96.6%)  |
| Anti-HPV 11 | 97.6%
(96.8, 98.3%) |
| Anti-HPV 16 | 99.6%
(99.2, 99.9%) |
| Anti-HPV 18 | 73.9%
(71.8, 75.9%) |

**Source: Table 5.3.5.3.3:14, p. 55, Integrated Summary of Immunogenicity**

**Notes:**
The Month 7 seropositivity rate for each of the 4 vaccine HPV types was nearly 100%.  
This slide presents serology data out to Month 24 in adult subjects who had all data points (N=2818).  It is noted that seropositivity remained at >95% for HPV 6, 11, and 16, but fell to 73.9% by Month 24 for HPV 18.  The GMT level remained above the seroconversion point. There was no evidence of breakthrough cases of HPV 18 related disease reported at this time point, so the significance of the lower seropositivity rate for HPV-18 is unclear that this time.  
It appears that antibody levels are generally maintained at or above the level seen in subjects who have natural infection at least out to Month 24.  

## Co-administration of Gardasil with Hepatitis B Vaccine

- Anti-HPV 6, 11, 16, and 18 immune responses were non-inferior when Gardasil was given with or without Recombivax (SC rates, GMT ratios)
- Anti-Hepatitis B immune response was similar when Recombivax was given with or without Gardasil (SC rates)
- Anti-Hep B GMTs lower in coadministration group

**Notes:**
Briefly, anti-HPV 6, 11, 16, and 18 immune responses were similar when Gardasil was given with or without Recombivax (by GMT ratios and seroconversion rate comparisons).
Anti-Hepatitis B immune response was similar when Recombivax was administered with or without Gardasil (seroconversion 96.5% concomitant versus 97.5% non-concomitant).  GMTs were somewhat lower when both vaccines were coadministered (535 mIU/mL) compared to when Hepatitis B vaccine was given alone (793 mIU/mL).  

## Applicant’s Proposed Post-marketing Commitments

- Routine pharmacovigilance
- Phase 4 studies
- Other studies

## Routine Pharmacovigilance

- Passive reporting of adverse events (AEs) including:
- Monthly submission of non-serious AE reports
- Regular FDA-CDC-Sponsor conference calls
- Pregnancy registry

## Phase 4 Studies

- Observational safety surveillance study in large U.S. MCO
- Investigation of serious AEs that occur in close temporal association with vaccination (60 days follow-up)
- Nordic Long Term Follow-up Study
- Longitudinal evaluation of subjects in Protocol 015 enrolled in Nordic countries using national registries

## Nordic Long Term Follow-up Study:  Outcomes 

- HPV-related diseases
- Long term effectiveness and duration of immune response
- Potential safety signals
- Pregnancy outcomes

## Other Studies

- Evaluation of long term effectivenesss and duration of immune response:
- Extension of protocol 007
- Extension of protocol 018
- Detection of unanticipated safety signals through active surveillance in all studies.

## Gardasil:FDA Review Conclusions

- The efficacy, safety, and “bridging” immune response data submitted to the BLA support licensure of Gardasil in females 9-26 years of age _naïve to the relevant vaccine HPV type_ for prevention of the following diseases/events:
- HPV 16/18 related cervical cancer, CIN 2/3 and AIS.
- HPV 6/11/16/18 related VIN 2, VIN 3, VaIN 2, VaIN 3
- HPV 6/11/16/18 related CIN 1, genital warts, VIN 1 and VaIN 1

## Gardasil:FDA Review Concerns (1)

**Applicant’s Per Protocol HPV type-specific analyses that indicated a very high level of efficacy in naïve subjects may not reflect the efficacy of Gardasil for all HPV related disease on a population basis.**
**HPV related disease occurred in Gardasil recipients.**
**Some vaccine recipients were **_**non-naïve**_** at baseline for one or more vaccine HPV type(s), and some of these subjects developed HPV disease related to that HPV type(s).**
**Subjects who were naïve to all four vaccine HPV types could still develop disease related to an HPV type **_**not included**_** in the vaccine.**

## Gardasil:FDA Review Concerns (2)

- Modified Intent to Treat analysis (MITT-3) of all vaccinated females across studies 005, 007, 013, and 015 demonstrate modest efficacy against CIN 2/3:
- MITT-3:  Overall efficacy CIN 2/3 or worse due to HPV6/11/16/18 [**39.0%** (23.5, 51.7%)]
- MITT-3:  Overall efficacy CIN 2/3 or worse due to any HPV type [**12.2%**
-   (-3.2%, 25.3%)].

## Gardasil:FDA Review Concerns (3)

- Longer-term efficacy
- Study 005 results suggest favorable longer term efficacy
- Duration of immune response
- Post-licensure commitments

## Questions for the Committee

- Do the data from studies 005, 007, 013, and 015 support the efficacy of Gardasil for the prevention of HPV 16/18 related  cervical cancer, cervical AIS, and CIN 2/3 or worse in females 16-26 years of age?

## Questions for the Committee

- Do the data from studies 007, 013, and 015 support the efficacy of Gardasil for the prevention of HPV 6/11/16/18 related VIN 2/3 and VaIN 2/3 in females 16-26 years of age?

## Questions for the Committee

- Do the data from studies 007, 013, and 015 support the efficacy of Gardasil for the prevention of HPV 6/11/16/18 related condyloma acuminata, VIN 1 and
- 	VaIN 1?

## Questions for the Committee

- Do the immunogenicity data support bridging of the younger female population (9-15 years of age) to the efficacy population (females 16-26 years of age)?

## Questions for the Committee

- Do the safety data from studies 007, 013, 015, 016 and 018 support the safety of Gardasil for use in females 9-26 years of age?

## Questions for the Committee

- Please comment on post-marketing commitments.