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SUMMARY BASIS OF DECISION (SBD): GARDASIL™

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Contact: Centre for Biologics Evaluation


GARDASIL™

Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18)
Recombinant Vaccine
Merck Frosst Canada Ltd.
Submission Control No. 102682

Date Issued: 2007/03/16

Health Products and Food Branch

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Health Canada

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Health Products and Food Branch

╔galement disponible en franšais sous le titre : Sommaire des motifs de dÚcision (SMD), GARDASILMD, Vaccin recombinant quadrivalent contre le virus du papillome humain (types 6, 11, 16, 18), Merck Frosst Canada LtÚe., N░ de contr˘le de la prÚsentation 102682

FOREWORD

Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within reviewer reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document. These documents are all available on the Health Canada website.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. For information related to post-market warnings or advisories as a result of adverse events, interested parties are advised to access the Health Canada website.

For further information on a particular product, readers may also access websites of other regulatory jurisdictions, available under 'Related Links' on the Health Canada website. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Drug Policies and Guidance:

Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

TABLE OF CONTENTS

1 PRODUCT AND SUBMISSION INFORMATION

2 NOTICE OF DECISION

3 SCIENTIFIC AND REGULATORY BASIS FOR DECISION
3.1 Quality Basis for Decision
3.1.1 Drug Substance (medicinal Ingredient)
3.1.2 Drug Product
3.1.3 Facilities and Equipment
3.1.4 Adventitious Agents Safety Evaluation
3.1.5 Summary and Conclusion
3.2 Non-clinical Basis for Decision
3.2.1 Pharmacodynamics
3.2.2 Pharmacokinetics
3.2.3 Toxicology
3.2.4 Summary and Conclusion
3.3 Clinical Basis for Decision
3.3.1 Human Pharmacology
3.3.2 Clinical Efficacy
3.3.3 Clinical Safety
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
3.4.2 Recommendation

4 SUBMISSION MILESTONES


1 PRODUCT AND SUBMISSION INFORMATION

Brand Name: Gardasil™

Manufacturer/Sponsor: Merck Frosst Canada Ltd.

Medicinal Ingredient: Recombinant human papillomavirus (Types 6, 11, 16, 18) L1 protein

Common Name: Human papillomavirus vaccine [Types 6, 11, 16, 18] (recombinant, adsorbed)

Strengths: 1 dose contains:
20 Ág Type 6 L1 protein,
40 Ág Type 11 L1 protein,
40 Ág Type 16 L1 protein, and
20 Ág Type 18 L1 protein


Dosage form: Suspension

Route of Administration: Intramuscular

DIN: 02283190

Pharmaco-therapeutic group (ATC Code): Active immunizing agent

Non-medicinal Ingredients: Amorphous aluminium hydroxyphosphate sulphate adjuvant, sodium chloride, L-histidine, polysorbate 80 (PS-80), sodium borate, and water for injection

Submission Type and Control No.: New Drug Submission, Control No. 102682

Date of Submission: 2005/12/12

Date of Authorization: 2006/07/10

GARDASIL™ is a Trademark of Merck & Co., Inc. Used under license.

2 NOTICE OF DECISION

On July 10, 2006, Health Canada issued a Notice of Compliance to Merck Frosst Canada Ltd. for the vaccine product Gardasil™.

Gardasil™ is a quadrivalent Human Papillomavirus (HPV) (Types, 6, 11, 16, 18) recombinant vaccine and an active immunizing agent. Gardasil™ contains as active ingredients, highly purified virus-like particles (VLPs) of the recombinant major capsid (L1) protein of HPV types 6, 11, 16, and 18. As the VLPs do not contain viral DNA, they cannot infect cells or reproduce. Data from pre-clinical studies suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.

Gardasil™ is indicated in girls and women 9-26 years of age for the prevention of infection caused by the HPV (Types 6, 11, 16, and 18) and the following diseases associated with these HPV types: cervical cancer, vulvar and vaginal cancer, genital warts (condyloma acuminata), cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3, vulvar intraepithelial neoplasia (VIN) grades 2 and 3, and vaginal intraepithelial neoplasia (VaIN) grades 2 and 3.

Gardasil™ was reviewed under the Priority Review Policy as it offers a new prevention method of the indicated conditions that is expected to at least complement and augment the prevention of cervical cancer, through the existing screening program in Canada.

The market authorization was based on submitted data from quality control studies and a total of 10 pre-clinical studies and 12 clinical studies. The efficacy of Gardasil™ was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical studies. Gardasil™ was efficacious against HPV disease caused by each of the 4 HPV types contained in the vaccine. The efficacy of Gardasil™ in reducing the incidence of CIN (any grade, including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) was demonstrated in a population consisting of individuals who received all three vaccinations within one year of enrollment, did not have major deviations from the study protocol, and were na´ve (negative cervicovaginal specimens and seronegative) to the relevant HPV types (6, 11, 16, and 18) prior to the first dose and one month following the third dose.

Gardasil™ (quadrivalent human papillomavirus [types 6, 11, 16, 18] recombinant vaccine) is presented as a suspension for injection. Gardasil™ should be administered intramuscularly as three separate 0.5 mL-doses according to the schedule outlined in the dosing guidelines available in the Product Monograph. Gardasil™ is contraindicated for patients who are hypersensitive to the active substance or to any of the excipients of the vaccine. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of Gardasil™ should not receive further doses. Gardasil™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Detailed conditions for the use of Gardasil™ are described in the Product Monograph. Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Gardasil™ is favourable for the prevention of infection caused by the HPV (Types 6, 11, 16, and 18) and the following diseases associated with these HPV types: cervical cancer, vulvar and vaginal cancer, genital warts (condyloma acuminata), cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grades 1, 2, and 3, vulvar intraepithelial neoplasia (VIN) grades 2 and 3, and vaginal intraepithelial neoplasia (VaIN) grades 2 and 3 in girls and women 9-26 years of age.

3 SCIENTIFIC AND REGULATORY BASIS FOR DECISION

3.1 Quality Basis for Decision

3.1.1 Drug Substance (medicinal ingredient)

Manufacturing Process and Process Controls

The manufacturing process for the human papillomavirus (HPV) monovalent bulk adsorbed product (MBAP) consists of two main steps. In the first step, L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and are self assembled into virus-like particles (VLPs). In the second step, the VLPs for each type are purified to produce the final aqueous product (FAP). The FAP for each type of HPV is then adsorbed on aluminium-containing adjuvant to produce the MBAP.

The MBAP undergoes release tests for sterility, endotoxin, in vitro relative potency, aluminium, and pH. Critical tests and specifications were provided for all raw materials. Tests and acceptance criteria for the release of new working seed lots were also provided. All critical process controls are monitored during process validation.

The materials used in the manufacture of the drug substance are considered to be suitable for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

Characterisation

A summary of the test methods used to characterize the structure and critical epitopes of the purified HPV VLPs was provided. Testing was carried out on the FAP, MBAP, and in some cases, an in-process intermediate. The results confirm the primary protein structure, characterize the higher order structures, and demonstrate the relationship between the VLP structure and biological activity.

All validation lots met the requirements for clearance both of host cell impurities (DNA, RNA, lipid, and carbohydrate) and process residuals.

Control of Drug Substance

All validation lots met all acceptance criteria with the exception of one lot. This deviation did not adversely impact the quality or consistency of the production fermentation process. As a result of an investigation, minor modifications were made to correct this issue.

The bulk product is tested to verify the presence of degradation products and the release limits for individual and total degradation products are within acceptable limits. Validation reports are considered satisfactory for all analytical procedures used for in-process and release testing of the drug substance, and to justify the specifications of the drug substance. The proposed packaging components are also considered acceptable.

Stability

Stability studies performed on the cell slurry and the MBAP under long-term storage and on the MBAP under accelerated conditions support the proposed hold times and storage conditions.

Based upon the data submitted, the proposed shelf-life, storage, and shipping conditions for the drug substance are supported and considered to be satisfactory.

3.1.2 Drug Product

Description and Composition

Gardasil™ [quadrivalent human papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] has been developed for active immunization against cancer, pre-cancerous or dysplastic lesions, genital warts, and infection caused by the HPV types targeted by the vaccine. Gardasil™ is a sterile liquid suspension for intramuscular (IM) injection and is prepared from the highly purified VLPs of the recombinant major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The quadrivalent HPV VLP vaccine is prepared by combining the adsorbed VLPs of each HPV type, the aluminium-containing adjuvant formulation, and a buffer.

Gardasil™ contains HPV 6, 11, 16, and 18 L1 proteins in addition to the following excipients: amorphous aluminium hydroxyphosphate sulphate adjuvant, sodium chloride, L-histidine, polysorbate 80 (PS-80), sodium borate, and water for injection (WFI). The product contains no preservative or antibiotics. Gardasil™ is not a live virus vaccine. It contains no viral DNA and is not capable of causing infection. All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

The manufacturing process for the quadrivalent final container product (QFCP) in vials or syringes consists of two main steps: formulation and filling. A detailed description of the primary packaging was submitted. The glass vials and glass syringes are compliant with the European Pharmacopoeia (Ph.Eur.) Section 3.2.1 and United States Pharmacopoeia (USP) Section <661>. The stoppers are compliant with the chemical test requirements for Type I closures, as described in Ph.Eur. section 3.2.9. They also meet the physicochemical test requirements as listed in USP Section <381>. The syringe barrels can be equipped with a passive safety device.

Pharmaceutical Development

Several studies which justified the type and proposed concentration of excipient to be used in the drug product were reviewed and these verified that there are no potential toxicological or immunological effects expected. The specifications for all the ingredients are approved in accordance with either USP/NF or Ph.Eur. standards.

Changes were made to the manufacturing process during the development of Gardasil™. The most significant changes to the process were the introduction of the quadrivalent formulation and changing the filling from a manual to an automated process.

Gardasil™ is prepared from sterile components and is processed and filled aseptically. The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

Manufacturing Process and Process Controls

The QBAP is formulated and then aseptically filled into vials or syringes. After each vial or syringe is filled, it is inspected for defects. Quality control samples are taken during the fill. The filled syringes are fit with plunger rods and labelled. They may be inserted into safety devices. The assembled syringe or syringe/safety device may then be packaged with zero, one, or two sterile needles and inserted into cartons of one or more, along with a package circular.

The formulation, filling in vials, and filling in syringes were successfully validated. All equipment, operating parameters, in-process tests and detailed instructions are adequately defined in the documentation. The manufacturing process is considered to be adequately controlled within justified limits.

Control of Drug Product

The specification for the drug product was established based on regulatory guidelines, process capability, clinical experience, and full-scale manufacturing experience with licensed Merck vaccines. A list of analytical tests performed and the acceptance criteria to confirm the quality of the drug product has been provided.

Gardasil™ is tested to verify its identity, in vitro relative potency, sterility, pH, and the presence of microbiological impurities. The test specifications and analytical methods are considered acceptable. In addition, the shelf life and the release limits for individual and total degradation products are within acceptable limits.

Through Health Canada's lot release testing and evaluation program, three lots of consecutively manufactured final product lots were tested, evaluated, and found to satisfactorily meet the specification of the drug product and demonstrate consistency in manufacturing.

The review of the Lot Release Documentation is considered to be acceptable.

Stability

Based upon the real-time and accelerated stability study data submitted, the proposed 36 month shelf life at 2-8°C for Gardasil™ is considered acceptable for both the vial and syringe presentations. It has been recommended, however, that the manufacturer commit to provide updated stability data, especially for the syringe presentation, as it becomes available.

3.1.3 Facilities and Equipment

All manufacturing operations take place at a multi-product site which is approved for the manufacture of biological products for human health. The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

Each of the facilities involved in the manufacture of the drug substance and drug product was inspected by a qualified team of inspectors from the Biologics and Genetic Therapies Directorate of Health Canada. The on-site evaluation and the review of the responses to the Exit Notice observations were found to be satisfactory.

3.1.4 Adventitious Agents Safety Evaluation

Information on the avoidance and control of non-viral adventitious agents (transmissible spongiform encephalopathy agents, bacteria, mycoplasma, and fungi) has been provided. The various tests are listed for the working seed, fermentation product, MBAP, QBAP, and QFCP.

There are no cell lines of human or animal origin or any live viruses used in the manufacture of Gardasil™.

3.1.5 Summary and Conclusion

The quality information submitted was approved and a request for two post-approval commitments was made. It has been requested that the manufacturer provide stability data, as it becomes available, to support the shelf life of 36 months for the syringe presentation. In addition, updated stability data should be provided for all ongoing stability studies for the vial presentation.

The Chemistry and Manufacturing information submitted for Gardasil™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

3.2 Non-clinical Basis for Decision

3.2.1 Pharmacodynamics

The pharmacological assessment of Gardasil™ was focused on the evaluation of the primary pharmacodynamics (PDs) in three species of non-human primates including: rhesus macaques, chimpanzees, and African green monkeys. The objectives of the studies were: to determine whether an HPV VLP specific immune response was elicited by the vaccine, to examine the duration of the response, and to determine whether the Merck Aluminium Adjuvant (MAA) was needed for optimal immunogenicity. The studies were also designed to determine whether the antigenicity of the four VLPs within Gardasil™ were similar and whether the immune response to each VLP when mixed together in a quadrivalent formulation was similar to that achieved by vaccination with a monovalent VLP formulation. The immune response was monitored using a competitive radioimmunoassay (cRIA) or a competitive ELISA method (cEIA).

In each of the three non-human primate species tested, the intramuscular (IM) administration of Gardasil™ or its monovalent components was found to be well tolerated and to elicit robust immune responses resulting in production of antibodies against the HPV VLP types present in the vaccine. The studies also showed that the MAA is necessary to induce an increased immune response against the vaccine antigens. The African green monkeys mounted a specific antibody response within an order of magnitude of each other to each HPV type (6, 11, 16, and 18). The titers generated by the quadrivalent vaccine, however, were slightly lower than those elicited by the monovalent formulation. The sponsor explained that this result is not uncommon as different assays were used to evaluate the different HPV types and the level of immune response elicited by one HPV type cannot be directly compared to the titer of another HPV type. In addition, all the assays used were competitive and therefore, the affinity of the monoclonal antibody used plays a role in the range of titers seen for a given type.

Serum antibodies to all four HPV types were shown to neutralize pseudovirus infection of a cervical carcinoma cell line (C33A) demonstrating the potential of HPV VLP vaccine to protect against HPV infection.

3.2.2 Pharmacokinetics

Non-clinical pharmacokinetic (PK) studies are not directly applicable to vaccines.

3.2.3 Toxicology

Acute Toxicity

Administration of Gardasil™ to mice and rats in a single-dose toxicity study at a dose representing an approximate 1200-fold excess in mice and a 300-fold excess in rats (relative to the projected human dose) was well tolerated. There were no treatment-related effects on mortality, physical signs, or body-weight over a 14-day observation period.

Repeat-dose Toxicity

Administration of Gardasil™ to mice in a repeat-dose toxicity study, at a dose representing approximately 1450-fold the projected human dose showed no adverse effects other than slight inflammation at the injection site and hyperplasia in the draining lymph nodes. There were no treatment-related antemortem findings or evidence of aluminium-induced systemic toxicity.

Reproductive and Developmental Toxicity

Reproductive and developmental toxicity were assessed in female rats prior to mating as well as during gestation and lactation. Gardasil™ was administered at a dose representing approximately 300-fold the projected human dose. Assessment of embryonic/fetal survival, fetal body weight, and fetal external, visceral, coronal, and skeletal morphology indicated no evidence of developmental toxicity. There were no treatment-related effects on developmental signs, behaviour, reproductive performance, or fertility of the offspring. In addition, antibodies against all four HPV types were transferred to the offspring during gestation and possibly lactation.

Carcinogenicity and Mutagenicity

Carcinogenicity and mutagenicity studies are normally not necessary for vaccines.

Local Tolerance

Local tolerance of Gardasil™ was assessed by IM administration in rabbits. A dose equivalent to the human therapeutic dose was administered representing up to a 40-fold excess by body-weight. The vaccine was generally well tolerated, with no treatment-related effects on mortality, physical signs, or body-weight over a 14-day observation period. Minimal irritation was observed at the injection sites. The severity of the local histopathology reaction was only slight, however, and closely resembled that caused by the aluminium adjuvant placebo control.

3.2.4 Summary and Conclusion

The studies conducted in the non-clinical program provided information on the safety and immunogenicity of Gardasil™ and support the use of the vaccine in clinical studies. In conclusion, Gardasil™ was generally well tolerated with no occurrence of serious adverse effects.

3.3 Clinical Basis for Decision

3.3.1 Human Pharmacology

The clinical program included studies with monovalent HPV 11, 16, and 18 L1 VLP vaccines, as well as studies which evaluated formulations of quadrivalent HPV (Types 6, 11, 16, and 18). Studies of monovalent HPV 6 vaccine were not conducted as the safety profile of this vaccine component was expected to be similar to that of the HPV 11 L1 VLP vaccine given that these proteins are very similar. The pharmacodynamics of Gardasil™ were assessed through the analysis of immunogenicity and are described in section 3.3.2. Pharmacokinetic studies are generally not required for injectable vaccines.

3.3.2 Clinical Efficacy

A total of 12 clinical studies (4 pivotal and 8 non-pivotal) were submitted to support the authorization of Gardasil™. The four pivotal studies (P005, P007, P013, and P015) were placebo-controlled, double-blind, randomized, Phase II and III clinical studies. Studies P005 and P007 were both Phase II studies. P005 evaluated the HPV 16 component of Gardasil™ while P007 evaluated all components of Gardasil™. The Phase III studies P013 and P015, were termed FUTURE (Females United to Unilaterally Reduce Endo/Ectocervical Disease) I and FUTURE II respectively. In total, these four studies evaluated 20 541 women who were 16-26 years of age at enrollment. The median duration of follow-up was 4.0, 3.0, 2.4, and 2.0 years for P005, P007, FUTURE I, and FUTURE II, respectively. Subjects received either the vaccine or a placebo on the day of enrolment, and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies combined.

Table 1 - Subject Demographics and Trial Design for Pivotal Clinical Efficacy Trials
Study # Trial Design Dosage, route of administration and duration Study Subjects (n=number) Gender, Mean Age (Range)

005

Randomized, double-blind, multicentre, placebo-controlled trial

(1) HPV 16 L1 VLP vaccine (40 mcg/0.5mL)

(2) Placebo

Intramuscular injection
3 doses of 0.5 mL

(1) Vaccine
n=1193

(2) Placebo
n=1198

Female,
21.5 years
(16 to 23 years)

007

Part A:
Randomized, double-blind, multicentre, placebo-controlled, dose-escalating trial














Part B:
Randomized, double-blind, multicentre, placebo-controlled, dose-ranging trial

Part A:

(1) Placebo (225mcg/0.5mL)

(2) Placebo (450mcg/0.5mL)

(3) Gardasil™ (20/40/40/20mcg/0.5mL)

(4) Quadrivalent HPV
(Types 6, 11, 16, 18) L1 VLP vaccine (40/40/40/40mcg/0.5mL)

(5) Quadrivalent HPV
(Types 6, 11, 16, 18) L1 VLP vaccine (80/80/40/80mcg/0.5mL)

Intramuscular injection
3 doses of 0.5 mL

Part B:
Same as Part A.



(1) Placebo (225mcg/dose)
Part A - n=11
Part B - n=135

(2) Placebo (450mcg/dose)
Part A - n=6
Part B - n=140

(3) Vaccine
(20/40/40/20mcg/dose)
Part A - n=13
Part B - n=276

(4) Vaccine
(40/40/40/40mcg/dose)
Part A - n=10
Part B - n=272

(5) Vaccine
(80/80/40/80mcg/dose)
Part A - n=12
Part B - n=280

Part A:
Female,
20.5 years
(18 to 23 years)
















Part B:
Female,
20.0 years
(13 to 24 years)

013

Randomized, double-blind, placebo-controlled, multicentre, multinational trial

(1) Gardasil™
(20/40/40/20mcg/0.5mL)

(2) Placebo

Intramuscular injection
3 doses of 0.5mL

(1) Vaccine
n=2717

(2) Placebo
n=2725

Female,
20.3 years
(16 to 24 years)

015

Randomized, double-blind, placebo-controlled, multicentre, multinational trial

(1) Gardasil™
(20/40/40/20mcg/0.5mL)

(2) Placebo

Intramuscular injection
3 doses of 0.5mL

(1) Vaccine
n=6082

(2) Placebo
n=6075

Female,
19.9 years
(15 to 26 years)

The endpoints in the clinical development program for Gardasil™ were divided into endpoints related to the cervix and endpoints related to other genital organs. This was due to the fact that cervical cancer and the dysplastic lesions that precede it are the most common and prognostically important lesions caused by genital HPV infection. In addition, the anatomy of the cervix differs from that of the remaining genital organs.

The authorization of a new vaccine should be predicated on a robust demonstration of the vaccine's efficacy against the most important clinical disease caused by the pathogen targeted by the vaccine. In the case of high-risk oncogenic HPV types such as HPV 16 and HPV 18, that disease is cervical cancer. However, a Phase III clinical trial to demonstrate the efficacy of a prophylactic HPV 16/18 vaccine using a cervical cancer endpoint is not feasible because: (1) the median time from acquisition of infection to the development of cervical cancer is greater than 20 years; and (2) the standard of care worldwide is to screen women for cervical intraepithelial neoplasia and to excise these lesions prior to the development of cancer. In the context of a clinical trial, women must receive the highest level of care. Thus, it is unethical to allow subjects to remain unscreened and untreated solely for the purposes of a cancer efficacy evaluation.

Cervical intraepithelial neoplasia 2/3 (CIN 2/3) and cervical adenocarcinoma in situ (AIS) are the immediate and necessary precursors of invasive squamous cell carcinoma and invasive adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent invasive cancer (secondary prevention), thus, they serve as surrogate markers for the prevention of cervical cancer. Vulvar intraepithelial neoplasia 2/3 (VIN 2/3) and vaginal intraepithelial neoplasia 2/3 (VaIN 2/3) are the immediate precursors to HPV-related vulvar and vaginal cancer, respectively.

Summary of Results from Pivotal Studies

Protocol 005: Study of Pilot Manufacturing Lot of HPV 16 VLP Vaccine in the Prevention of HPV 16 Infection

A total of 2391 healthy female patients between the ages of 16 to 23 were randomized in this multicentre study. The primary objectives were to demonstrate the safety and tolerability of three doses of HPV 16 L1 VLP vaccine and to demonstrate its ability to prevent persistent HPV 16 infection as compared to a placebo.

The participants in this study were HPV 16 na´ve at enrolment and remained HPV 16 DNA negative through the completion of the vaccination regimen. The results of this study suggest that the administration of a three-dose, 40 mcg regimen of HPV 16 L1 VLP vaccine to these subjects:

  • substantially reduces the risk for acquisition of persistent HPV 16 infection
  • prevents development of HPV 16-related CIN (including HPV 16-related CIN 2/3

Without the consideration of HPV 16 status or Pap test results at enrolment, the regimen reduces the overall risk for development of CIN as well as the risk for development of CIN 2/3 but does not result in protection from, or enhanced acquisition of, infection with HPV 6, 11, or 18.

With respect to immunogenicity, the administration of a three-dose, 40 mcg regimen of HPV 16 L1 VLP vaccine to subjects who adhered to the 0, 2, 6 month vaccination regimen resulted in robust anti-HPV 16 responses four weeks following the completion of the vaccination regimen. These immune responses remain durable through 3.5 years thereafter, however, larger studies will be required to confirm these preliminary observations.

Protocol 007: Dose-Ranging Study of Quadrivalent HPV VLP Vaccine

This multicentre study was divided into two parts. Part A was a sequential dose-escalating evaluation while Part B was a dose-ranging study. A total of 1155 healthy females 13 to 24 years of age from the United States, Latin America, and Europe were randomized into the study.

The primary study objective for Part A was to investigate the general tolerability of the quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine. The primary study objectives for Part B were the same as for Part A with one addition. Part B sought to identify formulations combining HPV 6, 11, 16, and 18 VLPs that, when administered by IM injection in a three-dose regimen, result in acceptable, type-specific, anti-HPV responses. The findings of the study indicate that the risk for acquisition of persistent HPV 6, 11, 16 or 18 related infection or genital disease is substantially reduced with use of this vaccine regimen. Additionally, the development of the composite endpoint of HPV 6, 11, 16 or 18 related CIN or external genital lesion (EGL) is substantially reduced following administration of a three-dose regimen of quadrivalent HPV vaccine.

With respect to immunogenicity, a robust anti-HPV 6, 11, 16, and 18 response occurred four weeks following completion of the vaccination regimen. Durable anti-HPV 6, 11, 16, and 18 responses through 2.5 years following completion of the vaccination regimen were generated.

Protocol 013: Study to Evaluate the Efficacy of Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP Vaccine in Reducing the Incidence of HPV (Types 6, 11, 16, 18)-Related CIN, AIS, and Cervical Cancer, and HPV (Types 6, 11, 16, 18)-Related External Genital Warts, VIN, VaIN, Vulvar Cancer, and Vaginal Cancer - The FUTURE I Study

A total of 5442 subjects were randomized in this multinational efficacy study which was conducted in North America, Latin America, Europe, and Asia-Pacific.

The primary study objectives were to demonstrate that a three-dose regimen of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine is generally well tolerated and that IM administration of this regimen reduces the incidence of the composite endpoint of HPV (Types 6, 11, 16, 18)-related cervical dysplasia (any grade CIN), AIS, orcervical cancer, compared with placebo, among women na´ve to the relevant vaccine HPV type at baseline. In addition, the primary objectives included the demonstration that IM administration reduces the incidence of the composite endpoint of HPV (Types 6, 11, 16, 18)-related external genital warts, VIN, or VaIN, vulvar cancer, or vaginal cancer compared with placebo, among women na´ve to the relevant vaccine HPV types at baseline.

Prophylactic administration Gardasil™ is highly efficacious in preventing the development of:

  • HPV 6, 11, 16 and 18-related CIN (any grade); HPV 16 and 18-related CIN 2/3 or AIS, thereby, preventing the development of HPV 16 and 18-related cervical cancer.

  • HPV 6, 11, 16, 18-related external genital warts; HPV 6, 11, 16, 18-related VIN 2/3 and VaIN 2/3, thereby, preventing the development of HPV 16 and 18-related vulvar and vaginal cancer.

Evidence of protection appears during the period in which the three-dose vaccination regimen is being administered. Administration of Gardasil™ to sexually naive girls and women reduces the risk for development of an HPV-related EGL.

With respect to immunogenicity, the administration of Gardasil™ generates robust and durable anti-HPV 6, 11, 16, and 18 responses through approximately 1.5 years following completion of the vaccination regimen.

Protocol 015: A Study to Investigate the Safety, Immunogenicity, and Efficacy on the Incidence of HPV 16/18-Related CIN 2/3 or Worse of the Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP Vaccine - The FUTURE II Study

This multicentre, multinational efficacy study was conducted in North America, Latin America, Europe and Asia-Pacific. A total of 12,157 women 15-26 years of age were randomized into the study.

There were two parts to this study. In the first part, the primary study objective was to demonstrate that the final manufacturing process (FMP) results in a quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine that, when given in a three-dose regimen, induces consistent serum anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 responses one month post the third dose.

The primary study objectives of the second part were to:

  • Demonstrate that a three-dose regimen of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine is generally well tolerated

  • Demonstrate that IM administration of a three-dose regimen of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine reduces the incidence of the composite endpoint of HPV 16- and 18-related high-grade cervical abnormalities (CIN 2/3) or HPV 16- and 18-related invasive cervical carcinoma in subjects who are PCR negative and seronegative at baseline and PCR negative through Month 7 for the relevant HPV type

The study concluded that the prophylactic administration of Gardasil™ is highly efficacious in preventing the development of HPV 16- and 18- related CIN 2, CIN 3, or AIS, thereby preventing the development of HPV 16- and 18-related invasive cervical cancer; HPV 6, 11, 16, 18-related VIN 2/3 and VaIN 2/3, thereby preventing the development of HPV 6, 11, 16, and 18 related vulvar and vaginal cancer; HPV 6, 11, 16, and 18-related CIN; and HPV 6, 11, 16, and 18-related EGLs. Evidence of protection appears during the period in which the three-dose vaccination regimen is being administered.

Administration of Gardasil™ to women who are naive to the relevant HPV types at initiation and remain PCR negative through the completion of the vaccination regimen generates robust and durable anti-HPV responses through approximately 1.5 years following completion of the vaccination regimen.

For all vaccine components, administration of a three-dose regimen (0, 2, 6 months) of quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine from three separate consistency lots of the final manufacturing process to 16 to 26 year old women induces consistent type-specific Month 7 anti-HPV competitive luminescence immunoassay (cLIA)responses (including geometric mean titres [GMTs] and seroconversion rates).

Combined Analyses of Pivotal Study Results

The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population consisting of individuals who received all three vaccinations within one year of enrolment, did not have major deviations from the study protocol, and were na´ve

(PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose one and through one month post-dose three (Month 7). Efficacy was measured starting after the Month 7 visit.

Protocols 005, 007, 013, and 015 provided data of the efficacy of Gardasil™ in reducing the incidence of the following clinical endpoints in subjects who were PCR negative and seronegative at baseline:

  • HPV 6/11/16/18-related CIN (all grades, and by specific grade)
  • PV 6/11/16/18-related genital warts, VIN, and VaIN (all severities, and by specific severity)

The validity of the endpoints was ensured by the use of the consensus diagnosis or determination of endpoints in the clinical trials.

Gardasil™ is a prophylactic vaccine and was found to be efficacious against HPV disease caused by each of the four vaccine HPV types. With respect to subjects with a current or prior HPV infection, there was no clear evidence of protection from disease caused by HPV types for which these subjects were PCR positive and/or seropositive at baseline. Gardasil™ does not prevent infection with other HPV types not contained in the vaccine and will not treat existing disease caused by the HPV types contained in the vaccine. Cases of disease caused by non-vaccine types were observed among subjects receiving Gardasil™ and placebo in Phase II and Phase III efficacy studies.

Immunogenicity

The duration of immunity following a complete schedule of immunization with Gardasil™ has not been established.

The immunogenicity of Gardasil™ was assessed in 8915 women (18-26 years old) and 3400 male and female adolescents (9-17 years old).

More than 99.5% of all individuals who received Gardasil™ became seropositive for each vaccine HPV type four weeks post-dose three, with high anti-HPV GMTs (substantially higher than those measured in women who presumably mounted an immune response that

led to clearance of the infection). It is important to note that the minimum anti-HPVGMT levels that provide protection against clinical HPV disease have not been determined and no immune correlate for protection against HPV infection has been established. It is not known whether subjects who mount an immune response to Gardasil™ and then lose detectable anti-HPV GMT later, continue to be protected from infection or disease. There were, however, no cases of breakthrough infection or disease in the persistence phase of the Phase III efficacy studies.

The overall efficacy of Gardasil™ will depend on the baseline prevalence of HPV infection related to vaccine types in the population vaccinated and the incidence of HPV infection due to types not included in the vaccine.

3.3.3 Clinical Safety

The twelve clinical studies used to assess efficacy were also used to evaluate the safety of Gardasil™. Two of the four pivotal studies (P007 and P013 - described above) are ongoing.

Throughout clinical testing, the overall adverse events (AEs) reported by subjects indicated that administration of Gardasil™ is generally well tolerated. The use of Gardasil™ was associated with increased injection-site AEs (most mild in intensity) and a modest increase in the incidence of transient low-grade fevers, compared with placebo. The proportion of subjects who reported serious AEs was comparable between the two vaccination groups.

The most commonly reported injection-site AEs were pain, swelling, and erythema. The proportion of subjects reporting an injection-site AE within 15 days of receiving any vaccination was higher in subjects who received Gardasil™ compared with subjects who received aluminium-containing placebo or non-aluminium-containing placebo. Notably, of the subjects who reported an injection-site AE, there was a large difference between Gardasil™ recipients and the non-aluminium-containing placebo group, as compared to that between those receiving Gardasil™ and the aluminium-containing placebo group. It is important to note, however, that all subjects who received the non-aluminium-containing placebo were aged 9 to 15 at enrolment, a group that generally reported fewer AEs following administration of either vaccine as compared to older aged populations. Nevertheless, the magnitude of the differences indicates that, of the two active components of the vaccine (aluminium adjuvant and HPV L1 VLPs), the adjuvant is more reactogenic.

The proportion of subjects who reported a systemic AE, and the proportion of the subjects who reported a vaccine-related systemic clinical AE, were comparable between the two vaccination groups.

Male subjects older than 15 years of age at enrollment were not studied in the initial Phase III studies. Due to the fact that the safety of Gardasil™ in 9- to 15-year-old boys was shown to be generally comparable to the safety of Gardasil™ in 9- to 15-year-old girls and 16- to 23-year-old adolescent and young adult women, it could be inferred that the safety of the vaccine in 16- to 23-year-old adolescent and young adult men will be comparable. Further clinical trials of Gardasil™ in 16- to 26-year-old boys and men are ongoing.

The safety and efficacy of Gardasil™ has not been evaluated in children younger than 9 years of age, nor in adults above the age of 26 years. Gardasil™ is contraindicated for patients who are hypersensitive to any of the excipients of the vaccine. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of Gardasil™ should not receive further doses of Gardasil™.

Special Populations

Pregnancy

It is not known whether vaccination with Gardasil™ is harmful to an unborn baby when administered to a pregnant woman. The use of the vaccine is not recommended during pregnancy. Women who become pregnant before completion of the three-dose schedule should complete the vaccination schedule after childbirth.

An independent expert reviewed each of twenty-five cases of congenital anomalies that occurred throughout the clinical studies (13 in the Gardasil™ group and 12 in the placebo group) for pathogenesis and any relationship to vaccination. It was determined that it was unlikely that any of the cases of congenital anomaly were causally related to vaccination. The safety profile will be completed by long-term follow-up studies. With the submission, the sponsor has included a pharmacovigilance plan.

A pregnancy outcome summary for various protocols was included in this submission. Overall, 1901 subjects experienced 2074 pregnancies. Outcomes were known for 1619 (78.1%) of the pregnancies. The summary indicates that the proportion of pregnancies that resulted in a live birth was higher among subjects who received Gardasil™ compared with the placebo group. Among the live births, the proportion of infants in whom a medical condition was detected was somewhat higher in subjects who received Gardasil™ compared with subjects who received placebo. The proportions of pregnancies with known outcomes that resulted in a normal infant were comparable between vaccination groups. Fetal loss occurred more often in subjects in the placebo group compared with subjects in the group that received Gardasil™. The proportion of spontaneousabortions among the live births and non-elective pregnancy losses (i.e., spontaneous abortions and late fetal deaths) was lower in the group that received Gardasil™ (20.9%) compared with
the placebo group (28.3%). The rate of overall spontaneous pregnancy loss (spontaneous abortions and late fetal deaths) was lower in the group that received Gardasil™ (21 of 91, or 23.1%) compared with the placebo group (26 of 92, or 28.3%). The proportion of subjects who experienced fetal loss and a medical condition related to the fetus was higher in the placebo group compared with the group that received Gardasil™.

Nursing Women

Gardasil™ may be administered to lactating women, however, it is not known whether vaccine antigens or antibodies induced by the vaccine are excreted in human milk. In one study 995 nursing women received Gardasil™. Rates of AEs in the mother and the nursing infant were comparable between vaccination groups. In addition, vaccine immunogenicity was comparable among nursing mothers and women who did not nurse during the vaccine administration.

In clinical studies, a higher number of breast-feeding infants (n = 6) whose mothers received Gardasil™ had acute respiratory illnesses within 30 days post-vaccination of the mother as compared to infants (n = 2) whose mothers received placebo. In these studies, the rates of other AEs in the mother and the nursing infant were comparable between vaccination groups.

HIV-infected Individuals

The safety, immunogenicity, and efficacy of Gardasil™, have not been evaluated in HIV-infected individuals.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

The overall objective of the sponsor's HPV vaccine program is to develop a quadrivalent vaccine that reduces the incidence of infection with common HPV types and the clinical pathology associated with these infections.

An important question related to the impact of the administration of vaccines targeting common HPV types on overall rates of CIN and cervical cancer is whether elimination of HPV types targeted by such vaccines will result in increases in the incidence of infection with non-vaccine HPV types (i.e. replacement of vaccine HPV types with non-vaccine HPV types). Indirect evidence from natural history studies has shown that infection with one HPV type does not preclude or inhibit infection with other HPV types. The submitted studies were not designed and powered for this.

The vaccine tested in these studies has several limitations:

  1. The vaccine offers no protection against other HPV types that can also cause cervical cancer.

  2. It is unknown whether the vaccine's protection against oncogenic HPV 16, 18 is long-lasting.

  3. It does not prevent HPV 16 and 18 infections already present at the time of vaccination from progressing to cancer.

  4. The efficacy data obtained in female subjects 16 to 23 years of age were bridged to subjects 9 to 15 years by demonstrating non-inferiority of immunogenic data obtained in the younger group compared with the older group.

  5. The vaccine has not been studied in pregnant women in randomized, placebo-controlled studies. The impact of Gardasil™ on pregnancy outcomes was, however, assessed in the Phase III studies.

A proportion of HPV-infected women will clear an HPV infection without any intervention beforedeveloping cervical cancer or other related lesions. HPV infection is not close in the temporal sequence of disease progression to cervical cancer, and HPV infection itself is asymptomatic and does not require treatment. CIN 2 is close in the temporal sequence of disease progression to invasive cervical cancer, therefore, the sponsor found it reasonable to assume that a vaccine that is shown to prevent the development of CIN 2/3 or AIS lesions will likewise result in reductions in cervical cancer incidence.

Definitive, confirmatory efficacy and safety data will not be available until ongoing and future trials are completed. The submission provides data from well controlled clinical trials establishing that the vaccine has an effect on a surrogate endpoint that was based on epidemiologic, therapeutic, and pathophysiological data.

The claimed 100% efficacy was proven in the PPE population. This is a very selective population that was obtained by applying a number of exclusion criteria. Also, the primary objectives of the clinical studies were studied only in a na´ve population. Long term follow-up is required to confirm the significance of the findings from clinical trials and to evaluate the duration of efficacy for each component of the quadrivalent HPV vaccine. Scandinavian subjects in Protocol 015 will be followed for 10 years to evaluate the duration of effectiveness. The need for a booster is not known. It is, therefore, important to obtain information on long-term immunogenicity and/or
effectiveness to determine whether the young population of 9-to 15-years old will be protected adequately over the long-term or whether a booster dose should be considered.

Prophylactic administration of a three-dose regimen of Gardasil™ to 16- to 26- year-old women is effective in preventing infection caused by HPV Types 6, 11, 16, and 18 and the following diseases associated with these HPV types: cervical cancer, vulvar and vaginal cancer, genital warts (condyloma acuminate), cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3, vulvar intraepithelial neoplasia (VIN) grades 2 and 3, and vaginal intraepithelial neoplasia (VaIN) grades 2 and 3.

Gardasil™ was granted Priority Review status as it fulfilled the conditions of the Priority Review Policy in that it provides effective prevention of a disease or condition for which no drug is presently marketed in Canada. Gardasil™ offers a new prevention method of the previously indicated conditions that is expected to at least complement and augment the prevention of cervical cancer, through the existing screening program in Canada.

Commitments and Recommendations

The following commitments were accepted by the sponsor as part of the authorization of Gardasil™:

  • To provide the results of the short-term U.S. safety study to be completed by December 21, 2008, as soon as the results become available and any safety signal that may be detected during the conduct of this study.

  • To provide regular interim reports from the Nordic Cancer Registry Study, as well as the final study report, as part of a plan to address the lack of information regarding long-term efficacy and the persistence of protection against the type specific HPV infections in Gardasil™.

  • To submit to the Biologics and Genetic Therapies Directorate, Health Canada, final study reports for Protocols 007, 013, 015, and 018 as soon as they become available.

  • To put in place a Registry for Canadian women who become pregnant during or shortly after receiving the Gardasil™ vaccination regimen. Plans for the registry must include clear instructions for vaccinated women to report such pregnancies, their outcome, and any associated AEs. In addition, analysis of data from the Canadian and other pregnancy registries to be established in the United States and Europe should be submitted on a regular basis. The analysis should include relevant AEs and maternal and fetal safety issues, as well as pregnancy outcomes.

  • Stability data will be provided (when available) to support the shelf life of 36 months for the syringe presentation. At this point, only 24 months are available.

  • Updated stability data for all ongoing stability studies for the vial presentation will be provided as they become available.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Gardasil™ is favourable in girls and women 9-26 years of age for the prevention of infection caused by the human papillomavirus (HPV) Types 6, 11, 16, and 18 and the following diseases associated with these HPV types: cervical cancer, vulvar and vaginal cancer, genital warts (condyloma acuminate), cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3, vulvar intraepithelial neoplasia (VIN) grades 2 and 3, and vaginal intraepithelial neoplasia (VaIN) grades 2 and 3. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.

4 SUBMISSION MILESTONES

Pre-submission meeting: 2005/10/28

Request for priority status

  • Filed: 2005/11/14
  • Approval issued by Director of the Centre for Biologics Evaluation: 2005/12/15

Submission filed: 2005/12/12

Screening

  • Screening Acceptance Letter issued: 2006/01/12

Review

  • On-Site Evaluation: 2006/06/12-16
  • Quality Evaluation complete: 2006/07/07
  • Clinical Evaluation complete: 2006/07/10
  • Labelling Review complete: 2006/07/05
  • NOC issued by Director General: 2006/07/10