Descriptive, Post-marketing, Surveillance Safety

Study of Menactra® Vaccine

By Meriem Taib Presented at AAPS, November 2015

Public Document available at clinicaltrials.gov

Research Program Director: Professor Peivand Pirouzi

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• Menactra® quadrivalent meningococcal ACYW-135 conjugate vaccine is indicated for active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135 conjugated to Diphtheria Toxoid protein

• Menactra® is approved for use in individuals 9 months through 55 years of age

• Dosage is a sterile, aqueous solution contains 4 μg of each meningococcal A, C, Y, and W-135 polysaccharides conjugated to a total of approximately 48 μg of Diphtheria Toxoid protein carrier

• Menactra® vaccine should be administered as a single 0.5 mL injection by the intramuscular route

• Menactra® approved by FDA in 2005 and licensed in Canada in 2006

• The vaccine was developed by Sanofi Pasteur a Sanofi company

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The Advisory Committee on Immunization Practices (ACIP) recommends:

Routine vaccination at age 11 or 12 years, with a booster dose at age 16 years

Vaccination for high risk individuals aged 9 months through 55 years

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Safety Information

• The most common adverse reactions include injection site pain, redness, and induration (all age groups); irritability, crying, drowsiness, loss of appetite, and diarrhea (infants and children); headache, fatigue, and malaise (adolescents and adults)

• Menactra vaccine is contraindicated in persons with known hypersensitivity to any component of the vaccine

• Persons previously diagnosed with Guillain-Barré syndrome (GBS) may be at increased risk of GBS following receipt of Menactra vaccine

• Vaccination with Menactra vaccine may not protect all individuals

*Guillain-Barré syndrome (GBS) is an acute autoimmune inflammatory disorder of the peripheral motor and/ or sensory nerves

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TABLE OF CONTENTS

1. INTRODUCTION

2. STUDY OBJECTIVES AND ENDPOINTS

3. STUDY DESIGN

4. STUDY POPULATION

4.1. Inclusion Criteria

4.2. Exclusion Criteria

5. STUDY TREATMENT AND DURATION

6. STUDY PROCEDURES

6.1. Data Source

6.2. Data Compilation Procedure

7. DATA ANALYSIS/STATISTICAL METHODS

7.1. Sample Size Calculation

7.2. Data Analysis

8. DATA COLLECTION AND DATA MANAGEMENT

8.1. Access to Data

8.2. Record Retention

9. ADVERSE EVENT REPORTING AND SERIOUS ADVERSE EVENT REPORTING

10. QUALITY CONTROL AND QUALITY ASSURANCE

11. ETHICS

11.1. Institutional Review Board IRB / Independent Ethics Committee (IEC)

11.2. Ethical Conduct of the Study

11.3. Subject Information and Consent

12. COMMUNICATION AND PUBLICATION OF STUDY RESULTS

13. REFERENCES

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1. INTRODUCTION

• Menactra® (Meningococcal [Groups A, C, Y and W-135] Polysaccharide Diphtheria Toxoid Conjugate Vaccine) is the only quadrivalent licensed conjugate vaccine for persons 9 months through 55 years of age for active immunization against IMD caused by N meningitidis serogroups A, C, Y, and W-135

• Since it was first licensed in the U.S. by FDA in 2005, more than 30 million doses of Menactra vaccine have been distributed in US followed by Canada in 2006 and now approved in over 30 countries

• This cohort study is a Post-licensure Safety Surveillance Study of Routine Use of Meningococcal (Groups A, C, Y, and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine (Menactra ™)

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Background • Concern for GBS as a safety signal shortly after licensure

• Guillain-Barré syndrome (GBS) is an acute neurologic disorder involving inflammatory demyelination of peripheral nerves

• 5 reports of GBS in VAERS* in the first 7 months of 2005

*VAERS The Vaccine Adverse Event Reporting System (VAERS) is a national vaccine safety surveillance program co-sponsored by the Centers for Disease Control and Prevention CDC and FDA.

VAERS is a post-marketing safety surveillance program, collecting information about adverse events (possible side effects) that occur after the administration of vaccines licensed for use in the United States

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2. STUDY OBJECTIVES AND ENDPOINTS

Objectives

• To further characterize the safety profile of Menactra vaccine, Guillain-Barré syndrome (GBS) as early safety concern

• To identify any signals of potentially vaccine-related adverse events (AEs) not detected during pre-licensure studies

Endpoints

• All emergency room visits and hospitalizations

• Outpatient visits for specified neurological conditions, hypersensitivity reactions, and new-onset autoimmune diseases

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3. STUDY DESIGN

• Retrospective, observational safety study conducted in Kaiser Permanente Northern California

• Self-controlled cohort analysis comparing risk interval 30 days after vaccine with control interval 31-60 days after vaccine

• Matched cohort design with historical control with 6-month follow-up period

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4. STUDY POPULATION

Past receipt of Menactra vaccine

4.1. Inclusion Criteria

Receipt of Menactra vaccine

4.2. Exclusion Criteria

There is NO exclusion criteria

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5. STUDY TREATMENT AND DURATION

• This is a descriptive, Post-licensure Safety Surveillance Study of Routine

Use of Meningococcal (Groups A, C, Y, and W-135) Polysaccharide

Diphtheria Toxoid Conjugate Vaccine (Menactra ™)

• There is no study mandated dosing or duration requirement

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6. STUDY PROCEDURES

6.1. Data Source

• The data source for this study will be the Vaccine Safety Datalink (VSD) is a collaborative project between CDC's Immunization Safety Office and nine health care organizations (one of the them is Kaiser Permanente Northern California)

• The VSD started in 1990 and continues today in order to monitor safety of vaccines and conduct studies about rare and serious adverse events following immunization

• Large, linked healthcare database including 9.5 million patients aged 11-18 years old from 2005-2008 ; 1.4 million (15%) had received Menactra

* CDC Centers for disease Control and Prevention

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6.2. Data Compilation Procedure

• Menactra Vaccine Recipients Participants who received Menactra vaccine as part of routine medical care during the study period in Kaiser Permanente

• Age-Matched Control Each individual receiving Menactra vaccine served as their own control for evaluation

• Databases were reviewed to identify persons who received Menactra vaccine within Kaiser Permanente and to identify all medical care events for the 6-month period following vaccination. Subjects served as their own control for 0-30 days surveillance, age-matched control served for the 6-month period

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7. DATA ANALYSIS/STATISTICAL METHODS

7.1. Sample Size Calculation

• This is a descriptive study of drug usage without any pre-defined hypothesis to be tested. Therefore, no power calculation is relevant

• All individual patients identified to have received Menactra in the Kaiser Permanente databases in the study period will be included in the study without any sampling procedure

• The actual numbers enrolled in the study around 62626

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7.2. Data Analysis

• No formal hypothesis tested

1660 comparisons by diagnostic code and age

• Preliminary results showed 21 (1.3%) of the comparisons between the risk and control intervals significantly elevated and 44 (2.7%) significantly decreased

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8. DATA COLLECTION AND DATA MANAGEMENT

8.1. Access to Data

• The Sponsor Sanofi Pasteur will not have access to health register records at the level of the individual patient but only to tables with aggregated data

• In case of an audit from a regulatory authority or Sanofi, the investigator Kaiser Permanente Northern California will be able to document the data processing and statistical analysis and thus verify the reported results

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8.2. Record Retention

• To enable evaluations and/or audits from regulatory authorities or Sanofi, the investigator Kaiser Permanente Northern California agrees to keep records, relevant correspondence (e.g., letters, meeting minutes, telephone calls reports)

• The records should be retained by the investigator Kaiser Permanente Northern California according to local regulations, or as specified in the Clinical Study Agreement, whichever is longer

• If the investigator Kaiser Permanente Northern California becomes unable for any reason to continue to retain study records for the required period (e.g., retirement, relocation), Sanofi should be prospectively notified

• The study records must be transferred to a designee acceptable to Sanofi, such as another investigator, another institution, or to an independent third party arranged by Sanofi

• The investigator Kaiser Permanente Northern California must obtain Sanofi's written permission before disposing of any records, even if retention requirements have been met

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9. ADVERSE EVENT REPORTING AND SERIOUS ADVERSE EVENT REPORTING

Preliminary Results for 0-60 Day Follow-up

• Automated results showed increased rates of abdominal pain, febrile illness, and suicidal ideation/attempt on days 0-30 versus 31-60 post vaccination

Preliminary Results for 6 Month Follow-up

• 11 diagnostic type 1 Diabetes, difficulty breathing, elective procedure, febrile illness, genital pain, rash, hyperglycemia, mononucleosis, otitis externa, tympanic perforation, vomiting had elevated rates in the 6-month post-vaccination period

There are no serious new safety concerns from preliminary data analysis

No cases of Guillain-Barré in vaccinated patients

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10. QUALITY CONTROL AND QUALITY ASSURANCE

Investigators are responsible for following their standard institutional procedures to ensure data quality and integrity

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11. ETHICS

11.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)

It is the responsibility of the investigator to have prospective approval of the study protocol,

protocol amendments, and other relevant documents from the IRB/IEC. All correspondence

with the IRB/IEC should be retained in the Investigator File. Copies of IRB/IEC approvals

should be forwarded to Sanofi

11.2. Ethical Conduct of the Study

The study will be conducted in accordance with legal and regulatory requirements, and

follow generally accepted research practices such as Good Pharmacoepidemiology Practices

(GPP) issued by the International Society for Pharmacoepidemiology (ISPE), Good

Epidemiological Practice (GEP), guidelines issued by the International Epidemiological

Association (IEA), International Ethical Guidelines for Epidemiological Research issued by the

Council for International Organizations of Medical Sciences (CIOMS), EMA ENCePP Guide on

Methodological Standards in Pharmacoepidemiology, and FDA Guidance for Industry: Good

Pharmacovigilance and Pharmacoepidemiologic Assessment

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11.3. Subject Information and Consent

• This is a retrospective study of de-identified data from existing databases in Kaiser Permanente Northern California without any direct enrollment of subjects

• Therefore, no informed consent is applicable

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12. COMMUNICATION AND PUBLICATION OF STUDY RESULTS

Sanofi must have the opportunity to review at least 60 days prior to

submission for publication or presentation

If review indicates that potentially patentable subject matter would be

disclosed, publication or public disclosure may be delayed for a

maximum of an additional 60 days to allow for filing the necessary

patent applications

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13. REFERENCES

• "Descriptive, Post-marketing, Surveillance Safety Study of Menactra Vaccine." Descriptive, Post-marketing, Surveillance Safety Study of Menactra Vaccine. Clinical Trials Gov, n.d. Web. 28 Oct. 2015.

• "Advice for Consideration of Quadrivalent (A, C, Y, W135) Meningococcal Conjugate Vaccine,." Advice for Consideration of Quadrivalent (A, C, Y, W135) Meningococcal Conjugate Vaccine, for Use by Provinces and Territories: Vaccine Characteristics. Public Health Agency of Canada, n.d. Web. 28 Oct. 2015.

• USFDA. "Menactra ® Post - Licensure Pediatric Safety and Adverse Event Review." Menactra: Post-licensure Pediatric Safety and Adverse Event Review (n.d.): n. pag. USFDA. Web.

• "Vaccine Safety Datalink (VSD)." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 05 Oct. 2015. Web. 28 Oct. 2015.

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