GARDASIL 9 Human Papillomavirus 9-valent Vaccine, Recombinant

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Valerie Cannon
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1 SWISS SUMMARY OF ACTIVITIES IN THE RISK MANAGEMENT PLAN FOR GARDASIL 9 Human Papillomavirus 9-valent Vaccine, Recombinant Active Substance: Human Papillomavirus 9-valent Vaccine, Recombinant MAH / MAA name: MSD Merck Sharp & Dohme AG Data lock point: 01-Dec-2015 RMP version number: 2.0

2 TABLE OF CONTENTS TABLE OF CONTENTS... 2 LIST OF TABLES ELEMENTS FOR SUMMARY TABLES IN THE EPAR Summary Table of Safety Concerns Table of Ongoing and Planned Studies in the Post-authorization Pharmacovigilance Development Plan Summary of Post-authorization Efficacy Development Plan Summary Table of Risk Minimization Measures ELEMENTS FOR A PUBLIC SUMMARY Overview of Disease Epidemiology Summary of Treatment Benefits Unknowns Relating to Treatment Benefits Summary of Safety Concerns Summary of Risk Minimization Measures by Safety Concern Planned Post-authorization Development Plan List of Studies in Post-authorization Development Plan Studies Which are a Condition of the Marketing Authorization Summary of Changes to the Risk Management Plan Over Time... 12

3 LIST OF TABLES Table 1 Summary of Ongoing Safety Concerns... 4 Table 2 Ongoing and Planned Additional Pharmacovigilance Studies / Activities in the Pharmacovigilance Plan: Imposed Activities, Specific Obligations and Required Activities (Categories 1-3)... 5 Table 3 Summary of Safety Concerns and Risk Minimization Activities... 6 Table 4 Summary of Important Identified Risks Table 5 Summary of Important Potential Risks Table 6 Summary of Missing Information Table 7 Major Changes to the Risk Management Plan... 12

4 1 ELEMENTS FOR SUMMARY TABLES IN THE EPAR 1.1 Summary Table of Safety Concerns Table 1 Summary of Ongoing Safety Concerns Important identified risks Hypersensitivity (Type 1) Important potential risks Product confusion between Gardasil and Gardasil 9 Mixed regimen between Gardasil/ Silgard and Gardasil 9 Missing information Long term effectiveness and immunogenicity Exposure during Pregnancy Viral type replacement Immunogenicity and Safety in Females greater than 26 years of age 1.2 Table of Ongoing and Planned Studies in the Postauthorization Pharmacovigilance Development Plan Table 2 Ongoing and Planned Additional Pharmacovigilance Studies / Activities in the Pharmacovigilance Plan: Imposed Activities, Specific Obligations and Required Activities (Categories 1-3) Study / Activity Pregnancy Registry V Nordic Longterm Follow-Up Study (10-Year extension in subjects from V ) Objectives To monitor pregnancy outcomes in women exposed to 9vHPV vaccine during pregnancy. To monitor the long term effectiveness and immunogenicity of 9vHPVvaccine Safety Concerns Addressed Exposure to vaccine during pregnancy Viral type replacement Long-term Effectiveness/ Immunogenicit y Status Planned Planned Date for Submission of Interim / Final Reports (target dates) Interim Reports: 31-AUG AUG AUG AUG AUG-2020 Final Report: ~18 months after enrollment of the last patient. Interim Reports: ~4Q2017 ~4Q2019 ~4Q2021 ~4Q2023 Final Report: ~31-Dec-2026

5 V Postdose 3 Follow-Up Study (10-Year Postdose 3 Extension) A postmarketing immunogenicity and safety study of the 9vHPV vaccine in women 27 to 45 years of age To monitor the long term effectiveness and immunogenicit y of 9vHPVvaccine - To demonstrate immunogenicity for the 9v HPV vaccine in women 27 to 45 years of age. - To collect data on the safety profile of 9vHPV vaccine in women 27 to 45 years of age. Long-term Effectiveness/ Immunogenicity Immunogenicity and safety in females greater than 26 years of age Planned Planned Interim 72-Month Report: ~4Q201 7 Interim 96 Month Report: ~4Q201 9 Final Report: ~31-Mar Final Report: ~1Q Summary of Post-authorization Efficacy Development Plan While there are no ongoing or proposed PAES for the 9vHPV vaccine, there are long-term extensions of 2 clinical studies of the 9vHPV vaccine. These extensions are designed to address missing information on long-term effectiveness of the 9V HPV vaccine.

6 1.4 Summary Table of Risk Minimization Measures Table 3 Summary of Safety Concerns and Risk Minimization Activities Safety Concern Hypersensitivity (Type 1) Product confusion between Gardasil and Gardasil 9 Mixed regimen between Gardasil /Silgard and Gardasil 9 Routine Risk Minimization Measures Important Identified Risks Hypersensitivity to Gardasil or Gardasil 9 vaccines components is included as a contraindication in section 4.3; hypersensitivity reactions including anaphylactic / anaphylactoid reactions are also included as an ADR reported during post-approval use of qhpv vaccine, in section 4.8 of the SmPC. Important Potential Risks Distinctive name and packaging of product The MAH, in agreement and in consultation with Member States National Competent Authorities, will consider whether nationally specific and healthcare system specific additional measures are required (e.g. communication to HCPs - prescribers and vaccinators - regarding distinctive characteristics between 9vHPV vaccine and qhpv vaccine) Text is included in the SmPC to indicate that Gardasil9 is not interchangeable with other HPV vaccines and that studies using a mixed regimen of HPV vaccines were not performed for Gardasil9 (Section 4.2 and 4.4). The MAH, in agreement and in consultation with Member Additional Risk Minimization Measures

7 Table 3 Summary of Safety Concerns and Risk Minimization Activities Safety Concern Exposure during pregnancy Long-term effectiveness and immunogenicity Routine Risk Minimization Measures States National Competent Authorities, will consider whether nationally specific and healthcare system specific additional measures are required (e.g. communication to HCPs - prescribers and vaccinators - regarding distinctive characteristics between 9vHPV vaccine and qhpv vaccine) Missing Information SmPC Section 4.6 Fertility, pregnancy and lactation includes language stating that Gardasil 9 is not recommended for use during pregnancy. Additional Risk Minimization Measures Viral type replacement Immunogenicity and safety in women greater than 26 years of age 2 ELEMENTS FOR A PUBLIC SUMMARY 2.1 Overview of Disease Epidemiology Gardasil 9 is a vaccine used in males and females above 9 years of age to prevent certain cancers and pre-cancerous conditions (abnormalities that can lead to cancer) caused by human papillomavirus (HPV) infection. HPV infection is the most common sexually transmitted disease worldwide. Over 50% of sexually active adults become infected with HPV during their lifetime. The highest rates of HPV infection occur soon after people become sexually active. The risk of an HPV infection increases with the number of sexual partners during an individual s lifetime. Of the many different types of human papillomavirus, some are harmless and others can cause diseases of the genital areas. While in most cases the virus is eliminated naturally, if it persists it can cause genital warts, precancerous conditions or cancer.

8 Gardasil 9 is indicated for active immunisation against: Pre-cancerous conditions and cancers affecting the cervix, vulva, vagina and anus caused by vaccine HPV types. Genital warts (condyloma acuminata) caused by specific HPV types. These conditions are described in detail below: Cervical cancer Cervical cancer develops in the cervix (the lower part of the womb) and may result from infection with HPV, generally transmitted during sexual activity. It is a common type of cancer in women, affecting about 530,000 women worldwide and causing 275,000 deaths each year. It usually affects women aged 35 to 55 years. Vaccination against HPV and regular screening (Pap smear tests) for early signs of precancerous conditions can prevent cervical cancer. Vulvar cancer Vulvar cancer is a cancer that develops in the external female genital organs (vulva). Vulvar cancer may result from infection with HPV, transmitted during sexual intercourse. There are no routine screening tests for this cancer. Vaginal cancer Cancer of the vagina is a cancer of the birth canal; it is uncommon. Vaginal cancer may result from infection with HPV, transmitted during sexual intercourse. There are no routine screening tests for this cancer. Genital warts Genital warts (condylomata acuminata) are generally benign growths in or around the vagina, penis, or rectum caused by sexually transmitted HPV. Genital warts grow rapidly and sometimes cause burning pain. Anal cancer Anal cancer is a rare type of cancer that affects the very end of the large bowel (large intestine) and that may result from infection with HPV. 2.2 Summary of Treatment Benefits Gardasil 9 can provide protection against infection by nine types of HPV (types 6, 11, 16, 18, 31, 33, 45, 52 and 58), as seen in four main studies. The first study looked at the effectiveness of Gardasil 9 in over 14,000 women aged between

9 16 and 26 years. The study looked at how many women given Gardasil 9 developed disease (growths or cancer) due to HPV infection caused by HPV types 31, 33, 45, 52 and 58 when compared with Gardasil vaccine (a previously approved vaccine which protects against types 6, 11, 16 and 18). This study showed that 1 out of 6,016 women vaccinated with 3 doses of Gardasil 9 developed disease related to HPV types 31, 33, 45, 52 and 58, compared with 30 out of 6,017 women vaccinated with 3 doses of Gardasil. This study also showed that antibody levels against types 6, 11, 16 and 18 were adequate to protect against these four types of HPV infection. The women were followed up for around three and a half years after the third dose of the vaccine. The second study in 3066 subjects compared the effect of Gardasil 9 in girls and boys aged nine to 15 years with the effect of Gardasil 9 in young women aged 16 to 26 years. The main measure of effectiveness was the development of antibodies against HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58 one month after the third dose. The study showed that the vaccine stimulates the production of adequate levels of antibodies against HPV of all nine types in girls and boys aged between nine and 15 years when compared with women years of age, for whom protection against disease was demonstrated in the first study. The third study compared the effect of Gardasil 9 with the effect of Gardasil in 600 girls aged 9 to 15 years. The study looked at the development of antibodies one month after the third dose, and it showed that girls vaccinated with Gardasil 9 have similar levels of protection against types 6, 11, 16 and 18 as girls vaccinated with Gardasil. The fourth main study compared the levels of antibodies against all nine HPV types one month after the third dose in around 1,419 young men aged 16 to 26 with those in 1,101 women aged 16 to 26. This study found that Gardasil 9 stimulates similar levels of protection against all nine virus types in young men and women. 2.3 Unknowns Relating to Treatment Benefits The long-term antibody response and the period that Gardasil 9 prevents HPV disease after vaccination are not yet known. In addition, the following groups were not studied in clinical trials, so it is not known if Gardasil 9 prevents HPV disease in these individuals: Individuals younger than 9 years of age or older than 26 years of age; Individuals with medical conditions that could affect the vaccine s safety, immunogenicity and/or how well the vaccine works; Pregnant women. 2.4 Summary of Safety Concerns Table 4 and Table 5 provide information on the important identified risks and potential risks, respectively, and their preventability (risk minimization). Important identified risks are safety issues or undesirable effects for which there is adequate

10 evidence of an association with the use of this vaccine. Important potential risks are safety issues or undesirable effects for which there is some basis for suspicion of an association with the use of the medicine of interest but where this association has not been confirmed. Table 6 provides information on missing information. Missing information is information about the safety of a medicine which is not available at the time of submission of a particular risk management plan (RMP). Examples of missing information include populations not studied (e.g. pregnant women or patients with severe kidney function problems) or where there is a high likelihood of off-label use (vaccine used for indication other than what it is approved for). Important Identified Risks Table 4 Summary of Important Identified Risks Risk What is Known Preventability Immediate hypersensitivity (sudden allergic reaction) Sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing. As with any medicine or vaccine, severe allergic reactions may occur with this vaccine. Allergic reactions may be serious and require immediate treatment. Allergic reactions usually develop very quickly after the injection. In clinical studies of Gardasil 9, most of the cases of hives (urticaria) were mild to moderate in intensity and reported as resolved. Individuals with a history of an allergic reaction to Gardasil or Silgard (an identical vaccine to Gardasil) are at increased risk of an allergic reaction to Gardasil 9. These individuals should not receive Gardasil 9, as indicated in the product information. In addition, individuals who develop symptoms of an allergic reaction after a dose of Gardasil 9 vaccine should not receive further doses.

11 Important Potential Risks Table 5 Summary of Important Potential Risks Risk Product confusion between Gardasil and Gardasil 9 Mixed Regimen between Gardasil /Silgard and Gardasil 9 (where more than one type of vaccine is given in the same series) What is Known There is the potential for confusing Gardasil 9 with the Gardasil vaccine. No safety issue in the case of product confusion has been identified. However, since Gardasil 9 protects against five more types of HPV viruses than Gardasil, the full benefit of Gardasil 9 vaccine in the prevention of disease related to the additional HPV types contained in the vaccine may be missed. Because there is more than one type of vaccine against HPV on the market, patients could receive a vaccination course involving more than one HPV vaccine type (a mixed regimen). The effects of such a mixed regimen have not been studied and if this happens, patients might not be fully protected against the additional HPV types included in Gardasil 9. It is recommended that patients who receive a first dose of Gardasil 9 complete the vaccination course with Gardasil 9 vaccine. Missing Information Table 6 Summary of Missing Information Risk Exposure during Pregnancy Viral Type Replacement Long term effectiveness and immunogenicity What is Known Gardasil 9 has not been systematically studied in pregnant women, but data involving more than 1,000 cases where women were inadvertently given the vaccine while pregnant did not indicate any birth defect or harm to the newborn child. However, this evidence is not enough to recommend use during pregnancy and vaccination should be postponed until pregnancy is over. Viral type replacement occurs when, by blocking infection with certain HPV types, use of the vaccine could result in increase of disease caused by other types of HPV infection. To date, there are no data to suggest that Gardasil 9 vaccine will cause viral type replacement. Gardasil 9 prevents HPV disease in most people for at least 4 years after receiving all 3 doses of vaccine. In studies with Gardasil/Silgard, the vaccine was shown to prevent HPV disease for at least 6 years following vaccination. It is expected that Gardasil 9 vaccine will also provide long-term protection. The duration of protection of Gardasil 9 vaccine against HPV disease beyond 4 years after receipt of the full 3-dose vaccination course has not yet been evaluated. However, a set of subjects participating in the Gardasil 9 vaccine clinical program will be followed for more than 10 years in order to evaluate long-term protection against HPV disease.

12 Immunogenicity and Safety in Females greater than 26 years of age Even though Gardasil 9 has not been evaluated in subjects over 26 years of age, Gardasil 9 effectiveness can be extrapolated to this population based on the following considerations: The Gardasil/Silgard vaccine clinical development program has demonstrated that the Gardasil/Silgard vaccine is efficacious in preventing HPV diseases for both females 16 to 26 years of age and females 24 to 45 years of age. The totality of results from the Gardasil 9 vaccine immunogenicity studies support that Gardasil 9 and Gardasil have similar immunogenicity profiles. Therefore, it is anticipated that this would also apply to female subjects 27 to 45 years of age. However, a post-marketing study of the Gardasil 9 vaccine in women 27 to 45 years of age will be conducted to confirm this assumption. 2.5 Summary of Risk Minimization Measures by Safety Concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimizing them. An abbreviated version of this in lay language is provided in the form of the Package Leaflet (PL). The measures in these documents are known as routine risk minimization measures. The SmPC and PL for 9vHPV vaccine can be found in the product s EPAR page. Routine risk minimization measures also include communications with healthcare providers (prescribers and vaccinators) regarding distinctive characteristics between 9vHPV vaccine and qhpv vaccine to avoid product confusion and the lack of interchangeability between 9vHPV vaccine and qhpv vaccine to avoid the use of mixed vaccine regimens. 2.6 Planned Post-authorization Development Plan List of Studies in Post-authorization Development Plan Refer to Table 2 in Section Studies Which are a Condition of the Marketing Authorization While there are no ongoing or proposed studies in the post-authorization development plan for 9vHPV vaccine, there are long-term extensions of 2 clinical studies of this vaccine. These extension studies are designed to address missing information on the long-term effectiveness of 9vHPV vaccine.

13 2.7 Summary of Changes to the Risk Management Plan Over Time Table 7 Major Changes to the Risk Management Plan RMP Version Date Safety Concerns Comment 1.4 Jun 2015 (at the time of authorization) Hypersensitivity (Type 1) Product confusion between Gardasil and Gardasil 9 Mixed regimen between Gardasil/ Silgard and Gardasil 9 Long term effectiveness and immunogenicity Exposure during Pregnancy Viral type replacement Immunogenicity and safety in females greater than 26 years of age Initial filing 2.0 Dec-2015 No change in safety concerns Addition of Clinical trial data for Protocol 003 Adolescent male study and for Protocol 010 (2-dose data).

HPV doesn t concern men?

Think HPV doesn t concern men? What you should know about HPV-related cancers and genital warts. One infected partner may be all it takes to get HPV. HPV=human papillomavirus Trying to decide if GARDASIL