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Dr -roberts-fda-intro-and-slides

  1. 1. Vaccines and Related Biological Products Advisory Committee Meeting Male Indication for GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] Jeff Roberts, M.D. FDA/CBER/OVRR/DVRPA September 9, 2009
  2. 2. GARDASIL® <ul><li>Each 0.5 mL dose contains </li></ul><ul><ul><li>20 mcg HPV 6 L1 VLP </li></ul></ul><ul><ul><li>40 mcg HPV 11 L1 VLP </li></ul></ul><ul><ul><li>40 mcg HPV 16 L1 VLP </li></ul></ul><ul><ul><li>20 mcg HPV 18 L1 VLP </li></ul></ul><ul><ul><li>Adjuvant: 225 mcg amorphous aluminum hydroxyphosphate sulfate (AAHS) </li></ul></ul><ul><li>Administered 0, 2, 6 months IM </li></ul><ul><li>Licensed June 2006 </li></ul>
  3. 3. GARDASIL® <ul><li>Current indications: </li></ul><ul><ul><li>Girls and women 9 through 26 years of age for the prevention of: </li></ul></ul><ul><ul><ul><li>Cervical, vulvar, and vaginal cancer caused by 16 and 18 </li></ul></ul></ul><ul><ul><ul><li>Associated precursor dysplastic lesions (CIN, VIN, VaIN, AIS) </li></ul></ul></ul><ul><ul><ul><li>Genital warts caused by 6 and 11 </li></ul></ul></ul><ul><li>Additional indication sought: </li></ul><ul><ul><li>“ Gardasil is indicated in boys and men 9 through 26 years of age for the prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11.” </li></ul></ul>
  4. 4. Agenda <ul><li>FDA Introduction Jeff Roberts, M.D., CBER </li></ul><ul><li>Sponsor Presentation Merck Representatives </li></ul><ul><li>FDA Presentation Jeff Roberts, M.D., CBER </li></ul><ul><li>Open Public Hearing </li></ul><ul><li>FDA Presentation of Questions Jeff Roberts, M.D., CBER </li></ul><ul><li>Committee Discussion and </li></ul><ul><li>Recommendations </li></ul><ul><li>Adjourn </li></ul>
  5. 5. Condyloma Acuminata (Genital Warts) in Males <ul><li>~200 per 100,000 U.S. men per year are newly diagnosed with genital warts (Koshiol et al) </li></ul><ul><li>Among males visiting an STD clinic, genital warts is second to nonspecific urethritis as the most common new diagnosis (Dempsey et al) </li></ul><ul><li>Treatment is unpleasant, and recurrence is common; causes psychosocial distress </li></ul><ul><li>70%-100% are HPV 6 and/or 11 positive (Partridge and Koutsky) </li></ul>
  6. 6. Prevention of Genital Warts <ul><li>Effectiveness of preventive measures is summarized in a recent WHO publication: </li></ul><ul><ul><li>“ Abstinence and condom use can reduce the risk of acquiring warts, but limited use of these methods reduces their impact at a population level. Condoms cannot prevent skin-to-skin HPV transmission in genital areas not covered by the condom or during non-penetrative intercourse” (WHO, 2008). </li></ul></ul>
  7. 7. Gardasil for Males: Clinical Development Program <ul><li>V501-020 : Pivotal Phase III Efficacy and Safety </li></ul><ul><ul><li>Randomized (1:1), double blind, placebo-controlled trial in males 16-26 years of age </li></ul></ul><ul><ul><li>Primary efficacy objective: prevention of external genital lesions </li></ul></ul><ul><li>V501-016 : Phase III Immunogenicity and Safety </li></ul><ul><ul><li>Double blind trial in both genders 10-15 years of age and females 16-23 years of age </li></ul></ul><ul><ul><li>Immunogenicity objective: non-inferiority in adolescents compared with adults </li></ul></ul><ul><li>V501-018 : Phase III Immunogenicity and Safety </li></ul><ul><ul><li>Randomized (2:1), double blind, placebo-controlled trial in both genders 9-15 years of age </li></ul></ul><ul><ul><li>Immunogenicity objective: non-inferiority in males compared with females </li></ul></ul>
  8. 8. Study V501-020 Design <ul><li>4065 males, 16-26 years of age, randomized 1:1 to: </li></ul><ul><ul><li>Gardasil 0.5mL IM, at 0, 2 and 6 months </li></ul></ul><ul><ul><li>Control (AAHS adjuvant in saline) 0.5mL IM, at 0, 2 and 6 months </li></ul></ul><ul><li>Subjects underwent genitourinary exam with HPV PCR (and biopsy if indicated after Day 1) on Day 1 and every 6 months from month 7-36 </li></ul><ul><li>Primary Efficacy Objective: vaccine type-related “external genital lesions” ( EGL ): genital warts , penile/perianal/perineal intraepithelial neoplasia ( PIN ) , and penile/perianal/perineal cancer </li></ul><ul><li>Men having Sex with Men (MSM) Substudy Efficacy Objective: vaccine type-related anal intraepithelial neoplasia ( AIN ) or Anal Cancer in MSM subjects </li></ul>
  9. 9. Study V501-020 Design (cont) <ul><li>Key Exclusion Criteria: </li></ul><ul><ul><li>No history of, or current clinical evidence of, genital warts </li></ul></ul><ul><ul><li>No gross genital lesion suggesting sexually transmitted disease </li></ul></ul><ul><ul><li>No autoimmune disorders or other conditions leading to immunocompromise, including a diagnosis of HIV infection </li></ul></ul><ul><ul><li>Lifetime number of sexual partners >0 and ≤5 </li></ul></ul>
  10. 10. Demographics Total (N = 4,065) n % Region Africa 538 13.2 Asia-Pacific 361 8.9 Europe 496 12.2 Latin America 1,575 38.7 North America 1,095 26.9 Race/Ethnicity Asian 406 10.0 Black 805 19.8 Hispanic American 835 20.5 Native American 3 0.1 White 1,431 35.2 Other 585 14.4
  11. 11. Subject Characteristics, HPV Status at Enrollment N = Number of subjects randomized. m = Number of subjects in the respective category. n = Number of subjects with non-missing data *14 HPV types were tested for by PCR (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) Characteristic Total (N = 4,065) m/n (%) Age (mean in years) 20.5 Age at first sexual intercourse (mean in years) 16.8 Sexual orientation HM 3458 / 4059 (85%) MSM 601 / 4059 (15%) PCR status at Day 1 Pos(+) for 6, 11, 16, 18 456 / 3736 (12%) Pos(+) for any HPV tested* 948 / 3723 (26%) Serostatus on Day 1 Pos (+) for 6, 11, 16, or 18 306 / 4042 (8%) Pos (+) by serology or PCR to 6, 11, 16, or 18 647 / 3737 (17%)
  12. 12. Analysis Populations <ul><li>Efficacy: </li></ul><ul><li>Per-protocol efficacy ( PPE ) - subjects who: </li></ul><ul><li>received all 3 doses </li></ul><ul><li>had Month 7 PCR results </li></ul><ul><li>were HPV-naïve (i.e., seronegative at Day 1 and PCR negative from Day 1 through Month 7) to the vaccine HPV type being analyzed </li></ul><ul><li>did not violate protocol </li></ul><ul><li>Cases for the PPE analysis were counted starting after Month 7 </li></ul><ul><li>Full analysis set ( FAS ) - subjects who: </li></ul><ul><li>received at least 1 dose of vaccine or placebo </li></ul><ul><li>Cases counted starting at Day 1 </li></ul><ul><li>Safety: </li></ul><ul><li>All-Subjects-As-Treated ( ASaT ): all randomized subjects who received at least 1 injection and had follow-up data. </li></ul>
  13. 13. Efficacy Against HPV 6/11/16/18-Related EGL in the PPE Population, by HPV Type N = Number of subjects randomized to the respective vaccination group. n = Number of subjects in the PPE population eligible for the respective analysis EGL = External genital lesions with a diagnosis of condyloma, PIN, or Penile/Perianal/Perineal Cancer; PIN = Penile/Perianal/Perineal intraepithelial neoplasia Endpoint Gardasil (N=2025) AAHS control (N=2030) Efficacy % (95%CI) n # of cases n # of cases HPV 6/11/16/18-Related EGL 1397 3 1408 31 90.4% (69.2, 98.1) HPV 6-Related EGL 1245 3 1244 19 84.3% (46.5, 97.0) HPV 11-Related EGL 1245 1 1244 11 90.9% (37.7, 99.8) HPV 16-Related EGL 1295 0 1271 2 100% (-420.8, 100) HPV 18-Related EGL 1335 0 1354 1 100% (-3804.6, 100)
  14. 14. Efficacy Against HPV 6/11/16/18-Related EGL in the PPE Population, by Disease Endpoint N = Number of subjects randomized to the respective vaccination group. n = Number of subjects in the PPE population eligible for the respective analysis EGL = External genital lesions with a diagnosis of condyloma, PIN, or Penile/Perianal/Perineal Cancer; PIN = Penile/Perianal/Perineal intraepithelial neoplasia Endpoint Gardasil (N=2025) AAHS control (N=2030) Efficacy % (95%CI) n # of cases n # of cases Condyloma 1397 3 1408 28 89.4% (65.5, 97.9) PIN1 1397 0 1408 2 100% (-431.1, 100) PIN1 or worse 1397 0 1408 3 100% (-141.2, 100) PIN2/3 or worse 1397 0 1408 1 100% (-3788.2, 100) Penile/Perianal/Perineal Cancer 1397 0 1408 0 N/A
  15. 15. Efficacy Against Condyloma in Different Analysis Populations n = Number of subjects in the relevant population eligible for the respective analysis PPE = Per Protocol Efficacy population GHN = Generally HPV Naïve (received at least 1 dose of vaccine or placebo; seronegative to 6, 11, 16, and 18 AND PCR negative to all 14 types tested (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59); cases counted starting at Day 1) FAS = Full Analysis Set CI = Confidence interval Analysis Population Gardasil AAHS control Efficacy % (95%CI) n # of cases n # of cases PPE (HPV 6/11-related) 1245 3 1244 28 89% (66, 98) GHN (any HPV type-related) 1275 5 1270 33 85% (62, 96) FAS (HPV 6/11-related) 1943 24 1937 71 67% (47, 80) FAS (any HPV type-related) 1943 32 1937 83 62% (42, 76)
  16. 16. Efficacy Against Any HPV Type Related Condyloma Stratified by Subject Characteristics ( FAS Population) N = Number of subjects randomized to the respective vaccination group. n = Number of subjects in the FAS population eligible for the respective analysis *Any HPV Type Tested = PCR (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59); serology (6, 11, 16, and 18) Subject Characteristic Gardasil (N=2025) AAHS control (N=2030) Efficacy % (95%CI) n # of cases n # of cases Any HPV Type Related Condyloma 1943 32 1937 83 62% (42, 76) 15-20 years old 966 17 1004 49 64% (36, 81) 21-27 years old 977 15 933 34 59% (23, 79) Sexual Orientation – HM 1653 22 1648 61 65% (42, 79) Sexual Orientation – MSM 290 10 289 22 55% (0, 81) Circumcised 743 11 699 24 56% (7, 81) Not Circumcised 1200 21 1238 59 65% (41, 80) PCR(+) and/or sero(+) for 6 and/or 11 at Day 1 186 19 178 22 21% (-53, 60)
  17. 17. Immunogenicity Bridging to Males 9-15 Years of Age: Month 7 anti-HPV GMTs ( in mMU* ) † 9-15 year-old male subjects from Protocols 016 and 018. ‡ 16-26 year-old male subjects from Protocol 020 χ For the null hypothesis that GMTBoys/GMTMen <=0.5 (2-fold decrease), a p-value <0.025 supports a conclusion that the specific type anti-HPV response in Boys is non-inferior to the response in Men. N = Number of subjects randomized in the respective group who received at least 1 injection. n = Number of subjects in the indicated immunogenicity population. *mMu = Milli Merck units (units for reporting titer by Merck’s competitive luminex immunoassay (cLIA) Group A ( 9-15yo’s ) † (N=1073) Group B ( 16-26yo’s ) ‡ (N=2025) Fold Difference Group A/Group B (95%CI) χ n GMT n GMT Anti-HPV 6 885 1036.9 1093 447.0 2.32 (2.10, 2.56) Anti-HPV 11 886 1386.3 1093 624.2 2.22 (2.03, 2.43) Anti-HPV1 6 883 6047.1 1136 2402.5 2.52 (2.27, 2.79) Anti-HPV 18 888 1356.9 1175 402.2 3.37 (3.02, 3.76)
  18. 18. Immunogenicity Stratified by Age and Gender: Month 7 anti-HPV GMTs(in mMU) † 9-15 year-old subjects from Protocols 018. ‡ 16-26 year-old female subjects from Protocols 007, 013, 015 (consistency lot substudy), 016 and 019. ║ 16-26 year-old male subjects from Protocol 020 N = Number of subjects randomized in the respective group who received at least 1 injection. n = Number of subjects contributing to the analysis. CI = Confidence interval; GMT = Geometric mean titer Females ( 9-15yo’s ) † (N=615) Males ( 9-15yo’s ) † (N=564) Females ( 16-26yo’s ) ‡ (N=9885) Males ( 16-26yo’s ) ║ (N=2025) n GMT (95%CI) n GMT (95%CI) n GMT (95%CI) n GMT (95%CI) Anti-HPV 6 501 884 (813, 962) 471 968 (885, 1,058) 3333 545 (528, 563) 1093 447 (423, 473) Anti-HPV 11 501 1,336 (1,225, 1,457) 471 1,383 (1,264, 1,514) 3357 749 (726, 773) 1093 624 (590, 660) Anti-HPV 16 502 5,007 (4,501, 5,570) 471 6,193 (5,540, 6,923) 3253 2,411 (2,312, 2,515) 1136 2,403 (2,238, 2,580) Anti-HPV 18 503 1,128 (1,017, 1,251) 474 1,475 (1,318, 1,650) 3571 476 (458, 494) 1175 402 (377, 429)
  19. 19. Duration of Efficacy/Immunogenicity <ul><li>As in females, correlate of protection is not established in males. </li></ul><ul><li>Reverse cumulative distribution curves of titers at 24 months indicate that the pattern of decline of titers is similar in males and females. </li></ul><ul><li>10 year follow-up extension of efficacy and immunogenicity in the pivotal study, V501-020, has been proposed by the sponsor. </li></ul><ul><li>Protocol 018, which includes males and females 9-15 years of age, has immunogenicity and efficacy follow-up to 10 years. </li></ul>
  20. 20. Safety – V501-020 <ul><li>Safety Assessments were done at each vaccination visit and every 3 months post-vaccination series </li></ul><ul><li>All subjects were given a Vaccine Report Card (VRC) to record: </li></ul><ul><ul><li>Oral temperature out to 5 days </li></ul></ul><ul><ul><li>Injection-site AE’s out to 14 days </li></ul></ul><ul><ul><li>Systemic AE’s out to 14 days </li></ul></ul>
  21. 21. Summary of AEs, Days 1-15 Following Any Vaccination, V501-020 N = number of subjects in the ASaT analysis set in the respective vaccination group who had follow-up data n = number of cases *Causality determined by clinical investigator **Deaths in the entire study period: Gardasil: 3 (2 MVAs and 1 gunshot wound); Control: 10 Gardasil (N=1945) AAHS control (N=1950) n % n % With one or more AEs 1345 69.2 1244 63.8 Injection-site AEs 1169 60.1 1047 53.7 Systemic AEs 615 31.6 613 31.4 With vaccine-related AEs* 1242 63.9 1134 58.2 Vaccine-related injection-site AEs 1169 60.1 1046 53.6 Vaccine-related systemic AEs 274 14.1 284 14.6 With SAEs 5 0.3 1 0.1 Who died** 0 0.0 0 0.0 Discontinued due to an AE 2 0.1 4 0.2 Discontinued due to an SAE 0 0.0 0 0.0
  22. 22. Systemic AEs* Days 1-15 Following Vaccination, V501-020 <ul><li>Analysis of AEs by System Organ Class was similarly unremarkable </li></ul>N = number of subjects in the ASaT analysis set in the respective vaccination group who had follow-up data n = number of cases *Incidence ≥2% in one or more vaccination groups **Pyrexia defined as maximum oral temperature ≥38.5°C Adverse Event Term Gardasil (N=1945) AAHS control (N=1950) n % n % With one or more systemic AE’s 615 31.6 613 31.4 Diarrhea 40 2.1 36 1.8 Pyrexia** 118 6.1 125 6.4 Influenza 42 2.2 44 2.3 Nasopharyngitis 44 2.3 50 2.6 Headache 179 9.2 207 10.6 Pharyngolaryngeal pain 38 2.0 37 1.9
  23. 23. Injection Site AEs, Days 1-5 Following Vaccination, V501-020 N = number of subjects in the ASaT analysis set in the respective vaccination group who had follow-up data n = number of subjects with the indicated characteristic Injection Site Reaction Gardasil (N=1945) AAHS control (N=1950) n % n % One or more injection-site AEs 1166 59.9 1046 53.6 One or more severe injection-site AEs 25 1.3 20 1.0 Injection-site pain 1113 57.2 991 50.8 Injection-site erythema 304 15.6 275 14.1 Injection-site pruritis 22 1.1 24 1.2 Injection-site swelling 219 11.3 187 9.6
  24. 24. Pooled Safety Population – Studies V501-020, -016, and -018 *Placebo was saline alone in Protocol 018, the only study in the clinical development program in which placebo did not contain adjuvant. <ul><li>Summary analyses of AEs in pooled safety dataset lead to conclusions similar to those from V501-020. </li></ul>Protocol Age Gardasil (N) Placebo* (N) Total 016 10-15 years 508 0 508 018 9-15 years 564 275 839 020 16-26 years 2025 2030 4055 Total 9-26 years 3097 2305 5402
  25. 25. SAEs, Days 1 to 15 Following Vaccination, Pooled Safety Population *There were a total of 7 subjects who received a mixed vaccine/placebo regimen that are not counted in the safety tables. SAE Gardasil* (N=3092) AAHS control* (N=2303) n % n % With Serious AEs 9 0.3 1 0.0 abdominal pain 1 0.0 0 0.0 acute renal failure 1 0.0 0 0.0 new onset type 1 diabetes mellitus 1 0.0 0 0.0 localized infection and pain (lower extremity) 1 0.0 0 0.0 appendicitis 1 0.0 0 0.0 cellulitis (lower extremity) 1 0.0 0 0.0 chest pain 1 0.0 0 0.0 peanut allergy 1 0.0 0 0.0 varicella infection with seizure 1 0.0 0 0.0 contusion 0 0.0 1 0.0
  26. 26. Injection Site Reactions in Boys Compared with Men † 9-15 year-old male subjects from Protocols 016 and 018. ‡ 16-26 year-old male subjects from Protocol 020 N = Number of subjects randomized in the respective group who received at least 1 injection. n = Number of subjects in the indicated immunogenicity population. Males ( 9-15yo’s ) † (N=506) Males ( 16-26yo’s ) ‡ (N=2025) n % n % One or more injection-site AEs 403 80.4 1046 53.6 One or more severe injection-site AEs 22 4.4 20 1.0 Injection-site erythema 101 20.2 275 14.1 Injection-site pain 398 79.4 991 50.8 Injection-site pruritis 13 2.6 24 1.2 Injection-site swelling 127 25.3 187 9.6
  27. 27. Postmarketing Experience with Gardasil in Women <ul><li>Syncope, sometimes accompanied by traumatic injury, has been noted </li></ul><ul><li>Other AEs being monitored*, no evidence of causation </li></ul><ul><li>Current postmarketing commitment: </li></ul><ul><ul><li>44,000 females receiving all three doses: Powered to detect a 2 fold increase in a risk, with a background rate of 1/10,000, with alpha 0.05 and power of 80%. </li></ul></ul><ul><li>*Guillan Barre, transverse myelitis, motor neuron disease, demyelinating disease, Bell’s palsy, Autoimmune diseases, DVTs, PEs (most on HCs, not an issue for boys), Pancreatitis, Unexplained death, Seizures </li></ul>
  28. 28. Need for Postmarketing Studies <ul><li>Clinical trial safety database (Gardasil: 3097 subjects; Control: 2305 subjects) and worldwide post-marketing safety data are limited in males </li></ul><ul><li>Literature documents gender differences in vaccine reactogenicity and adverse events (Cook) </li></ul><ul><li>Different background rates for morbidity and mortality </li></ul>
  29. 29. Postmarketing Proposed by Sponsor <ul><li>Phase IV Observational Study </li></ul><ul><li>27,000 males (9-26 y/o) who receive at least one dose of Gardasil </li></ul><ul><li>General short-term safety, ER visits and hospitalizations </li></ul><ul><li>Self-comparison reference period, beginning 60 days after vaccination </li></ul><ul><li>Safety Review Committee (SRC) review safety signals and determine follow up </li></ul>
  30. 30. CBER Summary and Conclusions <ul><li>Data submitted to the BLA supplement demonstrate that Gardasil is efficacious in the prevention of genital warts caused by HPV 6 and 11 in males 16-26 years of age. </li></ul><ul><li>Data from studies V501-016 and -018 demonstrate that anti-HPV GMT’s against each of the 4 VLP types in 9-15 year old males are non-inferior to those in 16-26 year old males. </li></ul><ul><ul><li>Immunogenicity bridging provides a basis for inferring protection of 9-15 year old males against genital warts. </li></ul></ul><ul><li>In the safety database, which includes ~5400 males, no safety signals have been identified. The details of the postmarketing plan are the subject of ongoing discussions with the sponsor. </li></ul>
  31. 31. Gardasil for Males: Review Team <ul><li>Chairperson Jeff Roberts, M.D. </li></ul><ul><li>Regulatory Project Managers Elizabeth Valenti </li></ul><ul><li>Laura C. Montague </li></ul><ul><li>Clinical Jeff Roberts, M.D. </li></ul><ul><li>Nancy Miller, M.D. </li></ul><ul><li>Statistical Martha B. Lee, Ph.D. </li></ul><ul><li>Bioresearch Monitoring Robert Wesley </li></ul><ul><li>Non-Clinical Ching-Long Joe Sun, Ph.D. </li></ul><ul><li>CMC Robin Levis, Ph.D. </li></ul><ul><li>Pharmacovigilance Andrea R. Sutherland, M.D., M.Sc., M.P.H. </li></ul><ul><li>Michael D. Nguyen, M.D. </li></ul><ul><li>Advertising/Promotional Labeling: Lisa L. Stockbridge, Ph.D. </li></ul>
  32. 32. References <ul><li>Cook IF. Sex differences in injection site reactions with human vaccines. Hum Vaccin. 2009 Jul;5(7):441-9. </li></ul><ul><li>Dempsey AF, Koutsky LA, Golden M. Potential impact of human papillomavirus vaccines on public STD clinic workloads and on opportunities to diagnose and treat other sexually transmitted diseases. Sex Transm Dis. 2007 Jul;34(7):503-7. </li></ul><ul><li>Koshiol JE, Laurent SA, Pimenta JM. Rate and predictors of new genital warts claims and genital warts-related healthcare utilization among privately insured patients in the United States. Sex Transm Dis. 2004 Dec;31(12):748-52. </li></ul><ul><li>Partridge JM, Koutsky LA. Genital human papillomavirus infection in men. Lancet Infect Dis. 2006 Jan;6(1):21-31. </li></ul><ul><li>World Health Organization. Human Papillomavirus (HPV) Vaccine Background Paper. September 2008. http://www.who.int/immunization/documents/HPVBGpaper_final_03_04_2009.pdf </li></ul>
  33. 35. Autoimmune-Associated Events, Pooled Safety Dataset N = Number of individuals who received at least one dose of either vaccine or placebo n = Number of individuals with specific new Medical Conditions Conditions GARDASIL (N = 3092) AAHS Control or Saline Placebo (N = 2303) n (%) n (%) Alopecia Areata Ankylosing Spondylitis Arthralgia/Arthritis/Reactive Arthritis Autoimmune Thrombocytopenia Diabetes Mellitus Type 1 Hyperthyroidism Hypothyroidism Inflammatory Bowel Disease Myocarditis Proteinuria Psoriasis Vitiligo 1 (0.0) 1 (0.0) 30 (1.0) 1 (0.0) 3 (0.1) 0 (0.0) 3 (0.1) 0 (0.0) 1 (0.0) 1 (0.0) 0 (0.0) 2 (0.1) 0 (0.0) 2 (0.1) 17 (0.7) 0 (0.0) 2 (0.1) 1 (0.0) 0 (0.0) 2 (0.1) 1 (0.0) 0 (0.0) 2 (0.1) 5 (0.2) All Conditions 43 (1.4) 32 (1.4)
  34. 36. Postmarketing Considerations <ul><li>Standard 42 day window </li></ul><ul><li>Variable onset windows and analysis time-frames, in addition to temporal statistical scanning methods to look for clusters of onset intervals </li></ul><ul><li>Identify a pre-specified list of AEs of primary interest (clinical trials, Gardasil in females, adolescent vaccines); flexibility to add signals detected </li></ul><ul><li>Determine background rates and use reported rates vs. expected background rates (in addition to self-control) to identify signals </li></ul><ul><li>Analysis to assess safety in younger age groups (9-15) </li></ul><ul><li>All SAEs reported and included in analysis regardless of the assessment of possible causality </li></ul><ul><li>Date by which the sponsor anticipates the final report will be available, although feasibility of this study will be influenced by vaccine policies and uptake. </li></ul>

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