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
GARDASIL®
Each 0.5 mL dose contains
20 mcg HPV 6 L1 VLP 40 mcg HPV 11 L1 VLP 40 mcg HPV 16 L1 VLP 20 mcg HPV 18 L1 VLP Adjuvant: 225 mcg amorphous aluminum hydroxyphosphate sulfate (AAHS)
Administered 0, 2, 6 months IM
Licensed June 2006
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GARDASIL® Current indications:
Girls and women 9 through 26 years of age for the prevention of:
Cervical, vulvar, and vaginal cancer caused by 16 and 18 Associated precursor dysplastic lesions (CIN, VIN, VaIN, AIS) Genital warts caused by 6 and 11
Additional indication sought:
“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.”
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Agenda
FDA Introduction Sponsor Presentation FDA Presentation Jeff Roberts, M.D., CBER Merck Representatives Jeff Roberts, M.D., CBER
Open Public Hearing
FDA Presentation of Questions Committee Discussion and Recommendations Adjourn
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Jeff Roberts, M.D., CBER
Condyloma Acuminata (Genital Warts) in Males
~200 per 100,000 U.S. men per year are newly diagnosed with genital warts (Koshiol et al) Among males visiting an STD clinic, genital warts is second to nonspecific urethritis as the most common new diagnosis (Dempsey et al) Treatment is unpleasant, and recurrence is common; causes psychosocial distress 70%-100% are HPV 6 and/or 11 positive (Partridge and Koutsky)
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Prevention of Genital Warts
Effectiveness of preventive measures is summarized in a recent WHO publication:
“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).
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Gardasil for Males: Clinical Development Program
V501-020:
Pivotal Phase III Efficacy and Safety Randomized (1:1), double blind, placebo-controlled trial in males 16-26 years of age Primary efficacy objective: prevention of external genital lesions Phase III Immunogenicity and Safety Double blind trial in both genders 10-15 years of age and females 16-23 years of age Immunogenicity objective: non-inferiority in adolescents compared with adults
V501-016:
V501-018: Phase III Immunogenicity and Safety
Randomized (2:1), double blind, placebo-controlled trial in both genders 9-15 years of age Immunogenicity objective: non-inferiority in males compared with females 7
Study V501-020 Design
4065 males, 16-26 years of age, randomized 1:1 to:
Gardasil 0.5mL IM, at 0, 2 and 6 months Control (AAHS adjuvant in saline) 0.5mL IM, at 0, 2 and 6 months
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 Primary Efficacy Objective: vaccine type-related “external genital lesions” (EGL): genital warts, penile/perianal/perineal intraepithelial neoplasia (PIN), and penile/perianal/perineal cancer
Men having Sex with Men (MSM) Substudy Efficacy Objective: vaccine type-related anal intraepithelial neoplasia (AIN) or Anal Cancer in MSM subjects
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Study V501-020 Design (cont)
Key Exclusion Criteria:
No history of, or current clinical evidence of, genital warts No gross genital lesion suggesting sexually transmitted disease No autoimmune disorders or other conditions leading to immunocompromise, including a diagnosis of HIV infection Lifetime number of sexual partners >0 and ≤5
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Demographics
Total (N = 4,065) n % 13.2 8.9 12.2 38.7 26.9 10.0 19.8 20.5 0.1
Region
Africa Asia-Pacific Europe Latin America North America Race/Ethnicity Asian Black Hispanic American Native American 406 805 835 3 538 361 496 1,575 1,095
White
Other
1,431
585
35.2
14.4
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Subject Characteristics, HPV Status at Enrollment
Total (N = 4,065) Characteristic Age (mean in years) Age at first sexual intercourse (mean in years) m/n (%) 20.5 16.8 3458 / 4059 (85%) 601 / 4059 (15%) 456 / 3736 (12%) 948 / 3723 (26%) 306 / 4042 (8%) 647 / 3737 (17%)
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Sexual orientation
HM MSM PCR status at Day 1 Pos(+) for 6, 11, 16, 18 Pos(+) for any HPV tested* Serostatus on Day 1 Pos (+) for 6, 11, 16, or 18 Pos (+) by serology or PCR to 6, 11, 16, or 18
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)
Analysis Populations
Efficacy:
Per-protocol efficacy (PPE) - subjects who: received all 3 doses had Month 7 PCR results 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 did not violate protocol Cases for the PPE analysis were counted starting after Month 7 Full analysis set (FAS) - subjects who: received at least 1 dose of vaccine or placebo Cases counted starting at Day 1
Safety: All-Subjects-As-Treated (ASaT): all randomized subjects who received at least 1 injection and had follow-up data.
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Efficacy Against HPV 6/11/16/18-Related EGL in the PPE Population, by HPV Type
Gardasil (N=2025) Endpoint n # of cases AAHS control (N=2030) n # of cases Efficacy % (95%CI)
HPV 6/11/16/18-Related EGL
HPV 6-Related EGL HPV 11-Related EGL HPV 16-Related EGL HPV 18-Related EGL
1397
1245 1245 1295 1335
3
3 1 0 0
1408
1244 1244 1271 1354
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19 11 2 1
90.4% (69.2, 98.1)
84.3% (46.5, 97.0) 90.9% (37.7, 99.8) 100% (-420.8, 100) 100% (-3804.6, 100)
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
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Efficacy Against HPV 6/11/16/18-Related EGL in the PPE Population, by Disease Endpoint
Gardasil (N=2025) Endpoint Condyloma PIN1 PIN1 or worse PIN2/3 or worse Penile/Perianal/Perineal Cancer n 1397 1397 1397 1397 1397 # of cases 3 0 0 0 0 AAHS control (N=2030) n 1408 1408 1408 1408 1408 # of cases 28 2 3 1 0 Efficacy % (95%CI)
89.4% (65.5, 97.9)
100% (-431.1, 100) 100% (-141.2, 100) 100% (-3788.2, 100) N/A
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
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Efficacy Against Condyloma in Different Analysis Populations
Gardasil Analysis Population n PPE (HPV 6/11-related) 1245 # of cases 3 AAHS control n 1244 # of cases 28
Efficacy % (95%CI)
89% (66, 98)
GHN (any HPV type-related)
FAS (HPV 6/11-related) FAS (any HPV type-related)
1275
1943 1943
5
24 32
1270
1937 1937
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71 83
85% (62, 96)
67% (47, 80) 62% (42, 76)
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
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Efficacy Against Any HPV Type Related Condyloma Stratified by Subject Characteristics (FAS Population)
Gardasil (N=2025) Subject Characteristic Any HPV Type Related Condyloma 15-20 years old n 1943 966 # of cases 32 17 AAHS control (N=2030) n 1937 1004 # of cases 83 49
Efficacy % (95%CI)
62% (42, 76) 64% (36, 81)
21-27 years old
Sexual Orientation – HM Sexual Orientation – MSM Circumcised Not Circumcised PCR(+) and/or sero(+) for 6 and/or 11 at Day 1
977
1653 290 743 1200 186
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22 10 11 21 19
933
1648 289 699 1238 178
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61 22 24 59 22
59% (23, 79)
65% (42, 79) 55% (0, 81) 56% (7, 81) 65% (41, 80)
21% (-53, 60)
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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)
Immunogenicity Bridging to Males 9-15 Years of Age: Month 7 anti-HPV GMTs (in mMU*)
Group A (9-15yo’s)† (N=1073) Group B (16-26yo’s)‡ (N=2025) Fold Difference Group A/Group B (95%CI)χ 2.32 (2.10, 2.56) 2.22 (2.03, 2.43) 2.52 (2.27, 2.79) 3.37 (3.02, 3.76)
n
Anti-HPV 6 Anti-HPV 11 Anti-HPV1 6 885 886 883
GMT
1036.9 1386.3 6047.1
n
1093 1093 1136
GMT
447.0 624.2 2402.5
Anti-HPV 18
888
1356.9
1175
402.2
†9-15 year-old male subjects from Protocols 016 and 018. ‡16-26 year-old male subjects from Protocol 020 χFor 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)
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Immunogenicity Stratified by Age and Gender: Month 7 anti-HPV GMTs(in mMU)
Females (9-15yo’s)† (N=615)
n GMT (95%CI) n 471
Males (9-15yo’s)† (N=564)
GMT (95%CI) n
Females (16-26yo’s)‡ (N=9885)
GMT (95%CI) n
Males (16-26yo’s) ║ (N=2025)
GMT (95%CI)
Anti-HPV 6
Anti-HPV 11
Anti-HPV 16 Anti-HPV 18
501
884 (813, 962)
1,336 (1,225, 1,457) 5,007 (4,501, 5,570) 1,128 (1,017, 1,251)
968 (885, 1,058)
1,383 (1,264, 1,514) 6,193 (5,540, 6,923) 1,475 (1,318, 1,650)
3333
545 (528, 563)
749 (726, 773) 2,411 (2,312, 2,515) 476 (458, 494)
1093
447 (423, 473)
624 (590, 660) 2,403 (2,238, 2,580) 402 (377, 429)
501
502 503
471
471 474
3357
3253 3571
1093
1136 1175
†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
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Duration of Efficacy/Immunogenicity
As in females, correlate of protection is not established in males.
Reverse cumulative distribution curves of titers at 24 months indicate that the pattern of decline of titers is similar in males and females.
10 year follow-up extension of efficacy and immunogenicity in the pivotal study, V501-020, has been proposed by the sponsor. Protocol 018, which includes males and females 9-15 years of age, has immunogenicity and efficacy follow-up to 10 years.
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Safety – V501-020
Safety Assessments were done at each vaccination visit and every 3 months postvaccination series All subjects were given a Vaccine Report Card (VRC) to record:
Oral temperature out to 5 days Injection-site AE’s out to 14 days Systemic AE’s out to 14 days
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Summary of AEs, Days 1-15 Following Any Vaccination, V501-020
Gardasil (N=1945) n With one or more AEs Injection-site AEs Systemic AEs 1345 1169 615 % AAHS control (N=1950) n 1244 1047 613 %
69.2 60.1
31.6
63.8 53.7
31.4
With vaccine-related AEs*
Vaccine-related injection-site AEs Vaccine-related systemic AEs With SAEs Who died** Discontinued due to an AE Discontinued due to an SAE
1242
1169 274
63.9
60.1 14.1 0.3 0.0 0.1 0.0
1134
1046 284
58.2
53.6 14.6 0.1 0.0 0.2 0.0
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5 0
2 0
1 0
4 0
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
Systemic AEs* Days 1-15 Following Vaccination, V501-020
Adverse Event Term With one or more systemic AE’s Diarrhea
Gardasil (N=1945)
n 615 40 % 31.6 2.1
AAHS control (N=1950)
n 613 36 % 31.4 1.8
Pyrexia**
Influenza Nasopharyngitis Headache Pharyngolaryngeal pain
118
42 44 179 38
6.1
2.2 2.3 9.2 2.0
125
44 50 207 37
6.4
2.3 2.6 10.6 1.9
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
22 Analysis of AEs by System Organ Class was similarly unremarkable
Injection Site AEs, Days 1-5 Following Vaccination, V501-020
Injection Site Reaction One or more injection-site AEs Gardasil (N=1945) n 1166 % 59.9 AAHS control (N=1950) n 1046 % 53.6
One or more severe injection-site AEs
Injection-site pain Injection-site erythema Injection-site pruritis
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1113 304 22
1.3
20
991 275 24
1.0
57.2
15.6 1.1
50.8
14.1 1.2
Injection-site swelling
219
11.3
187
9.6
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
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Pooled Safety Population – Studies V501020, -016, and -018
Protocol 016 018 020 Total Age 10-15 years 9-15 years 16-26 years 9-26 years Gardasil (N) 508 564 2025 3097 Placebo* (N) 0 275 2030 2305 Total 508 839 4055 5402
*Placebo was saline alone in Protocol 018, the only study in the clinical development program in which placebo did not contain adjuvant.
Summary analyses of AEs in pooled safety dataset lead to conclusions similar to those from V501-020.
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SAEs, Days 1 to 15 Following Vaccination, Pooled Safety Population
SAE Gardasil* (N=3092) AAHS control* (N=2303)
n
%
n
%
With Serious AEs
abdominal pain acute renal failure new onset type 1 diabetes mellitus
9
1 1 1
0.3
0.0 0.0 0.0
1
0 0 0
0.0
0.0 0.0 0.0
localized infection and pain (lower extremity)
appendicitis cellulitis (lower extremity) chest pain peanut allergy
1
1 1 1 1
0.0
0.0 0.0 0.0 0.0
0
0 0 0 0
0.0
0.0 0.0 0.0 0.0
varicella infection with seizure
contusion
1
0
0.0
0.0
0
1
0.0
0.0 25
*There were a total of 7 subjects who received a mixed vaccine/placebo regimen that are not counted in the safety tables.
Injection Site Reactions in Boys Compared with Men
Males (9-15yo’s)† (N=506) n One or more injection-site AEs One or more severe injection-site AEs Injection-site erythema Injection-site pain Injection-site pruritis Injection-site swelling 403 22 101 398 13 127 % 80.4 4.4 20.2 79.4 2.6 25.3 Males (16-26yo’s)‡ (N=2025) n 1046 20 275 991 24 187 % 53.6 1.0 14.1 50.8 1.2 9.6
†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.
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Postmarketing Experience with Gardasil in Women
Syncope, sometimes accompanied by traumatic injury, has been noted
Other AEs being monitored*, no evidence of causation Current postmarketing commitment:
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%.
*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
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Need for Postmarketing Studies
Clinical trial safety database (Gardasil: 3097 subjects; Control: 2305 subjects) and worldwide post-marketing safety data are limited in males Literature documents gender differences in vaccine reactogenicity and adverse events (Cook) Different background rates for morbidity and mortality
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Postmarketing Proposed by Sponsor
Phase IV Observational Study 27,000 males (9-26 y/o) who receive at least one dose of Gardasil General short-term safety, ER visits and hospitalizations Self-comparison reference period, beginning 60 days after vaccination Safety Review Committee (SRC) review safety signals and determine follow up
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CBER Summary and Conclusions
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.
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. Immunogenicity bridging provides a basis for inferring protection of 9-15 year old males against genital warts.
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.
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Gardasil for Males: Review Team
Chairperson Regulatory Project Managers Jeff Roberts, M.D. Elizabeth Valenti Laura C. Montague Jeff Roberts, M.D. Nancy Miller, M.D.
Clinical
Statistical
Bioresearch Monitoring Non-Clinical
Martha B. Lee, Ph.D.
Robert Wesley Ching-Long Joe Sun, Ph.D.
CMC
Pharmacovigilance
Robin Levis, Ph.D.
Andrea R. Sutherland, M.D., M.Sc., M.P.H. Michael D. Nguyen, M.D. Lisa L. Stockbridge, Ph.D.
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Advertising/Promotional Labeling:
References
Cook IF. Sex differences in injection site reactions with human vaccines. Hum Vaccin. 2009 Jul;5(7):441-9. 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. 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. Partridge JM, Koutsky LA. Genital human papillomavirus infection in men. Lancet Infect Dis. 2006 Jan;6(1):21-31. World Health Organization. Human Papillomavirus (HPV) Vaccine Background Paper. September 2008.
http://www.who.int/immunization/documents/HPVBGpaper_final_03_04_2009.pdf
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Autoimmune-Associated Events, Pooled Safety Dataset
Conditions GARDASIL (N = 3092) n (%) AAHS Control or Saline Placebo (N = 2303) n (%)
Alopecia Areata Ankylosing Spondylitis Arthralgia/Arthritis/Reactive Arthritis Autoimmune Thrombocytopenia Diabetes Mellitus Type 1 Hyperthyroidism Hypothyroidism Inflammatory Bowel Disease Myocarditis Proteinuria Psoriasis Vitiligo All Conditions
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) 43 (1.4)
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) 32 (1.4)
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N = Number of individuals who received at least one dose of either vaccine or placebo n = Number of individuals with specific new Medical Conditions
Postmarketing Considerations
Standard 42 day window Variable onset windows and analysis time-frames, in addition to temporal statistical scanning methods to look for clusters of onset intervals Identify a pre-specified list of AEs of primary interest (clinical trials, Gardasil in females, adolescent vaccines); flexibility to add signals detected Determine background rates and use reported rates vs. expected background rates (in addition to self-control) to identify signals Analysis to assess safety in younger age groups (9-15) All SAEs reported and included in analysis regardless of the assessment of possible causality 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.
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