Clinical Review of Biologics License Application Supplement for Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant (Gardasil®) to extend indication for prevention of vaginal and vulvar cancers related to HPV types 16 and 18.

September 11, 2008
From: Nancy B. Miller, M.D.
Medical Officer
Vaccines Clinical Trial Branch
Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research
Food and Drug Administration

Subject: Clinical Review of Biologics License Application Research

Tables can be found on pg. 136 & 137 of the document.

TABLE 79

New Medical Conditions After Day 1 in Studies HPV-007, -013, -015,-016, -018 in the Safety Population (Final Close-out data)

Event
Gardasil
N=11778
Placebo
N=9686

Subjects with new medical history
8628 (73.3%)
7390 (76.3%)

(Gardasil Adverse Reactions Listed 1st – Placebo Reactions Underneath)

Blood and Lymphatic system disorders
344 (2.9%)
322 (3.3%)
Anemia
240 (2.0%)
243 (2.5%)
Lymphadenopathy/lymphadenitis
60 (0.5%)
47 (0.5%)
Cardiac
44 (0.4%)
40 (0.4%)
Arrythmia
7 (0.1%)
8 (0.1%)
Myocarditis
2 (0.02%)
0 (0.0%)
Palpitations
9 (0.1%)
11 (0.1%)
Pericarditis
1 (0.01%)
0 (0.0%)
Congenital, Facial and Genetic disorders
35 (0.3%)
32 (0.3%)
Ear and Labyrinth Disorders
122 (1.0%)
88 (0.9%)
Deafness/Unilateral deafness
2 (0.02%)
2 (0.02%)
Ear pain
46 (0.4%)
27 (0.3%)
Vertigo/Positional vertigo
26 (0.2%)
20 (0.2%)
Endocrine
79 (0.7%)
81 (0.8%)
Autoimmune thyroiditis
6 (0.1%)
1 (0.01%)
Basedow’s disease
5 (0.09%)
2 (0.02%)
Goiter
11 (0.1%)
8 (0.1%)
Hyperprolactinemia
5 (0.09%)
10 (0.1%)
Hyperthyroidism
11 (0.1%)
10 (0.1%)
Hypothyroidism
34 (0.3%)
38 (0.4%)
Eye disorders
250 (2.1%)
210 (2.2%)
Conjunctivitis/Conjunctivitis allergic
158 (1.3%)
137 (1.4%)
Uveitis
3 (0.03%)
1 (0.01%)
Gastrointestinal disorders
1578 (13.4%)
1454 (15.0%)
Abdominal pain (discomfort)
516 (4.4%)
463 (4.7%)
Coeliac disease
10 (0.1%)
6 (0.1%)
Crohn’s disease
4 (0.03%)
3 (0.03%)
Ulcerative colitis/colitis/proctitis ulcerative
7 (0.06%)
16 (0.16%)
Diarrhea
221 (1.9%)
188 (1.9%)
Gastritis
280 (2.4%)
270 (2.8%)
Irritable bowel syndrome
64 (0.5%)
82 (0.8%)
Nausea
159 (1.3%)
163 (1.7%)
Pancreatitis
3 (0.03%)
1 (0.01%)
Vomiting
114 (1.0%)
86 (0.9%)
General and Administration site conditions
444 (3.8%)
324 (3.3%)
Asthenia
18 (0.15%)
13 (0.13%)
Fatigue
59 (0.5%)
50 (0.5%)
Gait disturbance
0 (0.0%)
3 (0.03%)
Influenza like illness
41 (0.3%)
27 (0.3%)
Malaise
17 (0.14%)
8 (0.08%)
Pyrexia
165 (1.4%)
122 (1.3%)
Hepatobiliary disorders
41 (0.35%)
54 (0.56%)
Cholecystitis
9 (0.08%)
15 (0.15%)
Cholelithiasis
27 (0.23%)
28 (0.29%)
Immune system disorders
288 (2.4%)
247 (2.6%)
Anaphylactic reaction
5 (0.04%)
2 (0.02%)
Anaphylactic shock
2 (0.02%)
0 (0.0%)
Drug hypersensitivity
66 (0.6%)
64 (0.7%)
TABLE 79 (CONT)
New Medical Conditions After Day 1 in Studies HPV-007, -013, -015,
-016, -018 in the Safety Population (Final Close out data)
Event
Gardasil
N=11778
Placebo
N=9686
Hypersensitivity
52 (0.44%)
48 (0.5%)
Infections and Infestations
6234 (52.9%)
5584 (57.7%)
Appendicitis
28 (0.2%)
30 (0.3%)
Bronchitis
309 (2.6%)
268 (2.8%)
Cervicitis
348 (3.0%)
357 (3.7%)
Cystitis
419 (3.6%)
407 (4.2%)
Ear infection
117 (1.0%)
89 (0.9%)
Gastroenteritis
306 (2.6%)
283 (2.9%)
Gyn Chlamydia infection
355 (3.0%)
408 (4.2%)
Mononucleosis
78 (0.7%)
56 (0.6%)
Influenza
627 (5.3%)
554 (5.7%)
Nasopharyngitis
1009 (8.6%)
897 (9.3%)
PID
300 (2.5%)
297 (3.1%)
Pharyngitis
398 (3.4%)
329 (3.4%)
Sinusitis
388 (3.3%)
359 (3.7%)
Tonsillitis
331 (2.8%)
287 (3.0%)
UTI
1004 (8.5%)
1037 (10.7%)
Vaginal candidiasis
1286 (10.9%)
1345 (13.9%)
Vaginal infection
372 (3.2%)
417 (4.3%)
Vaginitis bacterial
1151 (9.8%)
1129 (11.7%)
Vulvovaginal infections
676 (5.7%)
694 (7.2%)
Injury, Poisoning, and Procedural Complications
940 (8.0%)
654 (6.8%)
Investigations
1388 (11.8%)
1354 (14.0%)
Metabolism and Nutrition disorders
195 (1.7%)
162 (1.7%)
Musculoskeletal and connective tissue disorders
800 (6.8%)
632 (6.5%)
Arthralgia
122 (1.0%)
100 (1.0%)
Arthritis
12 (0.1%)
7 (0.1%)
Arthritis reactive
1 (0.01%)
1 (0.01%)
Arthropathy
7 (0.06%)
0 (0.0%)
Back disorder
267 (2.3%)
212 (2.2%)
JRA
1 (0.01%)
2 (0.02%)
Myalgia
45 (0.4%)
41 (0.4%)
Neoplasm, malignant, benign, including cysts
237 (2.0%)
189 (2.0%)
Hodgkin’s disease
3 (0.03%)
0 (0.0%)
Benign neoplasm of thyroid
5 (0.04%)
1 (0.01%)
Fibroadenoma of breast
18 (0.2%)
19 (0.2%)
Nervous system disorders
1108 (9.4%)
861 (8.9%)
Carpal tunnel syndrome
10 (0.1%)
2 (0.02%)
Convulsion/epilepsy
11 (0.09%)
15 (0.15%)
Dizziness
87 (0.7%)
81 (0.8%)
Encephalitis
0 (0.0%)
2 (0.02%)
Headache
712 (6.0%)
523 (5.4%)
Hypoaesthesia
7 (0.06%)
10 (0.1%)
Migraine
146 (1.2%)
130 (1.3%)
Multiple sclerosis
2 (0.02%)
4 (0.04%)
Optic neuritis
2 (0.02%)
0 (0.0%)
Paresthesia
5 (0.04%)
6 (0.06%)
Syncope.vasovagal syncope
61 (0.5%)
54 (0.56%)
TIA
2 (0.02%)
0 (0.0%)

TABLE 79 (CONT)
New Medical Conditions After Day 1 in Studies HPV-007, -013, -015,
-016, -018 in the Safety Population
Event
Gardasil
N=11778
Placebo
N=9686
Pregnancy, puerperium, and perinatal conditions
236 (2.0%)
255 (2.6%)
Psychiatric disorders
517 (4.4%)
473 (4.9%)
Bipolar disorder
14 (0.12%)
14 (0.14%)
Renal disorders
318 (2.7%)
295 (3.0%)
Glomerulonephritis
1 (0.01%)
1 (0.01%)
Nephritis
1 (0.01%)
4 (0.04%)
Reproductive and Breast Disorders
2916 (24.8%)
2812 (29.0%)
Respiratory, thoracic, and mediastinal disorders
651 (5.5%)
489 (5.0%)
Asthma
74 (0.6%)
68 (0.7%)
Pulmonary embolism
1 (0.01%)
2 (0.02%)
Skin and subcutaneous tissue disorders
876 (7.4%)
761 (7.9%)
Erythema multiforme
0 (0.0%)
1 (0.01%)
Erythema nodosum
2 (0.02%)
4 (0.04%)
Rash (multiple types)
77 (0.7%)
96 (1.0%)
Urticaria
51 (0.43%)
52 (0.54%)
Surgical Procedures
1200(10.2%)
1166 (12.4%)
Appendectomy
58 (0.5%)
56 (0.6%)
Vascular disorders
114 (1.0%)
127 (1.3%)
Deep vein thrombosis
3 (0.03%)
8 (0.08%)
Embolism
0 (0.0%)
1 (0.01%)
Hypertension
49 (0.4%)
37 (0.4%)
Hypotension/Orthostatic hypotension
14 (0.12%)
21 (0.22%)
Thrombosis
2 (0.02%)
3 (0.03%)
Source: STN 125126/-(b)(4)-, Table of Listing of Number (%) of Subjects With New Medical
History (Incidence >0% in One or More Vaccination Groups) by System Organ Class
(After Day 1) Safety Population (Protocols 007, 013, 015, 016 and 018)
Reviewer’s Comment: As noted in Table 79 above, the proportions of subjects with any new medical condition after Day 1 were comparable in both treatment groups.
New Medical Conditions in HPV-018 (Gardasil compared to true saline placebo)
Because there was interest in direct comparison of new medical conditions in Gardasil recipients as compared to those who received normal saline, Table 80 is included below. Girls 9-15 years of age are included in the tables below, and show summary of new medical conditions which occurred after Month 7 to Month 30 in this younger age group. As can be noted, there was comparable proportions of subjects with these new medical conditions in each treatment group.
139
TABLE 80
New Medical Conditions Month 7 to Month 30 in Study HPV-018
Girls 9-15 years of age
Event
Gardasil
N=591
Saline Placebo
N=301
Subjects with new medical history
386 (65.3%)
202 (67.1%)
Blood and Lymphatic system disorders
6 (1.0%)
7 (2.3%)
Lymphadenopathy/lymphadenitis
5 (0.9%)
4 (1.3%)
Cardiac
0 (0.0%)
2 (0,7%)
Congenital, Familial and Genetic Disorders
2 (0.3%)
2 (0.7%)
Ear and Labyrinth Disorders
10 (1.7%)
14 (4.7%)
Endocrine disorders
7 (1.2%)
4 (1.3%)
Eye Disorders
22 (3.7%)
12 (4.0%)
Gastrointestinal disorders
Abdominal pain
Colitis
Nausea
Vomiting
71 (12.0%)
30 (5.0%)
1 (0.2%)
8 (1.4%)
9 (1.5%)
36 (12.0%)
8 (2.7%)
4 (1.3%)
3 (1.0%)
2 (0.7%)
General Disorders and Administration site Conditions
24 (4.1%)
13 (4.3%)
Hepatobiliary Disorders
0 (0.0%)
0 (0.0%)
Immune System disorders
Anaphylactic reaction*
12 (2.0%)
1 (0.2%)
5 (1.7%)
0 (0.0%)
Infections and Infestations
261 (44.2%)
138 (45.8%)
Injury, Poisoning and Proecdural Complications
87 (14.7%)
44 (14.6%)
Investigations
9 (1.5%)
9 (3.0%)
Metabolism and Nutritional Disorders
11 (1.9%)
7 (2.3%)
Musculoskeletal and Connective Tissue Disorders
Juvenile arthritis
62 (10.5%)
1 (0.2%)
28 (9.3%)
0 (0.0%)
Neoplasms Benign, Malignant And Unspecified (incl Cysts
And Polyps)
17 (2.9%)
11 (3.7%)
Nervous system disorders
45 (7.6%)
25 (8.3%)
Pregnancy, Puerperium And Perinatal Conditions
1 (0.2%)
0 (0.0%)
Psychiatric Disorders
28 (4.7%)
15 (5.0%)
Renal And Urinary Disorders
Dysuria
14 (2.4%)
8 (1.4%)
1 (0.3%)
0 (0.0%)
Reproductive System And Breast Disorders
48 (8.1%)
24 (8.0%)
Respiratory, Thoracic And Mediastinal Disorders
51 (8.6%)
35 (12.6%)
Skin And Subcutaneous Tissue Disorders
Eczema
Urticaria
58 (9.8%)
3 (0.5%)
3 (0.5%)
34 (11.3%)
3 (1.0%)
3 (1.0%)
Social Circumstances
3 (0.5%)
3 (1.0%)
Surgical And Medical Procedures
29 (4.9%)
18 (6.0%)
Vascular disorders
114 (1.0%)
127 (1.3%)
Deep vein thrombosis
3 (0.03%)
8 (0.08%)
Embolism
0 (0.0%)
1 (0.01%)
Hypertension
49 (0.4%)
37 (0.4%)
Hypotension/Orthostatic hypotension
14 (0.12%)
21 (0.22%)
Thrombosis
2 (0.02%)
3 (0.03%)