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Vaccines and Related Biological Drug Products Advisory Committee Meeting December 14, 2005

Vaccines and Related Biological Drug Products Advisory Committee Meeting December 14, 2005. Rosemary Tiernan, MD, MPH CBER/FDA RotaTeq ™ (rotavirus vaccine, live, oral, pentavalent ) Merck & Co., Inc . Overview. Epidemiology Product Proposed Indication/Usage Regulatory History

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Vaccines and Related Biological Drug Products Advisory Committee Meeting December 14, 2005

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  1. Vaccines and Related Biological Drug Products Advisory Committee MeetingDecember 14, 2005 Rosemary Tiernan, MD, MPH CBER/FDA RotaTeq™ (rotavirus vaccine, live, oral, pentavalent) Merck & Co., Inc.

  2. Overview Epidemiology Product Proposed Indication/Usage Regulatory History Organization of Clinical Studies Efficacy Safety RotaShield® Experience Questions for the Advisory Committee

  3. Rotavirus Disease Almost all children are infected within the first few years of life. Rotavirus infection in the U.S.: -50,000 hospitalizations per year -20 deaths annually Rotavirus infection worldwide: -2 million hospitalizations per year -352,000 to 592,000 deaths per year in children less than 5 years of age

  4. Product • RotaTeq™ is a live, oral, pentavalent, human-bovine reassortant (Serotypes: Human G1, G2, G3, G4, P1a & Bovine G6, P7) vaccine. • Liquid formulation stored at 2-8 degrees centigrade.

  5. Proposed Indication and Usage • Prevention of rotavirus gastroenteritis in infants and childrencaused by serotypes G1, G2, G3, G4 and G serotypes that contain P1 (e.g. G9) • Administered as 3 dose series with the first dose given to healthy infants at 6-12 weeks of age followed by two additional doses administered at 4-10 week intervals

  6. Regulatory History for RotaTeq™ • June l993 Phase 1 Study 001 initiated • Aug l998 RotaShield® approved • July 1999 RotaShield® withdrawn • May 2000 AC meeting to discuss REST design • Jan 2001 Study 006 (REST) initiated • Nov 2003 60,000th subject randomized (REST) • Sept 2004 70,000th subject enrolled (REST) • Nov 2004 DSMB recommends stopping REST enrollment • April 2005 BLA submitted to FDA

  7. Clinical Studies Phase 1 and 2 trials: • Studies 001, 002, 003, 004 and 005 • 2470 infants and 30 adult subjects

  8. The Phase 3 Studies

  9. Phase 3 Studies: Demographics Across the treatment arms: • Gender • Approximately 50% male and 50% female • Race • 69% white Subjects participated from the following countries: - 48% U.S. and Puerto Rico - 33% Finland - 19% Costa Rica, Guatemala, Mexico, Jamaica, Taiwan, Belgium, Italy, Germany, Sweden

  10. Phase 3 Inclusion Criteria • Healthy infants aged 6 weeks through 12 weeks of age • Healthy, premature infants (<36 weeks of age) enrolled according to chronological age • No restrictions on breast-feeding • No restrictions on concomitant vaccines except OPV was not allowed

  11. Phase 3 Exclusion Criteria • Rectal temperature > 38.10C • Congenital abdominal disorder • Intussusception or abdominal surgery • Immune deficiency • Living in household with immunocompromised person • Chronic diarrhea, history of rotavirus disease • Receipt of blood products, immunoglobulins or immunosuppressive therapy • Receipt of OPV

  12. Important Cohorts in the Phase 3 Studies • Large Safety Cohort (N = 72,324) - Study 006, Study 007 and Study 009 • Detailed Safety Cohort (N = 11,753) - Subset of Study 006 subjects and - All subjects in Studies 007 and 009 • U.S. Concomitant Use Cohort (N = 1358) - Subset of the Efficacy Cohort

  13. Efficacy: Case Definition • Case definition of rotavirus gastroenteritis: • 3 or more watery or looser-than-normal stools within a 24 hour period and/or forceful vomiting and • Rotavirus antigen detected by enzyme immunoassay (EIA) in a stool specimen taken within 14 days of symptom onset. • For the primary efficacy analysis, only G1-, G2-, G3- or G4- specific rotavirus gastroenteritis cases naturally occurring through the first full rotavirus season that began at least 14 days after the third dose of RotaTeq™ or placebo were included.

  14. Study 006 Rotavirus Efficacy and Safety Trial (REST) • Phase 3 double-blinded, randomized, placebo-controlled, international, multi-center study to evaluate the efficacy, immunogenicity and safety of RotaTeq™

  15. Study 006 Primary objectives of Study 006: • Evaluate efficacy of 3 dose regimen of RotaTeq™ against rotavirus gastroenteritis caused by serotypes G1,G2, G3 and G4 occurring at least 14 days following the third vaccination and • Evaluate safety of RotaTeq™ with respect to intussusception within 42 days following any vaccination.

  16. Study 006 Efficacy Primary Null Hypothesis: Efficacy of RotaTeq™ against all G1-, G2-, G3- or G4- specific cases of rotavirus gastroenteritis occurring through the first rotavirus season that begins 14 or more days post-dose 3 would be < 35%.

  17. Efficacy (FDA)

  18. Study 007 End Expiry • Phase 3 double-blinded, randomized, placebo-controlled study to evaluate the efficacy of RotaTeq™ at end expiry.

  19. Study 007 Primary objectives: • Evaluate efficacy of 3 dose regimen of RotaTeq™ at expiry potency against naturally occurring rotavirus disease caused by composite of the serotypes contained within the vaccine (G1,G2, G3 and G4) occurring at least 14 days following the third dose. Primary null hypothesis: • Efficacy of RotaTeq™ at expiry potency against all G1-, G2-,G3-, or G4-specific cases of rotavirus gastroenteritis occurring at least 14 days post dose 3 through one rotavirus season would be less than or equal to 0%.

  20. Efficacy (FDA)

  21. The Safety Cohorts • Large Safety (Study 006, 007, 009) • 72,324 infants randomized • 7 days detailed safety and monitored q 6 weeks for SAEs and IT to 365 days post vaccine dose 1 • Detailed Safety (Subset study 006, all study subjects 007 & 009) • 11,753 infants randomized • 42 days detailed safety (SAEs and AEs) and monitored q 6 weeks for SAEs and IT to 365 days post vaccine dose 1

  22. Safety Endpoint Adjudication Committee (SEAC) - 3 physicians with expertise in pediatric surgery, pediatric radiology and clinical diagnosis of IT - Adjudication was blinded to treatment assignment using pre-specified case definitions and adjudication guidelines. - If disagreement, a majority ruling was made. - All adjudications made by the committee were final.

  23. Data Safety Monitoring Board (DSMB) • Experts in operational, medical, biostatistical aspects of clinical trials. • Not involved in the conduct of the study. • Considered all SAEs and specifically intussusception cases. • Unblinded the treatment arm of positively adjudicated IT cases and made recommendations regarding ongoing conduct of study.

  24. Primary Safety Hypothesis • RotaTeq™ would not increase the risk of IT relative to placebo within 42 days of any vaccine dose. The statistical criteria included: • Distribution of IT cases between vaccine and placebo (case split) would not reach predefined safety boundary for any of the two overlapping day ranges (1 to 7 or 1 to 42 days following any dose) being monitored by the DSMB and • Upper bound on the 95% CI estimate of the RR of IT had to be <10.

  25. Intussusception • Most frequent cause of intestinal obstruction in the first 2 years of life. • Uncommon illness with estimated annual incidence of 1 out of 2000 among infants less than 2 years of age. • Symptoms: irritability, abdominal pain, vomiting, lethargy, bloody or mucous-containing or “currant jelly” stools; may be fatal if left untreated. • Cases confirmed by contrast enema, ultrasound, surgery or autopsy. Some cases may spontaneously reduce.

  26. Intussusception Case of IT had to be diagnosed radiographically, at surgery or at autopsy. • IT case definition similar to Brighton Collaboration Intussusception Working Group except Brighton definition calls for initial ultrasound diagnosed cases of IT to be followed up with another ultrasound to demonstrate resolution/reduction of IT. The Merck definition permitted ultrasound cases alone in order to avoid missing IT cases that could have spontaneously reduced.

  27. Intussusception • For the pre-specified 42-day post-vaccination endpoint, results demonstrated 6 cases of IT versus 5 cases of IT in the placebo group. • Estimated RR of 1.2 with a 95% CI of (0.3, 5.0) was obtained. The upper bound of the 95% CI of the RR is less than 10, which satisfies the prospectively specified primary safety objective of REST.

  28. Intussusception (REST)

  29. Exploratory Analysis with IT Case from Study 005 • 7 month old Caucasian male • Received low dose pentavalent vaccine • Developed hematochezia, vomiting and IT diagnosed at surgery on day 9 post-dose 1 • Benign lymphoid hyperplasia • Merck exploratory analysis: • RR 1.4, 95% (CI: 0.4 - 5.6)

  30. Intussusception • No increased risk of IT at day 42 post-vaccination compared to placebo. - No clustering of IT cases within 7 day or 14 day window post-vaccination.

  31. IT Cases Requiring Surgical Reduction

  32. Positively Adjudicated Cases of IT with Hematochezia Reported

  33. Negatively Adjudicated Cases IT with Hematochezia Reported (Merck)

  34. Negatively Adjudicated Cases IT with Hematochezia Reported (FDA)

  35. Intussusception Results do not address use in infant populations who were not studied such as: • children with HIV • underlying gastrointestinal disorders • infants who reside in areas outside the U.S. where the standard of care is to give live oral polio vaccine. Limited data regarding administration of 1st dose to infants at age >12 weeks or administration of 3rd dose beyond approximately 34 weeks of age.

  36. Deaths (Phase 3 Studies) • No deaths in Phase 1 and Phase 2 • 52 deaths in the Phase 3 studies: • RotaTeq™ 25 • Placebo 27 • Most common cause of death was SIDS • RotaTeq™ 8 • Placebo 9

  37. Death with IT White male randomized to RotaTeq™ arm. On day 96 post dose 3, subject developed abdominal pain, vomiting, bloody stools and barium enema confirmed IT. Subject underwent surgery, had necrotic bowel resected, developed septicemia and died on day 99 post-dose 3 of vaccine.

  38. Serious Adverse Events (SAEs) • Serious Adverse Events in phase 1 and 2 - IT case in study 005 already discussed. • Incidence SAEs in Phase 3 at < 42 days: • RotaTeq™ 2.1% vs Placebo 2.2% • Discontinuations at <42 days post vaccine dose due to SAEs in Phase 3: • RotaTeq™ 0.23% vs Placebo 0.20%

  39. Most Frequent Serious Adverse Events in Phase 3 Trials

  40. Most Frequent SAEs that Led to Discontinuation in Phase 3 Trials

  41. Seizures in the Phase 3 Trials

  42. Hematochezia (Phase 3)

  43. Hospitalizations at <7 days Vaccine Dose(Safety Cohort)

  44. Most Common Reasons for Hospitalizationat <7 days Any Vaccine Dose (Safety Cohort)

  45. Solicited Adverse Events at <7 days (Detailed Safety Cohort)

  46. Concomitant Vaccines • All subjects in Phase 3 permitted to receive licensed pediatric vaccines on same day or within 42 days of vaccination • Subset of 1358 infants (662 RotaTeq™ and 696 Placebo) received concomitant COMVAX®, INFANRIX®, IPOL®, and PREVNAR® and evaluated for immune responses

  47. Concomitant Vaccines -Responses measured at age 7-8 months after 3 doses of vaccine: -Diphtheria, tetanus, pertussis and pneumococcal serotypes -Responses measured at age 5-6 months after 2 doses of vaccine: -PRP, Hepatitis B and polio

  48. Concomitant Vaccines

  49. Concomitant vaccines (Results) • Non-inferiority criteria RotaTeq™ versus placebo met for all antigens except tetanus, diphtheria and pertussis antigens • Assay validation under review for anti-FHA, PT, PRN, tetanus and diphtheria

  50. Summary • There was no increased risk of IT at day 42 post-vaccination when compared to placebo. • Clinical study data not sufficient to support: - administration of a first dose at an age less than 6 weeks or a third dose beyond approximately 34 weeks - use in immunosuppressed patients • Unable to rule out interference of immune responses when RotaTeq™ is co-administered with childhood vaccines to prevent pertussis and diphtheria/tetanus

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