|Date:||January 22, 2010|
|Re:||Pharmacovigilance plan review|
|Sponsor:||Novartis Vaccines and Diagnostics, Inc.|
|Product:||Menveo; Meningococcal (Groups A, C, W-135 and Y) CRM197 Oligosaccharide Conjugate Vaccine|
|Indication:||Active immunization of individuals 11 through 55 years of age to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W-135 and Y.|
Chair, BLA Committee
Medical Officer, Vaccine Safety Branch
Director, Division of Epidemiology
Director, Office of Biostatistics and Epidemiology
Background: In the Biologic License Application (BLA) referenced above, the sponsor is seeking the first approval worldwide for its Meningococcal (Groups A, C, W-135 and Y) CRM197 Oligosaccharide Conjugate Vaccine (MenACWY; proposed trade name, Menveo). This BLA seeks licensure for active immunization (by a single intramuscular administration) of individuals 11 through 55 years of age to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W-135 and Y. In the application, the sponsor presents reports of three pivotal and two supportive clinical studies in the intended indicated age range of 11-55 years. The safety profile of MenACWY was evaluated in 3,579 adolescents age 11-18 years and 2,606 adults age 19-55, and presented in this application. No safety issue has been identified that would warrant a Risk Evaluation and Mitigation Strategy (REMS) at this time.
Adverse Event reporting: The sponsor must submit adverse experience reports in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and must submit distribution reports as described in (21 CFR 600.81). In addition, the sponsor will provide expanded adverse experience reporting (in addition to complying with the requirements under 21 CFR 600.80) to the Vaccine Adverse Reporting System for one year following product licensure as follows:
- As 15 day reports: All serious adverse events whether expected/labeled or unexpected/unlabeled.
- As 30 day (monthly) reports if not already submitted as 15 day reports: all allergic events, including anaphylaxis; neurological events including Bell's palsy, Guillain-Barré Syndrome, encephalitis, encephalopathy, brachial neuritis, optic neuritis, other neuropathy, myelitis including transverse myelitis, ptosis, ataxia, multiple sclerosis, acute disseminated encephalomyelitis, cerebrovascular accidents, and transient ischemic attacks; idiopathic thrombocytopenic purpura; Kawasaki disease; myasthenia gravis; other new onset autoimmune disease; and all cases of non-intentional injury.
Current Status of Postmarketing Studies subject to reporting requirements of 21 CFR 601.70:
- The sponsor will conduct a Phase IV self-controlled case-series study to expand the understanding of the safety profile of Meningococcal [Groups A, C, Y, and W-135] Oligosaccharide Diphtheria CRM197 Conjugate Vaccine in a minimum of 50,000 HMO subjects 11 through 19 years of age. CBER reviewed this draft protocol (V59_34) and provided comments to Novartis on December 23, 2009. Novartis responded with a second draft protocol on January 5, 2010. This revised protocol was acceptable to CBER with the exception of masking procedures for clinical reviewers. In a telecom on January 7, 2010, Novartis agreed to the masking procedures requested by CBER. The final IRB approved study protocol will be submitted no later than June 20, 2010. The study will be initiated by August 20, 2010. The final study report will be submitted by 1 year after the last subject has completed the study and no later than August 20, 2015.
- The sponsor will collect pregnancy safety data for Meningococcal [Groups A, C, Y, and W-135] Oligosaccharide Diphtheria CRM197 Conjugate Vaccine by means of the Vaccine and Medications in Pregnancy Safety Surveillance [VAMPSS] program. VAMPSS will prospectively enroll individuals exposed to Meningococcal [Groups A, C, Y, and W-135] Oligosaccharide Diphtheria CRM197 Conjugate Vaccine during pregnancy, and odds ratios for several outcomes (spontaneous abortions, preeclampsia, fetal deaths, preterm births, intrauterine growth restriction, total major congenital malformations, and specific major malformations) will be calculated. Individuals identified by VAMPSS without documented exposure to known teratogens and without exposure to Meningococcal [Groups A, C, Y, and W-135] Oligosaccharide Diphtheria CRM197 Conjugate Vaccine will serve as controls. VAMPSS will also identify infants with specific malformations and perform case control analyses to determine the odds of exposure to Meningococcal [Groups A, C, Y, and W-135] Oligosaccharide Diphtheria CRM197 Conjugate Vaccine. CBER has reviewed a synopsis for both arms of the pregnancy surveillance program. The final IRB approved pregnancy registry protocols will be submitted by August 20, 2010. Subject accrual and data collection will begin at the time of CBER’s approval of the protocol and end no sooner than five years later. The U.S. pregnancy registry may be considered completed one month after discontinuation of patient accrual for the purpose of preparing a five-year final summary report. The five-year final summary report should be submitted to CBER five years and six months after initiation of patient accrual and data collection. After CBER review of the five-year data, the need to continue further data collection in the U.S. pregnancy registry will be discussed with CBER. CBER will have final approval regarding any decision to discontinue the U.S. pregnancy registry.
Recommendations to the BLA Chair and Review Committee:
- CBER will await submission of protocols for each arm of the sponsor’s pregnancy surveillance plan. The document submitted by the sponsor on January 7, 2010 serves as a synopsis for the entire VAMPSS program. CBER expects that multiple questions will be addressed by the expected submissions, but a few issues have already been identified.
- Both protocols will require inclusion and exclusion criteria as well as measures of severity for malformations.
- Both protocols will require an expanded description of planned data collection.
- The active recruitment plan for the cohort arm of the VAMPSS program should be delineated.
- The cohort arm requires a plan for disposition of retrospectively identified exposures.