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Vaccines

Telecon on Pharmacovigilance - May 13, 2009 - Menveo

System Info - 110073  SHONE, DEANNA   06-Nov-2009 11:52:48  SHONEDE

RECORD OF TELEPHONE CONVERSATION

Submission Type: Original Application   Submission ID:  125300/0    Office: OVRR  

Product:
Meningococcal [Groups A, C, Y, and W 135] Oligosaccharide Diphtheria CRM197 Conjugate Vaccine

Applicant:                                                                       
Novartis Vaccines and Diagnostics, Inc.          

Telecon Date/Time:  13-MAY-2009 04:56 PM              Initiated by FDA?  Yes
Telephone Number:    

Communication Categorie(s):
Advice

Author:  CARA FIORE

Telecon Summary:
Pharmacovigilance comments on their response to our comments send via email.

FDA Participants:  

Non-FDA Participants:   

Trans-BLA Group: No

Related STNs:  None

Related PMCs:  None

Telecon Body:
From:
Fiore, Cara
To:
"christopher.webster@novartis.com";
cc:
Valenti, Elizabeth;
Subject:
RE: 125300 PVP Comments
Date:
Wednesday, May 13, 2009 4:56:36 PM
Dear Chris,

We have the following comments to Novartis response (to our email below) on the Pharmacovigliance plan for Menveo ages 11-55 y.o.:

Novartis Responses to CBER regarding the proposed pharmacovigilance plans (3/9/09)

CBER ORIGINAL COMMENT: 1. Given the concern regarding Guillain Barré Syndrome (GBS) reports following Menactra, please propose specific plans for evaluating GBS after Menveo.

Novartis response: Enhanced Pharmacovigilance activities for reports of GBS include prompt notification of the Novartis Medical Case Review Committee members for any new report of GBS or GBS-like disease. Reports are reviewed on a weekly basis by physicians trained in and using case definitions established to capture GBS/GBS-like diseases. Data collection would follow a set of pre-established guidelines to ensure that specific information necessary for establishing the diagnosis, assessing causality, tracking the course of the diagnostic evaluations, and ascertaining the outcome of the event. This could include active follow-up (e.g. telephone contact with the reporter) and review of medical records.
(no comment)

CBER ORIGINAL COMMENT: 2. Please present as soon as possible your plans for conducting a large post-marketing safety study. We recommend that you conduct an open label, descriptive, epidemiological, safety surveillance study that enrolls 50,000 Menveo recipients or enrolls for 1 year, whichever results in the larger enrollment, to be reported in accordance with 21 CFR 601.70. Please propose deadlines (e.g., relative to a potential approval date) for: protocol submission to CBER, study initiation, study completion, and final study report submission to CBER. Please note that if a previously undetected safety concern is identified during the ongoing review of your BLA, the above recommended sample size and/or study design may require revision.

Novartis response: Novartis agrees to conduct a post-marketing safety study according to the general specifications described above. While Novartis has not yet generated a protocol for this phase IV trial, we anticipate that the final design would be similar to what is described below.

In the context of a large HMO or other healthcare organization with linked medical database (e.g., --b(4)------------------------------------------------------), Novartis would query the database to identify 50,000 persons aged 11-55 years who have received a dose of Menveo. These vaccine recipients would then be observed prospectively and used as self-controls. To date, no specific safety concern has been identified so certain general outcomes would be pre-specified (e.g., hospitalizations and emergency room visits) and events within specific time windows shortly after vaccination would be compared to events more distant to time of vaccination. Depending on the logistics and availability of the proper comparison cohort, Novartis may use a control population of Menactra recipients followed and analyzed in the same way.
Although even this sample size is limited for such events, some event rates could be calculated for conditions of interest. These might include those identified by CBER in Q3 below such as: major 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 assessed as possibly related to vaccination.

Regarding timelines for these activities: Novartis proposes to submit a protocol to CBER within 3 months of vaccine licensure and the study could begin enrolling within 2 months of concurrence with CBER on the study design. The study would be completed within 3 years of approval and make the report available within 3 months following the last subject’s completion.

Proposed CBER response: We concur with the above postmarketing commitment and ask that you please submit the protocol as soon as it is available, and if at all possible, prior to the initial action due date (6/29/09). In addition, please acknowledge that interim reports will be submitted annually unless requested more frequently (e.g., to address an emerging safety concern).

CBER ORIGINAL COMMENT: 3. We recommend that, if your BLA is approved, the following adverse events should be reported in addition to 21 CFR 600.80 requirements. This expanded adverse experience reporting should be provided to the Vaccine Adverse Event Reporting System for one year following product licensure as follows: a. 15 day reports: All serious adverse events whether expected/labeled or unexpected/unlabeled, including but not limited to vaccine failure, seizures, shock, respiratory distress or difficulty breathing, angioedema, inspiratory stridor, and bilateral wheezing.
Novartis response: We agree to this post marketing commitment. b. 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.

Novartis response: We agree to this post marketing commitment although would request clarification on whether CBER is requesting reports on all cases of non-intentional injury or those non-intentional injuries judged possibly related to vaccination.

Proposed CBER response: We are requesting reports on all cases of non-intentional injury, regardless of assessed relatedness.

CBER ORIGINAL COMMENT: 4. We note that you are planning to establish a pregnancy registry to prospectively collect safety data on spontaneously-reported exposures to Menveo during pregnancy and lactation, including courses and outcomes of such pregnancies. Please submit a protocol for a U.S. pregnancy registry that addresses elements found in FDA's Guidance for Industry on Establishing Pregnancy Exposure Registries (http://www.fda.gov/cber/gdlns/pregexp.htm). Please notify CBER of significant deviations from this guidance and/or specify the deviations in the protocol. Patient accrual/data collection should begin at the time of CBER's approval of the protocol and end no sooner than five years later. Please submit annual reports and a summary report of the U.S. pregnancy registry's findings five years after initiation of patient accrual/data collection. The five-year summary report should be submitted to CBER no later than five years and six months after initiation of patient accrual/data collection. After CBER's review of the five-year data, please discuss with CBER the possible need to continue further data collection in the U.S. pregnancy registry.

Novartis’ response: Novartis is currently in the process of evaluating several potential models for pregnancy registries, each of which is concordant with the guidelines defined by FDA indicated in Q4 above. Final determination of which model Novartis will adopt will occur in the next few months. The two models under consideration are described below:'

Model one
This is what would best be characterized as a ‘traditional’ pregnancy registry. Pregnancy exposures would be identified both through stimulated reporting (outreach to clinics, university health centers, scientific/professional meetings) and spontaneous adverse event report collection. In utero exposures would be identified prospectively (n=~250), and the birth and post partum outcomes ascertained over the first year of life, both by medical record reviews and by querying the clinicians attending the mother/infant during that first year. Rates of birth defects would then be indexed against established rates of disease (such as the Metropolitan Atlanta Congenital Defects Program (ACDP)) to generate relative risk ratios.

Model two
The second model under consideration is one that has been developed by Dr. Allen Mitchell’s group at the Boston University Sloane Epidemiology Center (BUSEC), entitled Vaccine And Medication in Pregnancy Safety Surveillance (VAMPSS). This innovative approach includes two systems in tandem, one using a prospective cohort methodology, and the second using a case/control design.

  • The prospective cohort consists of women identified through the organization of teratology information specialists (OTIS). OTIS is a North American-wide network of university or hospital-based teratology information services in existence since 1979. Pregnant women who report one or more of the targeted vaccines and medications are prospectively enrolled, typically in the first 6-8 weeks of gestation. Maternal interviews are conducted three times during pregnancy and once post-partum, and outcomes are confirmed by chart review. Outcomes among subjects exposed to the vaccines and medications under evaluation are compared to outcomes among participants who were not exposed either to those vaccines or medications or to known teratogenic exposures (“controls”). Relative risks with 95% confidence intervals will be calculated.

Please submit your answers to the BLA. Thanks! Cara

_____________________________________________
From: Valenti, Elizabeth Sent: Thursday, January 29, 2009 9:50 AM To: 'christopher.webster@novartis.com' Cc: Valenti, Elizabeth; Fiore, Cara Subject: 125300 PVP Comments
Chris,
We have the following pharmacovigilance plan comments for BLA 125300:

  1. Given the concern regarding Guillain Barre Syndrome (GBS) reports following Menactra, please propose specific plans for evaluating GBS after Menveo.
  2. Please present as soon as possible your plans for conducting a large post-marketing safety study. We recommend that you conduct an open label, descriptive, epidemiological, safety surveillance study that enrolls 50,000 Menveo recipients or enrolls for 1 year, whichever results in the larger enrollment, to be reported in accordance with 21 CFR 601.70. Please propose deadlines (e.g., relative to a potential approval date) for: protocol submission to CBER, study initiation, study completion, and final study report submission to CBER. Please note that if a previously undetected safety concern is identified during the ongoing review of your BLA, the above recommended sample size and/or study design may require revision.
  3. We recommend that, if your BLA is approved, the following adverse events should be reported in addition to 21 CFR 600.80 requirements. This expanded adverse experience reporting should be provided to the Vaccine Adverse Event Reporting System for one year following product licensure as follows:
    1. 15 day reports: All serious adverse events whether expected/labeled or unexpected/unlabeled, including but not limited to vaccine failure, seizures, shock, respiratory distress or difficulty breathing, angioedema, inspiratory stridor, and bilateral wheezing.
    2. 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.
  4. We note that you are planning to establish a pregnancy registry to prospectively collect safety data on spontaneously-reported exposures to Menveo during pregnancy and lactation, including courses and outcomes of such pregnancies. Please submit a protocol for a U.S. pregnancy registry that addresses elements found in FDA's Guidance for Industry on Establishing Pregnancy Exposure Registries (http://www.fda.gov/cber/gdlns/pregexp.htm). Please notify CBER of significant deviations from this guidance and/or specify the deviations in the protocol. Patient accrual/data collection should begin at the time of CBER's approval of the protocol and end no sooner than five years later. Please submit annual reports and a summary report of the U.S. pregnancy registry's findings five years after initiation of patient accrual/data collection. The five-year summary report should be submitted to CBER no later than five years and six months after initiation of patient accrual/data collection. After CBER's review of the five-year data, please discuss with CBER the possible need to continue further data collection in the U.S. pregnancy registry.

Thank you, Betsy

 

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