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Record of Telephone Conversation, January 9, 2013 am - Flublok
Submission Type: BLA Submission ID: 125285/0 Office: OVRR
Protein Sciences Corporation
Telecon Date/Time: 09-Jan-2013 08:25 AM Initiated by FDA? Yes
Telephone Number: Communicated via e-mail
2. Information Request
Author: TIMOTHY FRITZ
Request for updated PMR/PMC commitment letter
FDA Participants: Timothy Fritz
Non-FDA Participants: Penny Post
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
From: Fritz, Timothy
Sent: Wednesday, January 09, 2013 8:25 AM
To: 'Penny Post'
Subject: CBER request for updated Flublok PMR/PMC commitment letter
Dear Dr. Post-
We have reviewed your December 17, 2012 submission to STN 125285 (Amendment 74) containing a letter stating PSC’s intention of conducting 2 postmarketing required (PMR) studies and 4 postmarketing commitment (PMC) studies. Your proposals for items 1 and 2 (the 2 pediatric PREA PMRs) and the PMCs for the European Union pediatric efficacy study (item 5) and the CMC PMC (item 6) are acceptable.
We have the following recommendations regarding the Phase 4 general safety study (item 3) and the pregnancy registry (item 4) PMCs:
Regarding the Phase 4 general safety study PMC:
We ask that the following items be included in your study protocol/statistical analysis plan for an observational postmarketing safety study in approximately 25,000 Flublok recipients aged 18 to 49 years, to further characterize the safety profile of Flublok, using recipients of egg-based trivalent inactivated influenza virus vaccine as a comparator:
- primary and secondary safety objectives
- clinical settings (clinic, emergency department, hospital)
- observation periods for outcomes
- medical case review / confirmation of outcomes (clinic notes, hospital records, autopsy reports)
- statistical analysis (e.g., power and sample size, use of methods to adjust for multiple comparisons, appropriate adjustment or matching for important covariates)
Regarding the pregnancy registry PMC:
We ask that the pregnancy registry contain the elements described by the FDA guidance on pregnancy registries (Postmarketing Studies and Clinical Trials – Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act, available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064993.htm), including but not limited to the following:
- The system should have an active recruitment plan. Many women may receive the vaccine in “non-traditional” settings, such as immunization clinics or pharmacies. Therefore, the vaccination may not be in the patient’s medical record or recorded in an automated healthcare database, and sole reliance on one of these sources may present difficulties for recruitment and classification of exposures.
- Women should be enrolled in the registry prospectively, and any data from retrospective enrollments or other cohorts should be analyzed separately.
- The registry should include patient interviews (with both exposed and non-exposed individuals) that would allow the collection of detailed information, including information on confounding factors or risk modifiers that might be impossible to obtain by other means; family history of birth defects, smoking, alcohol, and exposures to over-the-counter medications.
- The pregnancy registry will include active recruitment of a cohort of 600 pregnant women, of whom at least 300 will have been exposed to Flublok. The statistical analysis will include both exposed women and concurrently enrolled women unexposed to Flublok, and it will be adjusted to control for important covariates.
- A plan should be developed for the extent and length of follow-up, and clinic and hospital charts should be available, so that outcomes can be confirmed. The protocol should specify a priori which pregnancy outcomes will be included and which fetal effects will be assessed. A published classification scheme for birth defects should be used.
- The statistical power of the registry to rule out or detect a difference in outcome based on sample size should be specified.
Please provide an updated PMR/PMC commitment letter incorporating the recommendations above with which you agree as an amendment to STN 125285 as soon as possible. You do not need to revise the PMRs/PMCs from your December 17, 2012 letter that were acceptable as noted above.
If you have any questions, please contact the Regulatory Project Chair, Dr. Timothy Fritz, at 301-796-2640.
Timothy A. Fritz, Ph.D.
1451 Rockville Pike
Rockville, MD 20852
1451 Rockville Pike
Rockville, MD 20852
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