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Vaccines, Blood & Biologics

Record of Telephone Conversation, December 13, 2012 - Flublok


Submission Type: BLA    Submission ID: 125285/0    Office: OVRR
Influenza Vaccine
Protein Sciences Corporation
Telecon Date/Time: 13-Dec-2012 03:07 PM        Initiated by FDA? Yes
Telephone Number:
Communication Categorie(s):
1. Advice
2. Information Request
Telecon Summary:
PMR/PMC request
FDA Participants: Timothy Fritz
Non-FDA Participants: Penny Post
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
Telecon Body:
From:                    Fritz, Timothy
Sent:                      Thursday, December 13, 2012 3:07 PM
To:                         'Penny Post'
Subject:                 CBER PMR/PMC request for STN 125285 (Flublok)
Importance:           High
Attachments:         STN 125285 PMR PMC request.pdf
Dear Dr. Post-
Our review of Protein Sciences Corporation’s Flublok Biologics License Application (STN 125285) is ongoing. We have identified the 6 following items as postmarketing requirements (PMRs) or postmarketing commitments (PMCs) for this submission. Please provide a written statement indicating your intention to implement each requirement/commitment and to provide results as noted for each item. For each of the PMR and PMC clinical studies (i.e., items 1-5), please propose dates for final study protocol submission, study completion and final report submission. Please provide the requested information as an amendment to STN 125285 as soon as possible so that the details of the PMRs/PMCs can be determined for inclusion in an Approval Letter and provided to PSC for final agreement.
Your deferred pediatric studies required under 505B(a) of the Federal Food, Drug, and
Cosmetic Act are required postmarketing studies.  The status of these postmarketing studies must be reported according to 21 CFR 601.70 and section 505B(a)(3)(B) of the Federal Food, Drug, and Cosmetic Act.  These required studies are listed below:
1.     Deferred pediatric study under the Pediatric Research Equity Act (PREA) to evaluate the safety, reactogenicity and immunogenicity of Flublok in children 6-17 years of age.
2.     Deferred pediatric study under PREA to evaluate the safety, reactogenicity and immunogenicity of Flublok in healthy children 3-5 years of age.
3.     We acknowledge PSC’s plans to collaborate with Kaiser-Permanente of Northern California to design and conduct a postmarketing safety study in adults 18-49 years old under a protocol with pre-specified statistical analyses, beginning in the 2013-14 influenza season. We ask that the following items be included in your study protocol/statistical analysis plan to be submitted as proposed in the written statement requested above: 
  • expected number of Flublok vaccinees
  • primary safety objectives and secondary safety objectives
  • comparators (e.g., self-control, concurrent cohort of trivalent inactivated influenza vaccine recipients matched for age and sex, concurrent cohort of unvaccinated individuals matched for age and sex)
  • risk windows (e.g., days 1-7, days 8-14, days 1-42)
  • clinical settings (clinic, emergency department, hospital)
  • 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, stratification by appropriate demographic and clinical characteristics)
4.     We acknowledge the receipt of the “Proposal for management of pregnancy registry,” in which PSC states its intention to evaluate individual and composite data, to use the Rule of Three to identify birth defects that require immediate investigation, and to include statistical considerations, power/relative risk calculation and probabilities associated with various birth defects using the March of Dimes database as a comparator.
The registry design that PSC has proposed does not meet many of the desirable qualities described in 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 
We ask that the following characteristics be part of your study protocol/statistical analysis plan to be submitted as proposed in the written statement requested above: 
  • 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 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 comparator group should consist, at a minimum, of a concurrent group of unexposed pregnant women matched for important covariates in relation to the exposed group.
  • 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.
5.     We request that you commit to provide the results of the European Medicines Agency pediatric efficacy study PSC09, if conducted.
6.     In your response to comment 4b of our November 9, 2012, Information Request, you indicated ----b(4)------------------------------------ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------b(4)----- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Additional request (non-PMR/PMC)
  • We request that you provide the complete study report for European Medicines Agency pediatric immunogenicity/safety study PSC08 to IND 11951 when available. 
If you have any questions, please contact the Regulatory Project Chair, Dr. Timothy Fritz, at 301-796-2640.
Thank you.
Timothy A. Fritz, Ph.D.
WOC2 HFM-478
1451 Rockville Pike
Rockville, MD 20852
Phone: 301-796-2640
Fax: 301-827-1597
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