System Info - 113141 SMITH, MICHAEL J 08-Dec-2009 14:51:44 SMITHM
RECORD OF TELEPHONE CONVERSATION
Submission Type: Original Application Submission ID: 125324/0 Office: OVRR
Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)
Wyeth Pharmaceuticals Inc.
Telecon Date/Time: 30-JUN-2009 12:00 AM Initiated by FDA? Yes
Author: COLLEEN SWEENEY
RE: Email regarding Marthe Bryant's comments on draft PVP
FDA Participants: Marthe Bryant, Bob Wise, Andrea Sutherland, Julie Vaillancourt and Colleen Sweeney
Non-FDA Participants: Jack Love and Carmel Devlin
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
Re: Comments on Pharmacovigilance Plan for July 1, 2009, Teleconference
Reference: June 11, 2009, amendment to BLA (Modules 1.2, 1.11.3 and 188.8.131.52):
Response to Agency Request Information, i.e., Response to 3/9/2009
CBER Letter under IND --(b)(4)---, regarding the Pharmacovigilance Plan
Provided below are comments from Dr. Marthe Bryant concerning proposed changes to your draft pharmacovigilance plan (PVP) per the June 11,2009, amendment to your BLA, which included a response to our March 9, 2009, comments on your draft PVP. We note that you originally submitted a draft PVP to IND (b)(4)-, and included a revised version of the draft PVP in the final portion of your original submission to your BLA (i.e., submitted March 31, 2009, Module 1.16, Risk Management Plans).
These comments are intended to facilitate our discussion with you tomorrow at 12:30 PM on your draft PVP:
MAIN SPECIFIC COMMENTS:
Phase 4 Study:
You had proposed to compare incidence rates of medically attended events occurring in the risk period window (day 0 - day 30 post vaccination) to 2 self-control windows (-30 to -5 days prior to vaccination and from day 31- day 60 post vaccination). In the last set of comments, you proposed to eliminate the pre-vaccination self-control window and asked FDA's feedback.
- Please explain the rational for eliminating the pre vaccination self-control period and the reason why the post vaccination window as the single self-control period was retained.
- OBE requests that you retains the 2 self-control periods.
You had proposed an epidemiologic study intended for hypothesis generating rather than hypothesis testing. The study was designed specifically to detect consistent statistically significant medical events to be further evaluated. FDA reminded you that the post-marketing study should be designed keeping the label in mind and should consider a design appropriate for hypothesis testing. FDA suggested that the study be designed to rule out possible associations between 13vPnC and specific adverse events for which the Prevnar 7 post marketing study was inconclusive. These events would include wheezing diagnoses, asthma, bronchiolitis, bronchitis (constrictive airway disease), pneumonia, URI, autoimmune diseases including Kawasaki disease fever, seizure, gastroenteritis, and diabetes mellitus. You agreed to conduct hypothesis testing for specific adverse events and for specific settings.
OBE noted that your proposed sequential statistical analysis is too restrictive and may prevent early detection of potential safety signals. Instead, OBE requests that the heuristic statistical filter be set at a p value of 0.1 (2-sided). OBE asks you to provide tabulations of ICD 9 codes for which the incidences rates are elevated compared to the self-control windows for each setting and for all settings combined. For these diagnoses, OBE requests that you provide the results of a comparative analysis with historical controls for which the p-value is less than 0.1. OBE requests that these tabulations be submitted every three month.
You proposed that children who have received at least one dose of Prevnar 7 be included in the historical control group.
OBE would prefer that the historical controls be separated into 2 distinct groups: one composed of infants who received only Prevnar 7 and one composed of infants who received at least one dose of Prevnar and continue the series with 13vPnC.
- Please explain which events will be undergoing chart review or scan statistics
Summary of Specific Requests Concerning the Phase 4 Safety Study
- OBE requests that you keep the 2 self-control windows.
- We request that you provide a tabulation of incidence rates with self-control comparative rates for pre- and post vaccination windows for all medically attended events for each setting and for all settings combined every three month.
- OBE requests that the decision tree for comparison analyses on historical control be based not on statistical significance level of p-value of 0.05 but rather on a p-value of 0.1 (2 sided).
- OBE requests that you provide causes of mortality for those infants who die within 2 months of vaccination.
- OBE requests that the comparison with historical controls be done on two distinct groups of infants, those who only received Prevnar 7 and those who started the series with Prevnar 7 and have received at least one dose of 13vPnC.
- High risk groups are defined as infants with sickle cell anemia, HIV, and airway constrictive diseases. Selections of such sub groups could be done based on the diagnosis or the corresponding medications. OBE asks that high risk expand to patients with steroids or other immunosuppressive medications.
- OBE requests that the line listing for children who are still in NCKP and did not complete the series during the study period be provided regardless of the status of other vaccination.
- OBE asks that all vaccine providers be instructed to report all serious adverse events potentially related to the vaccine, regardless whether labeled or unlabelled.
- OBE asks that the hypothesis testing analysis include all OBE's pre-specified diagnoses per utilization setting and for all settings combined.
- CBER would expect this study to be initiated immediately following pending licensure and introduction of Prevnar 13, particularly given the limited scale of pre-licensure and safety data for this product. Thus, we consider it necessary to agree on the main outlines and detailed principles of the Phase 4 acute safety study prior to licensure. Submission of an advanced protocol no later than the first week of August would facilitate this goal.
B. Spontaneous reports:
You proposed to provide a line listing of all non l5-day reports to the FDA's VAERS contractor on a monthly basis for the first 3 years as was done for Prevnar.
- OBE agrees with the proposed line listing. It should include a description of each individual adverse event report along with frequency distributions of MedDRA terms for these reports. One listing should identify every MedDRA PT. Another should group the PT's into higher level categories to facilitate recognition of patterns (System Organ Class (SOC), High Level Group Term (HLGT), and High Level Term (HLT)).
- Please describe the cumulative number of U.S. doses distributed with each of these monthly submissions.
End of telecon.