Submission Type: BLA Submission ID: 125296/0 Office: OVRR
Product: Adenovirus Vaccine Live Oral Type 4 and Type 7
Applicant: Teva Women's Health, Inc.
Telecon Date/Time: 06-Dec-2010 03:00 PM
Initiated by FDA? Yes
Communication Category: Information Request
Author: Helen Gemignani
Telecon Summary: Clinical Telecon Information Request.
FDA Participants: Lewis Schrager, Daryll Miller, Helen Gemignani
Non-FDA Participants: Kathy Reape, Howard Hait, Andy Towle, Valerie Mulligan
The review team held a teleconference call with Teva Women's Health, Inc. on December 6, 2010. The following clinical items were discussed:
1) Your definition of seroconversion is as follows: the development of
ADV (4 or 7) neutralizing antibodies at week 4 (Day 26) after study vaccine that was at least a fourfold increase in titer from baseline (visit 0) in a subject whose baseline ADV (4 or 7) titer was <1:4. Based on the data we have received from you, it appears that you have assigned a value of 1:2 for all titers less than 1:4, thereby making the lowest seroconversion value 1:8. Please confirm that this is the case or, if it is not, please describe the actual approach you have taken to define seroconversion.
2) Based upon the ADV-4 clinical and immunogenicity results, have you identified a specific antibody level that is protective against ADV-4 disease, and, by extrapolation, could be considered protective against ADV-7?
3) Please clarify the definitions used to describe the different cohorts analyzed in your submission, particularly the Initial Safety Cohort and the ITT Cohort. The Initial safety Cohort is described as 780 individuals where were randomized in a 3:1 ratio to receive vaccine or placebo, respectively, all from Lot 1 (therefore were not included in the lot-to-lot consistency analysis), and who recorded post-vaccination symptoms on a 2-week daily diary (p.43 of Clinical Report). The ITT Cohort is defined as "subjects enrolled subsequent to the 780 subjects enrolled in the initial safety cohort" (p.43, Clinical Report). In Table 6, p.41 of the Clinical Report, the table heading reads "ITT/Safety Cohort," noting that, for this descriptive table, these cohorts had been merged. Subsequent tables, however, only mention "ITT Cohort" yet seem to reflect this merged ITT/Initial Safety Cohort. Please confirm that, in fact, the tables occurring subsequent to Table 9 which are labeled "ITT Cohort" in fact reflect a merged ITT and Safety Cohort. If this is not the case, please clarify who, precisely, is included under the rubric of "ITT Cohort" in these tables.
4) Please separate the adverse events (AEs) listed in Tables 29 and 30 of your clinical report into tables of solicited AEs and unsolicited AEs. Similarly, in the revised Package Insert, while Table 2 represents a table of solicited AEs reported by ≥5% of subjects, Table 1 appears to include both solicited and unsolicited AEs. Please separate out the solicited AEs from Table 1 and revise the table accordingly.
5) Please refer to your August 24, 2006 submission to your IND (b)(4). Please submit this assay validation report to the BLA.
Teva stated that they will respond to these Information Requests as submissions to the BLA, and IND, in a timely fashion.