System Info - 107212 MCWATTERS, BERNARD 07-Oct-2009 16:30:01 MCWATTERS
RECORD OF TELEPHONE CONVERSATION
Submission Type: Original Application Submission ID: 125297/0 Office: OVRR
Novartis Vaccines and Diagnostics, Inc.
Telecon Date/Time: 22-SEP-2009 09:44 AM Initiated by FDA? Yes
Author: BERNARD MCWATTERS
Novartis questioned the reproductive toxicity comment that Marion Gruber changed in the PI and requested a telecon to discuss. Marion sent me a written response which is included in this email.
FDA Participants: Bernard McWatters
Non-FDA Participants: Joanne Totosy de Zepetnek
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
The toxicology reviewer who reviewed the reproductive toxicity studies addressed the concern in your email with the following response:
The following is to clarify FDA's proposed text "Potential vaccine related effects on post-natal development could not be fully evaluated."
You note (Feb 2, 2009, submission, BLA amendment 125297/0.4 containing response to CBER comments) that our concerns relate to the high number of pup deaths that occurred in both studies, b(4) 000-40 and b(4)000-43. In addition, and as acknowledged by the Director of Research at b(4), the number of pup deaths was higher than was observed historically. Even though the values of pup death observed between LD 2-5, i.e., 26.7% and 41.1% for treated and control groups are within the range of values reported in the historical control database (6.0 to 42.8%), they are still above the mean observed in the historical control data base. Furthermore, when calculating the viability indices based on the numbers of pups dead/euthanized between DL 1-7, the results are 52.5% (control group I) and 66.4% (vaccine group II). These values are markedly lower than the viability index observed for the same interval in the control data base (87.3% (81.1.6 - 96.7, data from 3 studies). You have not provided a response to this observation, however, you did acknowledge that the viability index (calculated by comparing the number of live pups on day 5 with the number of live pups on day 1) for the control group (57.9%) was outside the historical control range (59.6 – 93.6%). Due to the pup death that occurred in both studies, the number of evaluable litters was not sufficient to allow a postnatal assessment in each of the studies, b(4) 000-40 and b(4)000-43.
You have stated that there are sufficient numbers of control and treated animals to assess the effects of Agriflu on postnatal development when the total number of litters from both studies are combined. However, we consider it problematic (i.e. introduction of bias because of preferential inclusion of certain litters) to combine evaluable litters across studies to arrive at a sufficient sample size for an evaluation of postnatal parameters.
In summary, because there were insufficient numbers of evaluable litters to allow a postnatal assessment we proposed the statement "Potential vaccine related effects on post-natal development could not be fully evaluated."
She is hopeful that this clarifies the Agency's position enough to not need a teleconference to discuss the matter. Please let me know if it does.