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Vaccines, Blood & Biologics

Record of Telephone Conversation - Agriflu, December 8, 2009

System Info - 107030 MCWATTERS, BERNARD 06-Oct-2009 16:23:09 MCWATTERS


Submission Type: Original Application Submission ID: 125297/0 Office: OVRR

Influenza Vaccine

Novartis Vaccines and Diagnostics, Inc.

Telecon Date/Time: 08-DEC-2008 12:00 AM Initiated by FDA? Yes
Telephone Number:

Communication Categorie(s):
Information Request


Telecon Summary:
Information request about reproductive toxicity, CMC, and clinical issues.

FDA Participants: Bernard McWatters

Non-FDA Participants: Joanne Totosy de Zepetnek

Trans-BLA Group: No

Related STNs: None

Related PMCs: None

Telecon Body:
Good morning Joanne,
We are approaching the mid-cycle review point and the review team has some questions or comments that we would like you to address. Most of these comments directly refer to the BLA. The questions posed in the Clinical comments section of this email refer to documents included with your October 17, 2008 email communication to me as well as to the original application. If you have any points in this email that need clarification, please respond to this email and I will make sure that the appropriate reviewer can answer the question.

Reproductive toxicity comments:

  1. We concur that data derived from the Caesarean subgroup of study b(4)000-40 suggest that Agrippal does not adversely affect embryo-fetal development. We further concur that the limited number of litters in control group III and vaccine group IV in study b(4)000-40 is insufficient to allow a meaningful interpretation of possible effects of the Agrippal vaccine on postnatal development. We note that you have evaluated the serology in study b(4)000-40 on some animals to investigate possible infection of animals and findings were unremarkable. You further state that you attribute the high pup mortality to handling of the pups between DL 1-5. However, data from the follow-up study b(4)000-43 suggest that handling of pups during lactation days 2-5 only partially account for pup mortality (see item 2). Please provide any additional information on investigations you have performed to explain the finding of high pup mortality during LD 2-5 in studies b(4) 000-40 and b(4) 000-43. In addition, please provide information with regard to the data the animal supplier has on file to demonstrate health of the animals.
  2. In the repeat study b(4)000-43 you state that the total numbers of pups stillborn, found dead or euthanized due to adverse clinical signs was 93 in control group I and 46 in vaccine group II. You state that number of pups that died in the control group I (41.1% during postpartum days 2-5) was increased compared to the vaccine group II (26.7%) resulting in a viability index (defined as number of live pups on day 5 postpartum/number of liveborn pups on day 1 postpartum) of 70.0% in group II versus 58.0% in group I. Historical control data from 4 studies show that the % pups found dead or presumed cannibalized between days lactation 2-5 is 23 % (6.0-42.8). Thus, the % of pups found dead in the current study between lactation days 2-5 (26.7% and 41 %) is 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). Thus, as in study b(4)000-40, pup mortality across study groups does not allow a meaningful interpretation of the data with regard to potential effects of the Agrippal vaccine on postnatal development.
  3. The proposed language in section 8.1 of the product labeling follows the format of the proposed rule entitled “Content and Format of Labeling for Human Prescription Drug and Biological products; Requirements for pregnancy and lactation labeling” (May 29, 2008).
    1. It is acceptable to include the subheadings as described in the proposed rule in product labeling. However, as the proposed rule is not finalized, the pregnancy labeling section 8.1 must include a pregnancy category and language as prescribed in current 21 CFR 201.57(9)(i)(A). This will need to be addressed when negotiating the product labeling.
    2. While we agree that, based on study b(4)000-40, Agrippal does not affect embryo-fetal development, the data derived from the natural delivery subgroups from both studies, i.e., b(4)000-40 and b(4)000-43, are problematic due to the observed pup mortality across study arms, so that potential effects of Agrippal on postnatal development cannot be ascertained.
    3. Please comment on how data from postnatal observations will be described in product labeling.
  1. In study b(4)000-43 body weight and feed consumption values of the F0 generation are concerning because losses in body weight and feed consumption occurred primarily in animals assigned to the vaccine treated group. Moreover, there appear to be some differences in reproductive parameters, e.g., the number of rabbits achieving pregnancy in the vaccine treated group (21) was slightly decreased compared to the control group (25), there were differences in the fertility index (92.6% in the control group and 80.0% in the vaccine group), gestation index (100% in the control group and 85.7% in the vaccine group) and pregnancy rate (92.6 % in the control group and 77.8% in the vaccine group). We note that the gestation index in the vaccine group (85.7%) is below the gestation index observed in historical controls (97.8% (88.9-100). In addition, the number of liveborn pups in the vaccine treated group IV (82.0%) was reduced compared to the number of liveborn pups in group I (92.0). Even though these differences did not reach statistical significance, a possible vaccine related effect cannot be ruled out. Please comment.
  2. You state that in groups III and IV of study b(4)000 - 40, 78 and 69 pups were found dead, were stillborn or were euthanized, respectively (page 43 of 399). Please clarify the numbers of dead pups in group IV, i.e., Table 25 shows that 136 total pups were delivered, 12 were stillborn and an additional 68 pups died between LD 1 and 15. Thus, the total number of dead pups in group IV should be 80 rather than 69. Moreover, Table 28 states that the number of pups found dead in vaccine group IV was 57.
  3. You state that the total number of pups stillborn, found dead or euthanized due to adverse clinical sign was 93 and 46 in groups I and II in b(4)000-43, respectively (page 35 of 314). Please clarify these numbers. In Table 18 it is stated that in group I, there were 13 stillborn pups and 87 pups dying between LD 0-15, thus, the total number of dead pups should be 100. Furthermore, Table 18 shows that in group II, there were 15 stillborn pups (in contrast, Table 21 states that there were 11 stillborn pups) and that 40 pups died between LD 0-15. Thus the total number of dead pups should be 55, not 46, and not accounting for the 9 pups for which the viability status could not be confirmed.
  4. Please explain the variability in the number of studies included in the historical control database (period 1997-2007) for study b(4)000-43. For example, the number of studies included regarding viability indices ranges from 1 - 6 and the number of studies included regarding pups found dead on lactation days 1 - 29 ranges from 2 - 10.
  5. Your proposed labeling indicates that limited data are available from vaccinating pregnant women with Agrippal. Please provide these data.

Clinical comments:

  1. Please clarify whether the protocol deviations described in your letter of October 17, 2008 are described in the Agrippal BLA.
  2. Please clarify how many subjects had been enrolled and vaccinated at the time of staff re-training.
  3. Please provide the number of subjects for whom there were problems with either diary cards or informed consent.

CMC comments:

3 Pages determined to be not releasable


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  1. Viral Inactivation Test

Qualification Report for the viral inactivated test for trivalent formulated bulk has not yet been provided.

  1. Please submit the template of lot release protocol for the trivalent formulated bulk.

Thank you for your attention and we look forward to receiving your responses.

Bernard J.P. McWatters, Ph.D.
1401 Rockville Pike rm. 389N
Rockville, MD 20852
Office - 301-827-5379

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