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Vaccines

Reproduction Toxicity Study Review - Agriflu, May 8, 2009

STN number:  125297/013

DATS number/date/type of submission:  DATS#... /4/15/2009/BLA amendment 13

Relevant IND: -b(4)-

Sponsor: Novartis  Vaccines, 1 Via Fiorentina, 53100 Siena, Italy

Manufacturer of vaccine product:

Novartis Vaccines, 1Via Fiorentina, 53100 Siena, Italy

Reviewer name:  Marion F. Gruber, PhD                                               

Office/Division name/HFM#:  Office of Vaccines Research and Review/HFM 408         

Review completion date:    May 8, 2009      

Vaccine:

Trade name:  AGRIFLU (formerly Agrippal)

Nonproprietary name:  Influenza Virus Trivalent Subunit (A/A/B haemagglutinin and neuraminidase; embryonated hen’s egg) Vaccine, Inactivated (IVV)                 

Intended clinical population:   Persons 18 years of age and older

Clinical formulation:   0.5 ml solution

Route of administration:   IM

The amendment contained the sponsor’s response and proposed language for the pregnancy subsection of the labeling, section 8.1.  In brief, CBER requested that the pregnancy subsection of the label contain information regarding the high incidence of pup mortality which exceeded historical control data and was observed across the two postnatal development and reproduction toxicity studies, -b(4)-00040 and -b(4)-00043.  Due to these events, the potential effects on post-natal development could not be fully assessed.  CBER had proposed stating the following language under the pregnancy category of the label:

Pregnancy Category B.

Reproduction studies have been performed in female rabbits at a dose approximately 15 times the human dose (on a mg/kg basis) and have revealed no evidence of impaired fertility or harm to the fetus due to AGRIPPAL. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, AGRIPPAL should be given to a pregnant woman only if clearly needed.

In two reproduction toxicity studies, the effect of AGRIPPAL on embryo-fetal and pre-weaning development was evaluated in pregnant rabbits. Animals were administered AGRIPPAL 3 times prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 ml/rabbit/occasion (appr. 15-fold excess relative to the projected human dose on a body weight basis) by intramuscular injection.  No adverse effects on mating, female fertility, pregnancy, and embryo-fetal were observed. There were no vaccine related fetal malformations or other evidence of teratogenesis noted in this study.   Potential effects on post-natal development could not be assessed due to pup mortality occurring between lactation days 2 and 5 in the vaccine treated group and in the control group at an incidence higher than that observed historically. However, pup deaths were not considered related to any effect of the vaccine or associated health problem with either the does or kits. The higher incidence of pup deaths was likely a result of coincidental stress that the does underwent while on study.

The sponsor does not agree with the above highlighted text and provides the following reasons:

  1. There were no vaccine-related physical abnormalities seen at the necropsies on day 29 of gestation or lactation day 29 in either study. 
  2. The number of evaluable litters in study -b(4)00043 was increased compared with study -b(4)-00043 and the number of litter was sufficient to state that there was no adverse effects on reflex and physical development of the F1 generation.
  3. The number of animals in -b(4)-00043 is sufficient for the evaluation of post-natal development because the viability index for the control group (57.9%) was only slightly outside the historical control range ---b(4)----
  4. Sponsor considers -b(4)-00043 sufficient on its own but also feels that pooling litter results across studies is acceptable.

The sponsor is proposing the following for pregnancy subsection 8.1:

Pregnancy Category B.

Reproduction studies have been performed in female rabbits at a dose approximately 15 times the human dose (on a mg/kg basis) and have revealed no evidence of impaired fertility or harm to the fetus due to AGRIFLU. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, AGRIFLU should be given to a pregnant woman only if clearly needed.

In two reproduction toxicity studies, the effect of AGRIFLU on embryo-fetal or post-natal development was evaluated in pregnant rabbits. Animals were administered AGRIFLU 3 times prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 mL/rabbit/occasion (appr. 15-fold excess relative to the projected human dose on a body weight basis) by intramuscular injection.  No adverse effects on mating, female fertility, pregnancy, and embryo-fetal development attributable to the vaccine were observed. There were no vaccine related fetal malformations or other evidence of teratogenesis noted in this study. There were no vaccine related effects on post-natal development.

Response:  We remain concerned about the statement that “There were no vaccine related effects on postnatal development” because the available data derived from studies -b(4)-00040 and -b(4)-00043 do not allow such conclusion for the following reasons:

  1. The sponsor states that there were 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, i.e., -b(4)-00040 and -b(4)-00043 are pooled.  However, study -b(4)-00043 is a replicate study of the natural delivery group previously evaluated in -b(4)-00040 in which the limited number of litters available for evaluation was deemed insufficient by the sponsor to allow a meaningful interpretation of data.  Therefore, it is not acceptable to pool litter data from these 2 studies to arrive at a sufficient number of litters to be evaluated.
  2. As acknowledged by the Director of Research at -b(4)- the number of pup deaths in studies -b(4)-00040 and -b(4)-00043 was higher than was observed historically.  Thus, even though the number of evaluable litters in study          -b(4)-00043 was within the lower range (16) of the ICH recommended litter number that provides a degree of consistency between studies, i.e. 16-20, the  viability indices (based on the numbers of pups dead/euthanized between DL 1-7), i.e., 52.5% (control group I) and 66.4% (vaccine group II) are substantially lower than the viability index observed for the same interval in the control data base (87.3% [81.1 - 96.7%], data from 3 studies).  Thus, it is not appropriate to disregard the finding of pup mortality.
  3. The sponsor, in its Feb 2, 2009, submission (STN125297.04) acknowledges that the viability index in study -b(4)-00043 (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 --b(4)------------------

As stated previously, we do not consider pup death a vaccine related effect but rather, a result of coincidental stress that the does underwent while on study.  However, we do not agree that it would be acceptable to disregard the number of postnatal pup deaths that occurred in both, the initial study -b(4)00040 (42.6% in control and 50.5% in the vaccine group) and in the repeat study -b(4)-00043 (46.9 % in control and 36.4 % in vaccine group) and/or pool litter numbers across studies to arrive at an evaluable litter number.  We maintain for the labeling to describe this phenomenon or at least add a statement to indicate “Potential vaccine related effects on post-natal development could not be fully evaluated.”

In summary the pregnancy subsection 8.1 of the labeling should state:

 

Pregnancy Category B.

Reproduction studies have been performed in female rabbits at a dose approximately 15 times the human dose (on a mg/kg basis) and have revealed no evidence of impaired fertility or harm to the fetus due to AGRIFLU. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, AGRIFLU should be given to a pregnant woman only if clearly needed.

In two reproduction toxicity studies, the effect of AGRIFLU on embryo-fetal or post-natal development was evaluated in pregnant rabbits. Animals were administered AGRIFLU 3 times prior to gestation, during the period of organogenesis (gestation day 7) and later in pregnancy (gestation day 20), 0.5 mL/rabbit/occasion (appr. 15-fold excess relative to the projected human dose on a body weight basis) by intramuscular injection.  No adverse effects on mating, female fertility, pregnancy, and embryo-fetal development attributable to the vaccine were observed. There were no vaccine related fetal malformations or other evidence of teratogenesis noted in this study.  Potential vaccine related effects on post-natal development could not be fully evaluated.

 

Supervisory concurrence:   yes : _X_ no____