A Practical Approach, Second Edition=Ronald D. Ho.pdf

892 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITION2. DoseTraditional approaches, i.e., the selection of low, intermediate, and high doses to identify potentialdose response relationships with respect to adverse effects may not always be applicable to thereproductive toxicity studies for preventive vaccines because immune-based reactions frequentlydo not follow dose response relationships. The dose level(s) selected should elicit an immuneresponse in the animal model and, when feasible, should include a full human dose equivalent (e.g.,1 human dose equals 1 rabbit dose). Injection volume is one consideration for feasibility. Datafrom other available preclinical toxicology studies may guide in the selection of the doses for thereproductive toxicity studies. Control animals should be dosed with the vehicle at the same frequencyas test group animals.3. Immunization IntervalThe immunization interval and frequency of immunization(s) should be based on the clinicallyproposed immunization interval. Similarly, the route or routes of administration should mimic theintended clinical routes, if possible. Since preventive vaccines indicated for females of childbearingpotential or pregnant females are administered infrequently, episodic dosing of pregnant animalsis likely to be more relevant than daily dosing. Thus, in order to mimic potential exposure in theclinical situation, several groups of pregnant animals should be dosed only at defined intervals duringsensitive periods of organogenesis. Modifications to the timing and frequency of dosing may benecessary, depending on the kinetics of the antibody response induced in the animal species. Thus, inaddition to immunizing the female animal during gestation, it may be necessary to also administer apriming dose prior to conception to allow for an immune response to occur during gestation.4. Exposure Period and Follow-Up PeriodOf primary concern are potential adverse effects of the vaccine on embryo-fetal development, asunintentional clinical exposure to the vaccine will likely occur during early stages of pregnancy.Thus, the pregnant animal should be exposed to the vaccine during the period of organogenesis,i.e., from implantation to birth, defined as stages C to D of the ICHS5A document. In addition,some females should be allowed to deliver and the offspring should be followed until weaning toevaluate the health of the neonates as well as look for evidence of maternal antibody transfer. Dataon reproductive performance (i.e., fertility for males and females) are usually not necessary.Additional data regarding the integrity of the reproductive organs for both sexes can be obtainedfrom histopathology data generated in the toxicology studies in nonpregnant animals.5. Study EndpointsThe parameters and endpoints for assessing the potential reproductive toxicity of a preventivevaccine will be based on the theoretical risk and concern associated with the particular productunder study. For selection of standard developmental toxicity endpoints, the ICHS5a documentshould be consulted. Briefly, parameters that should be included are maternal weight gain, clinicalobservations, implantation number, corpora lutea number, litter size, number of live fetuses, fetaland embryonic deaths, resorptions, fetal weight, and crown-rump length, as well as incidence anddescription of external, visceral, and skeletal malformations. Other parameters may also be included.Postnatal evaluations may include maternal-newborn relationship, neonate adaptation to extrauterinelife, preweaning development and growth, survival incidence, developmental landmarks, andfunctional testing. Again, other parameters may also be included.Since the immune system represents the primary target organ for preventive vaccines, thepharmacodynamic effects of the vaccine antigen may potentially result in unwanted findings in the© 2006 by Taylor & Francis Group, LLC