Types of Toxicology studies -ICH M3 guidelines.
Genetic Toxicity Studies
• Evaluate the potential of a molecule to damage DNA
- Ames Test
- An in vitro test with cytogenetic evaluation of
chromosomal damage with mammalian cells
- An in vitro mouse lymphoma tk assay (mammalian cells)
- An in vivo test for chromosomal damage using rodent
haematopoietic cells (chromosome aberrations in bone
marrow cells or micronucleus assay) – moved from cell
into whole animal. Look at the effect of in vivo of the
animal and look at the damage.
NOTE: Compounds giving positive results in this standard
battery may, depending on their therapeutic use, need to be
tested more extensively. If we have a positive in the Ames
and negative in the other two – progress anyway. All
depends on the historical background of the Ames test
Reproductive Toxicity Studies
WHAT:
Evaluate the potential of a molecule to impair fertility or
damage the unborn child (embryo or foetus) or impede
development of the new-born child – assessment of the
embryo-foetal development should be completed prior to
Phase 1 trials.
Avoidance of adverse effects on any aspect of reproduction
and development resulting from the administration of or
exposure to an exogenous agent.
, Men:
Men may be included in Phase I and Phase II trials prior to
the conduct of the male fertility study
Careful histopathological examination of male reproductive
organs performed in the rodent repeat dose toxicity studies
Male fertility study should be completed prior to the
initiation of Phase III trials.
Female:
Female fertility studies should be completed prior to Phase III
trials
Evaluation of appropriate contraceptive precautions
Potential for interaction with hormonal contraceptive
efficacy
Pre- and post-natal development study should be submitted
for marketing approval or earlier if there is a cause for
concern
Stages in Reproductive Toxicology
• Premating to conception
• Conception to implantation
• Implantation to closure of the hard palate
• Closure of the hard palate to birth
• Birth to Weaning
• Weaning to Maturity
Study Design:
• Species and Strain
• Number of animals is crucial in these studies. Require 20
pregnant females per dose group .
• Background information to response of the test animal to
the compound
Genetic Toxicity Studies
• Evaluate the potential of a molecule to damage DNA
- Ames Test
- An in vitro test with cytogenetic evaluation of
chromosomal damage with mammalian cells
- An in vitro mouse lymphoma tk assay (mammalian cells)
- An in vivo test for chromosomal damage using rodent
haematopoietic cells (chromosome aberrations in bone
marrow cells or micronucleus assay) – moved from cell
into whole animal. Look at the effect of in vivo of the
animal and look at the damage.
NOTE: Compounds giving positive results in this standard
battery may, depending on their therapeutic use, need to be
tested more extensively. If we have a positive in the Ames
and negative in the other two – progress anyway. All
depends on the historical background of the Ames test
Reproductive Toxicity Studies
WHAT:
Evaluate the potential of a molecule to impair fertility or
damage the unborn child (embryo or foetus) or impede
development of the new-born child – assessment of the
embryo-foetal development should be completed prior to
Phase 1 trials.
Avoidance of adverse effects on any aspect of reproduction
and development resulting from the administration of or
exposure to an exogenous agent.
, Men:
Men may be included in Phase I and Phase II trials prior to
the conduct of the male fertility study
Careful histopathological examination of male reproductive
organs performed in the rodent repeat dose toxicity studies
Male fertility study should be completed prior to the
initiation of Phase III trials.
Female:
Female fertility studies should be completed prior to Phase III
trials
Evaluation of appropriate contraceptive precautions
Potential for interaction with hormonal contraceptive
efficacy
Pre- and post-natal development study should be submitted
for marketing approval or earlier if there is a cause for
concern
Stages in Reproductive Toxicology
• Premating to conception
• Conception to implantation
• Implantation to closure of the hard palate
• Closure of the hard palate to birth
• Birth to Weaning
• Weaning to Maturity
Study Design:
• Species and Strain
• Number of animals is crucial in these studies. Require 20
pregnant females per dose group .
• Background information to response of the test animal to
the compound
