2. Guideline Requirements for
Testing Chemicals
Established and proposed guidelines for studies
which include postnatal assessment
Two-generation reproduction study
OPPTS 870.3800; OECD 416; updating and/or
harmonizing drafts
Developmental Neurotoxicity study
OPPTS 870.6300 and DCI for organophosphate
pesticides; OECD 426; harmonizing drafts
3. EPA vs. OECD Harmonization
Issues
Dosing schedule:
Pre-weaning activity:
Reflex ontogeny:
Sample size:
Neuropathology:
Assignment to testing:
Emerging request:
to PND 10 vs. PND 21
3 vs. 1 assessment
non vs. some
10 vs. 20/sex/group
PND 11 vs. PND 21; some
morphometry vs. tiered
1/litter for each test vs.
1/sex/litter for all behavior
kinetics/biomarker effects
4. Guideline Requirements for
Testing Pharmaceuticals
1994 ICH guidelines for medicinal products
Evaluation of postnatal survival, growth,
development, behavior and reproductive performance
following parental exposure (usually Segment II/III or
I/II/III)
FDA, 1998 – possible direct neonatal exposure
to support pediatric use of medicinal products
Exposure period(s) and endpoints determined on a
case-by-case basis
5. Segments Defined by Parental
Exposure Period(s)
Exposure Conventions
Reproductive and Developmental Toxicity Studies
Segment I
II
Gestation
III
Lactation
Mating
Sexual maturity (F0
Conception
Birth
Weaning
Implantation
adults)
Closure of hard palate
7. FDA-Defined Pediatric
Populations
Pre-Term Neonate
Term Neonate
Infant/Toddler
Child
Adolescent
Born at < 38 weeks
Birth to 1 month
1 month to 2 years
2 to 12 years
12 to 16 (or 18) years
Comparable stage/age categories for animal species
dependent on individual organ or system
9. Study Design Considerations:
Target Organ Systems
Organ systems and endpoints of greatest
concern are those that continue to
develop postnatally in humans, e.g.:
Nervous System
Immune System
Kidney
Bone
Reproductive System
Metabolizing Enzymes
Lung
Growth
10. Study Design Considerations: Parental
or Maternal Exposure Studies
Chemicals:
Exposure periods and endpoints specified in
guidelines
Pharmaceuticals:
Standard sample sizes, exposure periods,
and reproductive and developmental
endpoints measured in the offspring
Occasionally include additional assessments
for target organ characterization
11. Study Design Considerations:
Basic Principles
Study design directly affects interpretation of
developmental outcome
Preliminary studies often very useful
Critical period(s) of exposure – TK/PK value
Critical period(s) for assessment of age- and
sex-specific expressions of toxicity
“Litter” is the largest contributor to outcome
Via maternal exposure and maintenance
Similarity among siblings increases with age
12. Study Design Considerations: Are
Direct Exposures Needed?
Rule #1: Talk to the FDA or EPA
Gaps in existing data and/or exposures
Pharmaceutical Considerations:
Medical condition
Target Population
Duration of treatment
Clinical trial schedule
Labeling for pediatric efficacy/safety
Outcome of standard nonclinical
reproductive and developmental studies
13. Study Design Considerations:
Pharmaceutical Direct-Exposure Studies
Therapeutic usage in children –
Primary or secondary therapeutic population
Treatment duration – acute vs. chronic
Probable age(s) at initiation of treatment
What and when to monitor –
Standard toxicity evaluations
Standard developmental evaluations
During and/or after exposure
14. Study Design Considerations:
Direct-Exposure Studies
Case-by-Case Decisions
Exposure period(s) – value of PK/TK information
Assessment period(s) – during/after treatment
One vs. two species
Within-litter vs. between litter designs
Feasibility of studies in animal model
Direct-dosing issues
Compound- and/or age-specific evaluations