This document summarizes the 43rd Annual meeting of the European Teratology Society. It discusses new FDA labeling requirements for pregnancy and lactation information, including removing pregnancy categories and providing risk summaries. It outlines the specific content requirements for sections 8.1 on Pregnancy, 8.2 on Lactation, and 8.3 on Females and Males of Reproductive Potential. Timelines are provided for applications to conform to the new requirements. Presentations are described on inflammation in pregnancy and effects on fetal development, and using zebrafish embryos for chemical screening.

1. 43rd Annual meeting of the
European Teratology Society
JY Han

2. FDA New Labeling
- ETS Counseling Meeting – I
Industry Perspective
Clinical Perspective
Pharmacovigilance perspective
- ETS Counseling Meeting – II
Workshop : Labels without Categories
How to comply with the New FDA rule on content
and Format of labeling for Human Prescription Drug and
biological products

3. FDA PLLR(Pregnancy and Lactation Labeling Rule)
8.1 Pregnancy
Pregnancy Exposure Registry(omit if not applicable)
Risk Summary(Required subheading)
Clinical Considerations(omit if none of the headings are applicable)
Disease-associated maternal and/or embryo/fetal(omit if not applicable)
Dose adjustments during pregnancy and the postpartum period
(omit if not applicable)
Maternal adverse reactions(omit if not applicable)
Labor or Delivery(omit of if not applicable)
Data(omit if none of the headings are applicable)
Human Data(omit if not applicable)
Animal Data(omit if not applicable)

4. 8.2 Lactation
Risk Summary(required subheading)
Clinical Considerations(omit if not applicable)
Data(omit if not applicable)
8.3 Females and Males of Reproductive Potential
(omit if none of subheadings are applicable)
Pregnancy Testing(omit if not applicable)
Contraception(omit if not applicable)
Infertility(omit if not applicable)

5. Applications Required To Conform to New
Pregnancy/Lactation Content Requirements
Time by Which Labeling with New
Pregnancy/Lactation Content Must be
Submitted to FDA for Approval
New or Pending Applications:*
Applications submitted on or after the effective date
of the final rule
Time of submission
Applications pending on the effective date of the
final rule
4 years after the effective date of the final rule or
at time of approval, whichever is later
Approved Applications Subject to the Physician Labeling Rule:
Applications approved any time from June 30,2001, up
to and including June 29,2002, and from June 30, 2005,
up to and including June 29,2007
3years after the effective date of the final rule
Applications approved any time from June 30,2007, up
to and including the effective date of the final rule
4 years after the effective date of the final rule
Applications approved from June 30,2002, up to and
including June 29,2005
5 years after the effective date of the final rule
Implantation Plan
• If the labeling for applications approved before, June 30,2001, the application
holder remove the pregnancy category by 3 years and report the labeling change
in their annual reports.

7. Background
Labeling : communication tool
Objective : to make available to HCP detailed prescribing
information for the safe and effective use of drug
PLR(Physician Labeling Rule) : 2006.1
Requirements on content and format of labeling for
human prescription drug and biological products were
revised
PLLR : 2014.12
Revises PLR content and format requirements for
subsections 8.1 through 8.3 of section 8 USE IN SPECIFIC
POPULATIONS of the FPI

8. 8.1 Pregnancy
Including Labor and delivery
Remove Pregnancy category(A, B, C, D, X)
: confusing, not accurately or consistently
so, poorly informed clinical decision making
Narrative summaries of risk and data
8.2 Lactation
Replaces Nursing mothers
8.3 Female and Males of reproductive potential
New subsection : pregnancy testing, contraception and infertility

9. General Principles
A. Revising Labeling
must be updated
opportunity for revising
add background rate of birth defects and miscarriage
B. Formatting
Subsection number and titles in the FPI must be bolded(8.1 Pregnancy)
Subheading titles within these sections : italicized and underlined
C. Cross-reference
Clinically significant drug-associated adverse development outcome
will cross-reference.
Recommended method of within-subsection cross-reference:
(see Data)

10. Specific Subsections
A. 8.1 Pregnancy
Drug or drug product :
human prescription drug and biological products
I. Pregnancy Exposure Registry
PER : scientifically acceptable when it is consistent with FDA guidance
If there is PER for the drug,
“ There is a PER that monitors pregnancy outcomes in women
exposed to (name of drug) during pregnancy.”
If there is no PER, this subheading should be omitted.

11. 2. Risk Summary
Always required even when there are no data or information available
Provide “risk statement(s)”:
risk of adverse develmental outcomes based on all relevant human data,
animal data and drug’s pharmacology
Adverse developmental outcomes : 4 groups of D. toxicities
“Structural abnormalities” –malformations, variations, deformations, and disruptions
“Embryo-fetal and/or infant mortality”- miscarriage, stillbirth, and infant death
“Functional impairment” – deafness, endocrinopathy, neurodevelopmental effects,
and impariment of reproduction
“Alteration to growth”- growth restriction, excessive growth, and delayed and
early maturation

12.  Risk statement must be presented in the following order:
human, animal, and pharmacologic data
 Risk summary : should be presented as an integrated summary
 Information should be placed in the order of clinical importance
 Must include a cross-reference to additional detail
 If a drug is systemically absorbed, risk summary must include
information about the background risk of major birth defects(2-
4%) and miscarriage(15-20%) in US population regardless of
drug exposure
 When use of a drug is contraindicated during pregnancy,
this information must be stated first in the Risk Summary

13. If data demonstrate that a drug is not systemically absorbed,
“(Name of drug) is not absorbed systemically following(route of
administration), and maternal use is not expected to result in fetal
exposure to the drug”
a. Risk statement based on human data
Human data: Clinical trials, PER, Other large scale epidemiologic studies
*Case series - rare structural abnormality, relatively high frequency
Human data: Its incidence, the effect of dose, the effect of duration of
exposure, the effect of gestational timing of exposure
Human data : if an increased risk, the risk must be quantitatively compared
No human data: this must be stated in the risk summary

14. b. Risk statement based on animal data
When animal data are available, the risk statement must describe the
potential risk for adverse developmental outcome in humans.
- The number and type(s) of species affected
- Timing of exposure
- Animal dose expressed in terms of human dose or
exposure equivalents
- Outcome for pregnant animals and offspring
Risk statement must state when animal studies do not
meet current standards or when there are no animal data.
FDA does not believe it is possible to conclude that a drug causes an
increased risk of a particular type of developmental effect based on
animal data alone.
However, more concerning when the outcome occurs in more than one
animal species, especially if the outcome is consistent across species.

15. C. Risk statement based on pharmacology
When the drug has a well-understood pharmacologic
mechanism of action that may result in adverse
developmental outcomes, the Risk summary must explain the
MOA and the potential associated risks.
Examples,
cytotoxic drugs , drugs that inhibit normal sex hormone
production.
Other drugs : concern may be based on biological plausibility
or human experience(e.g., drugs that interfere with DNA
replication, include cell death, or alter transmission in major
neurotransmitter systems)
Cross-reference should be provided to CLINICAL
PHARMACOLOGY.

17. 3. Clinical Considerations
To provide information to further inform prescribing and risk-benefit
counseling
5 headings:
Disease-associated maternal and/or embryo/fetal risk
Dose adjustments during pregnancy and the postpartum period
Maternal adverse reactions
Fetal/Neonatal adverse reactions
Labor or Delivery
Heading should be omitted if there are no data

18. a. Disease-associated maternal and/or embryo/fetal risk
Include:
information on any serious risks of the untreated
disease/condition in pregnancy for informed decision about
tretment
e.g., diabetes if poorly controlled,
Maternal risk: diabetic ketoacidosis, preeclampsia, delivery
complications due to macrosomia
Fetal risk: NTD, CV malformations, oral clefts, stllbirth,
neonatal hypoglycemia

19. b. Does adjustments during pregnancy and the postpartum period
If there are PK data that support dose adjustment(s) during
pregnancy and postpartum period, this information must be provided
and should be cross-referenced.
Other relevant information: CYP 450 enzymes, known metabolic
pathways of the drug.
e.g., during pregnancy CYP1A2 activity decrease, CYP2D6 activity
increase.
However, vaccine is not applicable due to dose adjustment not made
based on PK data

20. C. Maternal adverse reactions
Describe the drug-associated adverse reactions that are unique
to pregnancy or occur with increased frequency or severity in
pregnant women.
If clinical interventions are available to help monitor or
mitigate drug-associated maternal adverse drug reaction, the
intervention must be described.
(e.g., monitoring bl. Glucose for a drug that cause hyperglycemia
in pregnancy)
If known, the effect of dose, timing, and duration of exposure on
the maternal risk of these adverse reaction must be included

21. d. Fetal/Neonatal adverse reactions
Describe fetal/neonatal adverse reactions that are not adverse
developmental outcomes.
e.g., Opiates administered during labor for intrapartum analgesia
may cause reversible respiratory depression in the neonate.
Administration of naloxone is an available intervention for
mitigation this reaction.

22. e. Labor or delivery
If the drug is expected to affect labor or delivery, the labeling
must provide available information about the drug’s effects on
the mother and the fetus or neonate, and the duration of labor
and delivery.
For drugs approved for use only during labor and delivery,
this heading may be omitted

24. 4. Data
Must describe the data that provide the scientific basis
for the information presented in the Risk Summary and
Clinical Considerations
Human data and animal data must be presented separately,
and Human data must be presented first.

25. a. Human data
 Both positive and negative study findings must be included
Applicants must update labeling as new data become available
 Data source(e.g., controlled clinical trials, ongoing or
completed pregnancy exposure registries, other
pharmacological or surveillance studies, case series)
 Number of subjects
 Study duration
 Exposure information(timing, duration, and dose of exposure)
 Limitations of the data, including potential confounders
and biases

26. b. Animal data
Labeling must describe
 Types of studies
 Animal species
 Animal doses or exposures describe in terms of human dose or
exposure equivalents and the basis for those calculations
 Duration and timing of exposure
 Study findings – dose-response/ severity of adverse development
outcomes
 Presence or absence of maternal toxicity

27. Various factors may affect the level of concern raised by a
positive signal.
 Cross-species concordance of developmental effects
 Multiplicity of effects
 Adverse effects on different stages of the developmental process
 The relationship between maternal and development toxicity
 The presence of a dose-response relationship
 Observation of rare events
 Similarity between pharmacologic and developmental toxicological
mechanisms
 Concordance of the animal and human metabolic and general toxicity
profiles
 Relative animal to human exposure
 Positive signals in other drugs in class or with the same mechanism of
action
 Presence or absence of maternal toxicity

28. B. 8.2 Lactation
Replace the Nursing mothers subsection
Risk Summary / Clinical Considerations/Data
 Drug or drug products : human prescription drugs and
biological products that are regulated as drugs.
 Drug levels in human breast milk will be collected on the
drug, prodrug and the active metabolite(s).

29. I. Risk Summary
 Always required even no data or information available.
 Should summarize information on the presence of a drug and/or
its active metabolite(s) in human milik,
the effects of a drug and/or its active metabolite(s) on the
breastfed child, and the effects of a drug and/or its active
metabolite(s) on milk production.
 When human data are available, animal data must not be included
unless the animal data is specifically known to be predictive for
humans.
 When use of a drug is contraindicated during breastfeeding(e.g.,
radioactive iodine-containing imaging and therapeutic products), the
information must be stated first in the Risk Summary.

30. If data demonstrate that the drug is not systemically absorbed
by the mother,
“(Name of drug) is not absorbed systemically by the mother
following(route of administration), and breastfeeding is not
expected to result in exposure of the child to (name of drug)
a. Presence of drug in human milk
Must state whether the drug and /or its active metabolite are
present or absent in human milk.
If studies demonstrate the presence, must include the
concentrations in human milk and the actual or estimated
infant daily dose for safety concern.
If only animal data are available, must state only whether or
not the drug were detected in animal milk and specify the
animal species, with cross-reference

31. b. Effects of drug on the breastfed child
Systemic and/or local(e.g., GI tract) adverse reactions.
Pediatric age-related differences in absorption, distribution,
metabolism, and elimination of the drug
c. Effects of drug on milk production/excretion
Must describe the effects of a drug on
human milk production/excretion if data
are available.
And specify whether the effect is
temporary or permanent

32. d. Risk and benefit statement
For drugs absorbed systemically by the mother, and not
contraindicated,
“ The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for
(name of drug) and any potential adverse effects on the
breastfed child from(name of drug) or from the underlying
maternal condition.”

33. 2. Clinical considerations
a. Minimizing exposure
Must describe ways to minimize exposure to the breastfed child if :
1. Are present in human milk in clinically relevant contraindications.
2. do not have an established safety profile in infants,
3. are used either intermittently(e.g., acute migraine therapies), in
single dose(e.g., Radio-imaging drugs, anesthetic agents) or for
short course of therapy(e.g., some antibiotics)
Interventions that are intended to minimize exposure should be
described when applicable.
Drugs used chronically by lactating women does not require,
because of drugs are at steady state.

34. b. Monitoring for adverse reactions
A description of available interventions for monitoring and
mitigating drug adverse reaction in breastfed child that
were described in the Risk Summary must be provided.
3. Data
Must describe the data on which the Risk
Summary and Clinical Considerations on based.

35. C. 8.3 Females and Males of Reproductive Potential
Require information for these population when (1) there are
recommendations or requirements for pregnancy testing and/or
contraception before, during , or after drug therapy, and/or (2)
there are human and/or animal data suggesting drug-associated
effects on fertility and/or preimplantation loss effects.
Pregnancy testing/ contraception/ infertility
If data from animal studies raise concerns about mutagenesis or
impairment of human fertility in females or males, this information
must appear under Females and Males of Reproductive Potential

40. President’s Award Lecture
Reduction of risk of drug-related teratogenic effects: A 50 year review
1966 WHO : convened a Scientific group
Proposals for reducing the risk of another thalidomide tragedy :
internationally, organized, multi-disciplinary, long-term research efforts to
improve the predictability of non-clinical screening for teratogenicity
through a better understanding of fundamental developing processes and
mechanism of teratogenic drug action; supplementing postmarketing
surveillance with epidemiologic studies of congenital malformations;
improving methods of informing clinicians of the balance between
therapeutic benefit and teratogenic risk in women at all times during the
reproductive span.

41. First safety classification system : Sweden 1978
--- USA 1979
Recently, refined drug labeling to better inform clinicians of
the balance between therapeutic benefit and teratogenic risk
in USA
ICH(International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human
use ) : provide a timely harmonization of study designs
between the major drug regulating authorities in the USA,
Europe and Japan, reducing unnecessary use of animals.

42. Symposium: Inflammation in pregnancy, and effects on fetal development and health
Why study inflammation in pregnancy?
Inflammation :
normal feature of the healthy mammalian immune system
Source : Injury, infection
Xenobiotics(small inhaled particles, air poliution)
Chronic condition: asthma, diabetes, obesity, stress
Trigger specific signaling events:
Phagocyte cells release: cytokines(TNF, IL1, IL6)
--- ROS(reactive oxygen species)
In pregnancy: parturition, Preeclampsia
offspring CNS, metabolic, immune system

43. Symposium : Zebrafish embryo: Fit for all purposes
Using the AOP framework to develop zebrafish embryo
assays for screening of chemicals
AOP(adverse outcome pathway) framework:
 Basis for the development of new non-animal test methods
 Provides biological context for mechanistic information from
existing assays
 A single AOP may not capture all events that contribute to any
relevant toxic effect
 Analysis of AOP: aid the prioritization of assay development

44. Symposium : Mouse modes
Nutrition during pregnancy and long term risk of type 2 diabetes
Epidemiological studies: association between patterns of early growth and
long term risk of type 2 diabetes
Critical period envirment – permanent impact on long-term health
Both fetal undernutrition and overnutrition appear to have the same
phenotypic consequences in terms of metabolic disease
Animal models : 3 key programming mechanisms
1. Permanent structural changes( suboptimal hormone, nutrients)
2. Accelerated cellular ageing of key metabolic and reproductive
tissues(increased oxidative stress)
3. Epigenetic programming of gene expression(DNA methylation and/or
histone modifications)
--- develop markers of disease risk --- design of intervention strategies

45. TS/ETS Exchange Lecture
Endocrine disruptors: Are they causing adverse effects in humans?
1990s : concern about ED, reports of adverse effects in wildlife
following environmental exposure
DES: adverse effects of reproductive tracts
PCBs : cognitive deficit
Are there other chemicals/targets? Be concern in human?
Cause-effect relationship : a careful review and judgment of all
relevant information
Evidence of causality (Bradford-Hill 1965)
: consistency of findings, dose-response relationship etc.

46. Elsevier Award Lecture: Best manuscript in reproductive Toxicology in 2014
Zebrafish embryotoxicity test for developmental (neuro)
toxicity: Demo case of an integrated screening approach
system using anti-epileptic drugs
Multiple endpoints :
Morphology, Motor activity, histopathology and kinetics
AEDs: VPA, CBZ, ETH, LEV
Contribute to the elucidation of the mode of toxic action
and applicability of ZET

47. Placental transport of synthetic oxytocin as used for
augmentation of labor – A human ex vivo placental perfusion study
 Concern about possible hormonal imprinting effects on brain
when synthetic oxytocin is administered
 To investigate the trans-placental transport of synthetic oxytocin
using the human ex vivo placental perfusion model
 A simplified model for
placental transport using term placenta
 A positive control : antipyrine 100mcg/ml
 Test sub stance: synthetic oxytocin 5-10pg/ml
 ELISA to quantify the presence of synthetic oxytocin

48. Application of a biomarker-based developmental toxicity screen
using human induced pluripotent stem cells
 Thousands of chemicals : safety screen
 Reducing or replacing the use of animal models
 Human induced pluripotent stem cells
: 70 compounds
 cell viability / dose-response curves/ rank toxic potency
 highly predictive of developmental toxicity :
thalidomide, all trans retinoic acid show strong
biomarker responses

50. Thanks