why do we worry about pregnancy testing? teratogens and
TRANSCRIPT
Why do we worry about pregnancy testing?
Teratogens and teratogenic risk
Why do we worry about pregnancy testing?
Teratogens and teratogenic risk
Melissa S Tassinari PhD DABT
FDA/CDER/Office of New Drugs
Pediatric and Maternal Health Staff
July 15, 2013
July 15, 2013 CTTI Expert Meeting; Pregnancy Testing in Clinical Trials 1
Outline
• Background
– Clinical trials
– The scientific evidence for teratogenic potential
– Managing teratogenic risk
July 15, 2013 CTTI Expert Meeting; Pregnancy Testing in Clinical Trials 2
Lab Studi@s Several Years
Trials
Human Safety Days or Weeks
·ii
E.xpa ndc-d Saf@ty \!\feels or Months
ttttt
Efficacy & Safety Several Yea rs
• • • • • •
Predinkal----+ Phase 1----• Phase 1111- - - • Phase 111---
• e I e •
Stages of Cllinical Trials
Percentage of Participants by Phase (n=33~ 551 )*
Phase Uns
Phase 3
Phase 2/3
Phase 2
Phase 1/2
Phase 1
0% 20% 40% 60% 80% 100%
I □ Female ■ Male I
Clinical Trials
http://www.fda.gov/ForConsumers/ByAudience/ForPatie International partnership for microbocides http://www.ipmglobal.org ntAdvocates/ParticipatinginClinicalTrials/ucm197788.htm
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Human Data
~
Human Data
• 15-20% of recognized pregnancies will end in miscarriage
• There is a 2-3% risk of a birth defect with every live birth
• For most the causes are genetic or unknown
and there’s a 97% chance your baby is perfect
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All substances are poisons; there is none which is not a poison. The r(qht dose differentiates a poison from a re111edy
Teratogen
Any substance, agent, or process that interferes with normal prenatal development, causing the formation of developmental abnormalities of the embryo or fetus
All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy
Paracelsus (1493-1541)
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Teratogenicity can happen anytime
1 2 dividing zygote, implantation and gastrulation
-+-- not ---+-susceptible to
teratogens
prenatal death
CNS
.,J Yi: \
AJ heart
Teratogenicity can happen anytime
KL Moore, The Developing Human
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Human Data Human Data
Human teratogens (examples)
– Maternal disease, or condition
• insulin dependent diabetes
• folic acid deficiency
• hyperthermia
• alcohol, smoking
– Radiation • atomic weapons,
radioiodine,
• therapeutic high doses (not diagnostic X-rays)
– Intrauterine infection • rubella, toxoplasmosis
– Environmental Agents and Drugs
• heavy metals; lead, mercury
• anticonvulsants, retinoic acid, warfarin
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Timeline of development
Days Gestation
Trimesters
Periods
0
Egg
F irst Second
Embryo Fetu s
280
Third
Key Events and Phases
~ft~=====:::--...,,......-------~ -----.r=iiiiiii;;;;;II-*-=: Organogenesis
Ferti lizat ion Cleavage
Blastulation Implantation
Gastrulation
Teratogenic Exposure Outcomes
Primary Morphogenesis
Example<;: Neural Tube Defects
Gastroschisis Single O u tflow Tract
P hocomelia
Miscarriage
Major Structural D efects
Examples: Mental Rctard;ition
Hearing Loss Hypoglycemia
Cardiomyopathy Lung Immaturit y
Abnormal Organ Differentiation , Growth, and Function
Birth
Timeline of development
Adapted from; Bleyl and Schoenwolf What Is the Timeline of Important Events During Pregnancy That May Be Disrupted by a Teratogenic Exposure? Teratology Primer 2nd Edition http://www.teratology.org/primer.asp 2010
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Scientific Ev· dence for Teratogenicity Scientific Evidence for Teratogenicity
• Biological Plausibility
– Based on what you know, is it a reasonable possibility?
• Animal data
– Evaluates the full range of developmental endpoints (e.g., survival, teratogenesis, behavior and learning)
– Assess hazards that cannot be assessed in clinical trials
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When is a drug a teratogen? Gathering the scientific evidence
► ►
► ►
When is a drug a teratogen? Gathering the scientific evidence
• Reproductive and developmental toxicity studies
– Investigate exposure of mature adults and all stages of development from conception to sexual maturity.
– Pre-mating conception implantation end of
pregnancy (birth) weaning sexual maturity
• Most common study designs*
– Fertility and Early Embryonic Development (one species)
– Embryo/Fetal Development (two species)
– Prenatal and Postnatal Development (one species)
*International Conference on Harmonization (ICH) Detection Of Toxicity To Reproduction For Medicinal Products & Toxicity To Male Fertility S5(R2)
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Types (Classes) of Data • Reproductive toxicity
• Developn1ental toxicity
Types (Classes) of Data
• Reproductive toxicity refers to structural and functional alterations that affect reproductive competence in sexually mature males and females.
– male fertility
– female fertility
– parturition
– lactation.
• Developmental toxicity refers to adverse effects on the developing organism that result from exposure prior to conception, during the prenatal period, or postnatally up to the time of sexual maturity.
– mortality
– dysmorphogenesis (structural abnormalities)
– alterations to growth
– functional impairment.
Taken from FDA guidance: Reproductive and Developmental Toxicities —Integrating Study Results to Assess Concerns.
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Integration of Data Integration of Data
• Positive signals are evaluated to estimate the likelihood of increased reproductive or developmental risk for humans
• All relevant information considered
– reproductive and developmental toxicity data
– general toxicology data as well as human and animal pharmacodynamic and pharmacokinetic data.
– The analysis accounts for the quality and type of data.
• A weight of evidence approach is applied to arrive at an overall conclusion for reproductive or developmental toxicity
Taken from FDA guidance: Reproductive and Developmental Toxicities —Integrating Study Results to Assess Concerns.
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Guidances: International Conference on Harmonization [ICH]
must be performed before large scale or long duration clinical trials are initiated
must be completed not using 'highly effective birth control' or whose pregnancy status is unl<nown
Guidances: International Conference on Harmonization [ICH]
• Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals [ICH M3(R2)] – Reproduction toxicity studies can be staged but must
trials are initiated be performed before large scale or long duration clinical
– Reproduction toxicity and genotoxicity studies must be completed to include women of childbearing potential not using ‘highly effective birth control’ or whose pregnancy status is unknown
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D1ata from anima studies
Lab Studies s.everal Years
Hum ain Safety Days or 1,i1/eeks
:ii
Expanded Safety Effitacy& Safety Weeb or Months Several Yea rs
ttttt ttttttt - Preclinical--.. Phase 1---- Phase 1/11--- Phase 111--......
Stages of Clinical Trials ttttttt
Data from animal studies
Carcinogenicity studies
Safety Pharmacology genetic toxicology, general toxicology (short duration)
General toxicity studies (increasing duration) Reproductive and developmental toxicity studies
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2__Guideline.pdf
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Managing a Teratogenic Risk Managing a Teratogenic Risk
• Risk management options
– Avoid treatment • use other non-teratogenic products
• interrupt treatment until after pregnancy ends
– If treatment necessary/unavoidable • inform/educate stakeholders about risks and safe use
conditions
• ensure safe use through measures to
– avoid/minimize fetal exposure
– prevent pregnancy
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Summary Summary
• Females of Reproductive Potential participate in all phases of clinical trials.
• The understanding of risks for teratogenicity is developed over time and is not usually known prior to the conduct of clinical trials
• Teratogenicity is not just a first trimester event
• The focus for clinical trials is pregnancy prevention
– Pregnancy testing
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