PREGNANCY EXPOSURE REGISTRIES: MONITORING RISK FROM DRUG EXPOSURE IN PREGNANCY

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PREGNANCY EXPOSURE REGISTRIES MONITORING RISK
FROM DRUG EXPOSURE IN PREGNANCY

• Kathleen Uhl, MD
• Pregnancy Lactation Team
• US Food Drug Administration
• Center for Drug Evaluation Research
• May 19, 2005

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OVERVIEW

• Background
• Definition
• Types of pregnancy exposure registries
• When and why
• Uses of data from pregnancy registries
• Benefits (what they can do)
• Limitations (what they cant do)
• Challenges

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BACKGROUND

• 60 million women of reproductive age, in U.S.
  (15-44 yrs)
• 10 of women become pregnant annually
• 6 million pregnancies
• gt 4 million deliveries

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BACKGROUND (cont)

• Pregnant women NEED medications
• Enter pregnancy with medical problems
• Develop new medical problems
• Pregnant women USE medications
• Inadvertent exposures to drugs in pregnancy are
  common
• Exposure before pregnancy is known
• Over 50 of pregnancies in U.S. are unplanned

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BACKGROUND (cont)

• At approval no data on drug effects during HUMAN
  pregnancy
• Pregnant women are excluded from clinical trials
• Risk data derived almost exclusively from animal
  data
• Depend on post-marketing surveillance to assess
  HUMAN fetal safety
• Historically relied on spontaneous reports
• Primary concern is teratogenesis (birth defects)

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BACKGROUND (cont)

• Paradigm shift from typical post-marketing
  studies
• Not looking at safety in the patient being
  treated, but impact on the developing fetus
• Looking for a signal
• With drug exposure during pregnancy it is just as
  important, or more important, to find that there
  is no signal (or no increased risk)

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Published August 2002 http//www.fda.gov/cder/guid
ance/3626fnl.pdf
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PREGNANCY REGISTRY GUIDANCE

• How to document
• Planning and protocol development
• Design considerations

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DEFINITION

• A prospective observational study that actively
  collects information on medical product exposures
  during pregnancy associated pregnancy outcomes
• Enrollment based on drug exposure that occurs
  before outcome is known
• Birth defect rate in exposed compared to
  background rate or to specific comparison groups

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REGISTRY

• Problematic nomenclature
• Not a study
• A list of patients
• Not protocol driven data collection and analysis
• Broad in scope
• Variability in amount and type of data
• Patient satisfaction
• Marketing uses

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Pregnancy Registries Home Page
The US Food and Drug Administration Office of
Womens Health
Guide to Pregnancy Registries
Promoting Healthy Pregnancies
Promoting Healthy Pregnancies
To help women make informed and educated
decisions about using medicines during pregnancy,
it is necessary to determine the effect of these
medicines on the unborn baby. Pregnancy Registry
studies are one way to do this. If you are
pregnant and currently taking medicine--or have
been exposed to a medicine during your
pregnancy--you may be able to participate and
help in the collection of this needed
information. This Website provides a list of
pregnancy registries that are enrolling pregnant
women.
Information about Pregnancy Registries
What is a Pregnancy Registry?
How can you participate in a Pregnancy Registry?
Whether or not you should continue taking
medicine during pregnancy is a serious question.
However, if you stop taking medicine that you
need, this could harm both you and your baby.
Unfortunately, this Website cannot give
personalized health advice, so please speak with
a health-care provider who knows you, your
condition, and your medicine before making any
decision about the use of medicine during
pregnancy.
List of Pregnancy Registries enrolling pregnant
women
Learn more about taking medicines while you are
pregnant

• Information about Pregnancy Registries
• What is a Pregnancy Registry?
• How can you participate in a Pregnancy Registry?
• List of Pregnancy Registries enrolling pregnant
  women
• Learn more about taking medicines while you are
  pregnant

http//www.fda.gov/womens/registries/general.html
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TYPES

• Voluntary
• Patient
• Physician, HCP
• Manufacturer
• Mandatory
• Manufacturer part of Phase 4 commitment

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TYPES (cont)

• Country-specific
• UK Anti-epileptic Drug (AED) Registry
• International

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TYPES (cont)

• Disease specific
• Rheumatoid arthritis OTIS
• Seizure disorders - Antiepileptic Drug (AED)
  Pregnancy Registry
• Allergy and asthma (OTIS AAAAI)
• Drug specific
• Multiple examples

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TYPES (cont)

• Single drug, single company
• GSK Lamotrigine Pregnancy Registry
• Single drug, multiple companies
• Ribavirin Pregnancy Registry
• Multiple drugs, single company
• Merck Pregnancy Registry Program
• Some companies think they are doing this
• Multiple drugs, multiple companies
• Antiretroviral Pregnancy Registry

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TYPES (cont)

• Manufacturer
• Biogen Avonex (interferon beta-1a)
• Contract Research Organization (CRO)
• Inveresk
• Ribavirin Pregnancy Registry
• Lamotrigine Pregnancy Registry
• Antiretroviral Pregnancy Registry
• Scientific Organization or Academic Institution
• OTIS Organization of Teratogen Information
  Services
• Rheumatoid Arthritis and Pregnancy Study
• Motherisk Program (Toronto)
• Antipsychotic Medicines during Pregnancy
• Temple University
• National Transplantation Pregnancy Registry

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WHEN TO ESTABLISH A REGISTRY?

• Most frequently and most feasible when product
  first marketed
• Phase IV commitment
• At any time considering both
• Need for risk information
• May be needed with a new indication or dosage
  form

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GOOD CANDIDATE PRODUCTS

• Likely to be used
• In pregnant women for conditions that require
  treatment
• By women of child-bearing potential
• Over conventional therapies (teratogenic)
• Amevive (alefacept)
• Treatment of moderate to severe chronic plaque
  psoriasis
• Pregnancy category B
• Live-attenuated virus vaccines
• Varivax (varicella virus)

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USES OF DATA FROM REGISTRIES

• Change pregnancy letter category
• Zovirax (acyclovir) category C to B
• Burroughs Wellcome CDC, 1984-1999
• 749 pregnancies 756 outcomes
• Pulmicort (budesonide) - category C to B
• Swedish medical birth registry, 1995-1997
• gt 2500 infants
• Sustiva (efavirenz) category C to D
• 100 pregnancies neural tube defects in humans
  consistent with animal (monkey) data

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USES OF DATA FROM REGISTRIES (cont)

• Provide summary of HUMAN data in labeling
• Meruvax II (rubella virus live)
• Provide a signal for further investigation
• Bupropion Pregnancy Registry
• Scientific Advisory Committee
• Noted the repeated occurrence of heart defects
• Agreed with plan for more rapid methods of
  accumulating data
• Monitoring intensified and under further
  investigation

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BENEFITS

• Important step in building prospective HUMAN data
  sets on pregnancy and infant outcomes
• Starting place to get handle on fetal risks
• Monitor for suspected risks
• Identify factors that affect risk
• Provide an estimate of increased risk of birth
  defects over background

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BENEFITS (cont)

• Potential to establish broad margins of safety
  and provide reassurance regarding lack of fetal
  risk
• Provide clinically relevant HUMAN data to help
  prescribers patients make decisions about drug
  use during pregnancy and counsel regarding
  inadvertent exposure

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LIMITATIONS

• Best suited for big risk signals major
  teratogens
• Ability to detect that a drug is NOT another
  thalidomide is critically important

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LIMITATIONS (cont)

• Limited ability to
• Pick up more modest teratogens
• Look at teratogenic effects on a specific organ
  system or specific defect
• Detect increase in spontaneous abortions
• Detect outcomes that manifest late after birth,
  e.g., behavioral or intellectual development or
  reproductive function

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LIMITATIONS (cont)

• Multiple registries may apply to the same patient
  who takes multiple drugs
• Clinicians have short time and attention
• Attribution of effect across studies is
  problematic
• May take a long time to collect enough exposures

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METHODOLOGIC CHALLENGES

• Sample size
• How big is big enough?
• Is it feasible?
• Data capture procedures
• Source of information
• Outcome of interest
• Length of follow-up
• Comparison group(s)
• Internal vs. external

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BROADER CHALLENGES

• IRB review
• Informed consent
• Independent data monitoring committee
• Heterogeneity of international registries
• Data release criteria
• Discontinuation of registry

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BROADER CHALLENGES

• Nomenclature of registry
• Handling of generic manufacturers
• How to further investigate a signal
• Inexperience discomfort with using this kind of
  data

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CONCLUSIONS

• There is no single study methodology to assess
  the complete teratogenic effects of a drug
• Pregnancy exposure registries are
• An important component of overall post-marketing
  surveillance of the safety of drug use during
  pregnancy
• One tool
• Useful, not perfect
• A place to start