1. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 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 Kathleen Uhl, MD Pregnancy & Lactation Team US Food & Drug Administration Center for Drug Evaluation & Research May 19, 2005

2. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 2 OVERVIEWOVERVIEW Background Definition Types of pregnancy exposure registries –When and why Uses of data from pregnancy registries Benefits (what they can do) Limitations (what they can’t do) Challenges Background Definition Types of pregnancy exposure registries –When and why Uses of data from pregnancy registries Benefits (what they can do) Limitations (what they can’t do) Challenges

3. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 3 BACKGROUNDBACKGROUND 60 million women of reproductive age, in U.S. (15-44 yrs) 10% of women become pregnant annually –~ 6 million pregnancies –> 4 million deliveries 60 million women of reproductive age, in U.S. (15-44 yrs) 10% of women become pregnant annually –~ 6 million pregnancies –> 4 million deliveries

4. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 4 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 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

5. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 5 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) 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)

6. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 6 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) 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) BACKGROUND (cont)

7. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 7 Published August 2002 http://www.fda.gov/cder/guidance/3626fnl.pdf

8. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 8 “How to” document Planning and protocol development –Design considerations “How to” document Planning and protocol development –Design considerations PREGNANCY REGISTRY GUIDANCE

9. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 9 DEFINITIONDEFINITION “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 “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

10. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 10 “REGISTRY”“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 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

11. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 The US Food and Drug Administration Office of Women’s Health Pregnancy Registries Home Page Information about Pregnancy Registries Promoting Healthy Pregnancies What is a Pregnancy Registry? How can you participate in a Pregnancy Registry? Guide to Pregnancy Registries 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? List of Pregnancy Registries enrolling pregnant women Learn more about taking medicines while you are pregnant 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 http://www.fda.gov/womens/registries/general.html

12. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 12 TYPESTYPES Voluntary –Patient –Physician, HCP –Manufacturer Mandatory –Manufacturer – part of Phase 4 commitment Voluntary –Patient –Physician, HCP –Manufacturer Mandatory –Manufacturer – part of Phase 4 commitment

13. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 13 TYPES (cont) Country-specific –UK Anti-epileptic Drug (AED) Registry International Country-specific –UK Anti-epileptic Drug (AED) Registry International

14. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 14 TYPES (cont) Disease specific –Rheumatoid arthritis – OTIS –Seizure disorders - Antiepileptic Drug (AED) Pregnancy Registry –Allergy and asthma (OTIS & AAAAI) Drug specific –Multiple examples Disease specific –Rheumatoid arthritis – OTIS –Seizure disorders - Antiepileptic Drug (AED) Pregnancy Registry –Allergy and asthma (OTIS & AAAAI) Drug specific –Multiple examples

15. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 15 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 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

16. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 16 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 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

17. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 17 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 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

18. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 18 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) 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)

19. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 19 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 > 2500 infants –Sustiva (efavirenz) [category C to D] ~100 pregnancies – neural tube defects in humans consistent with animal (monkey) data 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 > 2500 infants –Sustiva (efavirenz) [category C to D] ~100 pregnancies – neural tube defects in humans consistent with animal (monkey) data

20. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 20 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 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

21. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 21 BENEFITSBENEFITS 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 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

22. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 22 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 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

23. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 23 LIMITATIONSLIMITATIONS Best suited for big risk signals – major teratogens –Ability to detect that a drug is NOT another thalidomide is critically important Best suited for big risk signals – major teratogens –Ability to detect that a drug is NOT another thalidomide is critically important

24. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 24 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 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

25. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 25 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 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

26. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 26 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 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

27. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 27 BROADER CHALLENGES BROADER CHALLENGES IRB review Informed consent Independent data monitoring committee Heterogeneity of international registries Data release criteria Discontinuation of registry IRB review Informed consent Independent data monitoring committee Heterogeneity of international registries Data release criteria Discontinuation of registry

28. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 28 BROADER CHALLENGES Nomenclature of “registry” Handling of generic manufacturers How to further investigate a signal Inexperience & discomfort with using this kind of data Nomenclature of “registry” Handling of generic manufacturers How to further investigate a signal Inexperience & discomfort with using this kind of data

29. Drug Safety and Risk Management Advisory Committee May 18 & 19, 2005 29 CONCLUSIONSCONCLUSIONS 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 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