1. Pregnancy Registries’ Contribution to Informed Clinical Practice Third Annual International Conference for Individualized Pharmacotherapy in Pregnancy Indianapolis, Indiana June 7, 2010 Kristine Shields MSN, MPH Global Safety, Merck

2. Course Objectives  To understand the processes in place for evaluating the safety profile of pharmaceutical products used during pregnancy  To appreciate how Pregnancy Registries contribute to the evaluation of pregnancy exposures in the post-marketing environment  To encourage health care provider participation in product safety evaluation

3. Course Outline  Sources of pregnancy data  Pregnancy Registries  Signal detection vs signal investigation  Other sources for data analyses and their uses, strengths and limitations  Risk Management

4. Background  About 64% of pregnant women are prescribed one or more drugs during pregnancy (excluding vitamins/minerals) Chronic health problems that require continuous or intermittent medicine use Acute or new problems that arise during pregnancy  50% of pregnancies are unplanned Inadvertent exposures For most drugs, there are little or no data about use during pregnancy.

5. Source of data  Animal testing  Clinical Trials  Post-marketing surveillance “ The true picture of a product’s safety actually evolves over the months and years that make up the product’s lifetime” - FDA

6. Routine Pregnancy Surveillance  Required  Not a pregnancy registry

7. Definition  Pregnancy Registries are prospective active data collections in systems which can facilitate the early detection of teratogenicity and other serious adverse experiences in patients who inadvertently or purposefully use a drug during pregnancy. Useful information about the outcome of exposure in pregnancy can best be obtained by the careful collection and analysis of postmarketing surveillance data. merckpregnancyregistries.com

8. FDA and Pregnancy Exposure Registries  FDA Guidance for Industry (August 2002): Establishing pregnancy exposure registries  “the ultimate goal of pregnancy exposure registries is to provide clinically relevant human data that can be used in a product’s labeling…”

9. Pregnancy Registry Evolution  Voluntary  Phase IV Commitment  Risk Management Plans

10. Pregnancy Registries  There are different kinds of registries Single drug Multiple drugs Sponsor-managed vs. contract organization

11. Purpose  Primary Signal detection of teratogen or other serious adverse events

12. Purpose  Secondary Help patients and providers to make informed decisions Avoid consequences of poor information  Patients denied treatment  Termination of wanted pregnancies

13. Encourage Participation  FDA website  Product label  Publications  Universal Call Center  Miscellaneous

14. Data  Prospective Reports Learn about the exposure before the outcome of pregnancy is known  Retrospective Reports Learn about the exposure and the outcome of pregnancy at the same time

15. Registry Strengths and Limitations Strengths  Real time  Information to women  Prospective reports  New products  Low cost Limitations  Low numbers  Reporting bias  Variable report quality  No comparator  Loss to follow-up

16. Risk Management  Surveillance, signal detection Monitoring reports, literature, studies Consultant teratologist review, advisory committee Sources of additional information

17. Risk Management  Signal investigation Case reports, literature Registries, call centers Large databases Case-control studies

18. Data Sources and Strengths

19. Risk Management  Provide human data in label  Change pregnancy category Acyclovir; Budesonide (C to B) Efavirenz; mycophenolate mofetil and mycophenolic acid (C to D)  Provide information in periodic reports to regulatory agencies  Provide information in interim reports to health care providers

20. Risk Management  Maternal and fetal outcomes  Pediatric medical record review, long- term follow-up  Other information Causes of inadvertent exposure Product confusion Use patterns

21. Benefit-Risk Relationship  Changes throughout product life cycle  Depends on whether drug is preventive, cosmetic, symptomatic, or curative  Related to risk of non-treatment  Comparative to alternative products

22. Questions?

23. Resources Proposed Pregnancy and Lactation Labeling Rule: CDER Pregnancy and Lactation Labeling http://www.fda.gov/CDER/regulatory/preg nancylabeling/default.htm http://www.fda.gov/CDER/regulatory/preg nancylabeling/default.htm  Pregnancy Registries webpage, FDA Office of Women’s Health http://www.fda.gov/womens/registries/def ault.htm http://www.fda.gov/womens/registries/def ault.htm

24. Back-up Slides

25. Proposed rule: 8.1 Pregnancy Required labeling elements Pregnancy registry contact information (when available) - encouragement to enroll Standard statement about background population risk of fetal abnormalities Three main parts Fetal risk summary Clinical considerations Data

26. Sifontis et al. Transplantation 2006 Dec 27; 82(12): 1698-1702  Overall, 25 transplant recipients with 33 pregnancy outcomes: 15 spontaneous abortions (45%)  all first trimester (3 – 9 weeks gestation) 18 live births/ 4 with malformations (22%)  1 infant with multiple anomalies (including microtia) and death at one day of age  Two infants with microtia (one preterm)  Two infants with cleft lip/palate  One preterm infant with hypoplastic nails and short 5 th fingers. Rates of SAB and malformations increased over background rates (general and transplant recipients)

27. Call Centers, Registries Examples  Pregnancy outcome following maternal use of the new serotonin reuptake inhibitors Kulin et al, JAMA 1998 (OTIS)  Pregnancy outcomes following systemic prenatal acyclovir exposure Stone et al, BDRA 2004 (GSK)  Measles, Mumps, and Rubella MMWR 1998 (CDC)  Immunosuppression in pregnancy Drugs 2002 (Nat’l Transplantation Preg Registry)

28. Large Database Examples  Spina bifida in infants of women treated with carbamazepine during pregnancy Rosa, NEJM 1991 (Medicaid)  Exposure to NSAIDS during pregnancy and risk of miscarriage Li, BMJ 2003 (Kaiser Permanente)  Congenital malformation after the use of inhaled budesonide in early pregnancy Kallen et al, OB/GYN 1999 (SMBR)

29. Retrospective Case-control Examples  Folic acid antagonists during pregnancy and the risk of birth defects Hernandez-Diaz et al, NEJM 2000 (Slone)  Evaluation of an association between loratadine and hypospadias – U.S., 1997-2001 Werler et al, MMWR 2004 (NBDPS)  No teratogenic effect after clotrimazole therapy during pregnancy Czeizel et al, Epidemiology 1999 (HCCSCA)