1. Andrews 3/27/00 SP1 Pregnancy Follow-up Studies Lessons from Glaxo Wellcome Experience

2. Andrews 3/27/00 SP2 Outline  Historical case study  Lessons learned  Future possibilities  Key issues

3. Points to Consider in Deciding When to Establish a Pregnancy Follow-up Study  Likelihood of 1st trimester exposure  Potentially large exposed population of sexually active women Ages 15-44  Animal data and relationship to effect on human fetus  Underlying medical condition  Medication’s mechanism of action  FDA pregnancy category rating

4. Andrews 3/27/00 SP4 Case-study: Acyclovir Background  Antiviral medicine to treat herpes simplex virus infections  Pregnancy registry established in 1984 due to: Potential for unintentional 1st trimester exposure to new chemical entityPotential for unintentional 1st trimester exposure to new chemical entity Historic precedent of less specific antiviral agents for toxic effectsHistoric precedent of less specific antiviral agents for toxic effects

5. Andrews 3/27/00 SP5 Acyclovir Study - Origins  Acyclovir Study established 1984 –Part of broad epidemiologic safety program –Joint effort with CDC –Objective: Monitor for risks of birth defects following antenatal acyclovir exposure –Duration: Use registry approach until other, more efficient, methods could address the question

6. Andrews 3/27/00 SP6 Design Considerations (1) Exposures of potential interest –Oral acyclovir –IV acyclovir –Topical acyclovir –Maternal exposures –Paternal exposures –Trimester 1, 2, 3 Outcomes of potential interest –Overall major birth defects –Specific birth defects –Minor events –Delayed development –Maternal complications –Spontaneous abortion

7. Andrews 3/27/00 SP7 Design Considerations (2)  Objective: Estimate risk of major birth defects  Cohort study neither ethical nor feasible because outcomes are too rare  Case-control not feasible –Exposures too rare –No a priori hypotheses  No existing data resources available and sufficient

8. Andrews 3/27/00 SP8 Design Considerations (3)  Exposure registration and followup study –Prospective enrollment required –Birth defect comparator needed (population rate) –Outcomes: birth defects consistent with CDC definitions –Other outcomes not within scope (e.g., maternal events, spontaneous abortion) because different / more data neededdifferent / more data needed methods not appropriatemethods not appropriate

9. Inclusion Criteria Trimester 1 Trimester 2 Trimester 3Birth Ultrasound 16 weeks PROSPECTI VE (included) Case reported before outcome known RETROSPECTIVE (excluded) Case reported after outcome known

10. Andrews 3/27/00 SP10 Method - Data Collection  Initial data collected at enrollment –Exposure, timing, EDD, prenatal testing –Potential confounders specific to the study  Basic information from single reporter –Likely to be motivated –Likely to have exposure and outcome information –Will not require additional steps

11. Methods - Follow-Up  Follow-Up: –Form sent to health professional at EDD –Monthly reminders until data obtained –Patient identifiers (not names) used and deleted at completion –Thank you letter with encouragement to register other exposures, and to solicit longer term outcomes, if known

12. Andrews 3/27/00 SP12 Targeted Follow-Up of Birth Defects  Initiated by registry staff  Targeted to specific birth defect cases reported  Based on CDC teratology review  Could include questions from GW Drug Surveillance M.D.

13. Methods - Analysis  Separate prospective/retrospective reports  Estimate birth defect risk (proportion) from prospective reports  Compare risk against “expected” risk  Evaluate specific birth defects  Analyze defects for evidence of patterns or uniqueness  Review of all data by Advisory Committee

14. Andrews 3/27/00 SP14 Recruitment  Challenge: Encourage enrollment without communicating an inappropriate message –Avoid implying drug should be used in pregnancy –Avoid suggesting a known risk exists  Options: –Use existing health information lines –Referrals from TIS, CDC, FDA –Medical newsletters, journals, MMWR –Scientific meetings, presentations –Package insert

15. Andrews 3/27/00 SP15 Sources of Calls and Referrals Registry CDC Health Care Providers Patients Clinical Trials Operating Companies International Sources Genetic Counselors Company Sales Force Teratogen Information Services Other Manufacturers

16. Advisory Committee  Reviewed data  Assisted in disseminating information  Members represented - Centers for Disease Control and Prevention - Academic medical practitioners/epidemiologists - Glaxo Wellcome medical department - Could be expanded to include other disciplines, groups  Expertise in STDs, Obstetrics, Teratology, Pediatrics, Epidemiology

17. Andrews 3/27/00 SP17 Acyclovir Registry -- Prospective Reports June 1984 - April 1999

18. Andrews 3/27/00 SP18 Results: Birth Defects  First -Trimester Exposure: 19/596 3.2% (95% CI: 2.0%, 5.0%) 3.2% (95% CI: 2.0%, 5.0%)  Any Trimester Exposure: 28/1082 2.6% (95% CI: 1.8%, 3.8%) 2.6% (95% CI: 1.8%, 3.8%)  Does not differ from general population

19. Andrews 3/27/00 SP19 Conclusions  No pattern among prospectively or retrospectively reported birth defects  Potential limitations should be recognized (underreporting, differential reporting, losses to follow-up)  Despite these limitations, these results are useful in the course of counseling women following inadvertent prenatal exposure

20. Andrews 3/27/00 SP20  Information useful to patients and physicians  Useful to GW in evaluation of safety  Information included in product label  Changed label from Category C to B  Study data informed the CDC STD Treatment Guidelines Value of the Study

21. Pregnancy Follow-up Studies  Acyclovir -- June 1984 (now closed)  Antiretrovirals a -- 1 Jan 1989  Lamotrigine -- 1 Sept 1992  Valacyclovir -- Jan 1995 (now closed)  Sumatriptan -- 1 Jan 1996  NA AED Pregnancy Registry a -- Nov 1996  Bupropion -- 1 Sept 1997  Naratriptan -- 1 Oct 1997 a Multi-company sponsored studies

22. Andrews 3/27/00 SP22 Lessons  Design must be targeted to the questions  Simplicity is essential in data gathering  Voluntary recruitment of sufficient numbers of relevant exposures is difficult  Follow-up is a challenge  Ideal must be balanced by practicality

23. Andrews 3/27/00 SP23 Ideal study design Probability of obtaining usefuldataProbability usefuldata MEDICATION SAFETY STUDIES

24. Andrews 3/27/00 SP24 Broad surveillance for increased risks of major birth defects ? Basic Approach Monitoring for specific birth defect? Case-control study Monitoring for subtle or delayed event? Targeted follow up study Yes NO Basic Approach Yes TAILOR DESIGN TO THE QUESTION

25. Andrews 3/27/00 SP25 SELECT THE METHOD APPROPRIATE TO THE OUTCOMES OF INTEREST  Basic registry designed to evaluate risk of major birth defects  Other outcomes can be better studied with different methods –spontaneous abortion –maternal outcomes –infant outcomes requiring long-term follow-up –infant outcomes requiring medical examination for confirmation

26. Andrews 3/27/00 SP26 Selecting the Right Approach High Low Sample Size Complexity Nature of Information Frequency of major birth defects Delayed effects Cross-drug comparison Frequency of all birth defects in first year

27. Andrews 3/27/00 SP27 Impact of Methods on Case Capture and Follow-up Consent required Number of Referral steps Complexity of data collection Duration of follow-up 100% ? 50 %

28. Andrews 3/27/00 SP28 Other Approaches Large linked databases offer promise  Identification of all exposures within a population  Not dependent on voluntary reporting  Follow-up information collected for other purposes  Sample size may be achievable if multiple populations can be used Case-Control studies remain useful

29. Andrews 3/27/00 SP29 Issues  New consent/IRB considerations must balance individuals’ interests with impediments to conducting voluntary registries. Regulations should facilitate, not hinder, public health monitoring functions  Adverse event reporting should follow study guidelines, not spontaneous guidelines  Value and use of information need to be better understood (confirm safety & identify new signals)