1. Guidance for Industry Establishing Pregnancy Registries Pregnancy Registry Working Group Pregnancy Labeling Taskforce March, 2000 Evelyn M. Rodriguez M.D., M.P.H. OPDRA, CDER, FDA

2. Outline ä Why A Guidance Document? ä What is a pregnancy registry? ä Purpose of a pregnancy registry protocol. ä Registry study design. ä Recruitment ä Reporting source ä Follow-up ä Comparison groups ä Data analysis ä Reporting results

3. Why a Pregnancy Registry Guidance Document? ä To provide useful data to health care providers in caring for their patients

4. What is a Pregnancy Registry? ä ä Could have many designs ä ä Often hypothesis generating ä ä Hypothesis testing ä ä Design depends on the hypothesis and outcomes of concern ä ä Ideally, prospective enrollment of subjects ä ä Actively collects information for providing scientifically based outcome data

5. What is the Purpose of a Pregnancy Registry? ä ä Determine risks associated with drug use during pregnancy ä ä Measurement of this risk ä ä Determine risk factors associated for adverse outcome ä ä Could provide margins of reassurance regarding lack of risk

6. Limitations of Current Data Sources ä ä Population-based surveillance systems - no linkage of maternal exposures and fetal outcome is available ä ä Spontaneous Reports - bias in reporting and no incidence estimate available ä ä Clinical Trials - Lack of meaningful data

7. What is the Purpose of a Pregnancy Registry Protocol? ä ä To assure quality & validity of data elements collected ä ä To assure documentation and consistency of research methods

8. What are Pregnancy Registries? ä ä Observational (non-experimental) studies that actively enroll subjects ä ä Registration is ideally prospective ä ä Early in pregnancy ä ä Drug exposure prior to or during pregnancy

9. What are Pregnancy Registries? (continued) ä ä Determine rates of outcome among mothers exposed to drug ä ä Comparison Groups ä ä Known background population rates ä ä Concurrently enrolled unexposed mothers with or without underlying disease of interest

10. Pregnancy Registry Studies ä ä Baseline information is collected at enrollment ä ä Prospective subjects ä ä Subject enrollment during pregnancy with unknown fetal outcome to provide risk estimate ä ä Retrospective subjects - case series ä ä Subject enrollment after abnormal fetal results or adverse infant outcome are known

11. Considerations for Design of a Pregnancy Registry ä ä What is the feasibility of successfully completing the study? ä ä Anticipate patterns of product use relative to fetal development ä ä Definition and identification of outcomes

12. What Products are Good Candidates? ä ä Products used frequently where inadvertent exposures are apt to occur ä ä Products initiated or continued during pregnancy as therapy

13. What Products are Good Candidates? (continued) ä ä When available information suggests a need: ä ä Pharmacologic class ä ä Animal reproductive data ä ä Structure/activity relationships ä ä Human case reports

14. When in a Medical Product’s Lifetime should a Registry be Established? ä ä A pregnancy registry should be established when the need is perceived ä ä Most likely at the time of approval ä ä Possibly with a new indication ä ä When a postmarketing signal is observed

15. What are the Elements to Consider in the Pregnancy Registry Design? ä ä Protocol should assure consistency in data collection and analysis ä ä Consult FDA in design

16. Registry Design: Protocol ä ä Background Section ä ä Animal reproductive toxicity studies ä ä Relevant pharmacologic and toxicolgic studies ä ä Any human experience from spontaneous reports or earlier human studies ä ä Estimate of risk in human pregnancy

17. Registry Design: Research Methods ä ä Description of Research Methods ä ä Patient Recruitment - Active enrollment strategies and follow-up plans ä ä Draft of registry announcements of ä ä informational pieces containing contact number, website ä ä Product label containing contact information

18. Research Design: Recruitment ä ä Announcements may appear: ä ä Professional journals ä ä Women’s magazines ä ä Professional and maternal/infant advocacy group newsletters ä ä Internet sites ä ä Mailings to specialists ä ä Lectures ä ä Informational booths at professional meetings

19. Research Design: Recruitment (continued) ä ä However, unless specifically approved for use during pregnancy, any recruitment effort should not promote the use of the product during pregnancy

20. Research Design: Recruitment (continued) ä ä All product specific promotional materials must be submitted to FDA at the time of first use ä ä Review prior to use not necessary UNLESS product was approved under expedited approval regulations

21. Research Design: Recruitment (continued) ä ä Protocol should include scripts that will be used in response to registry announcements and to recruit subjects ä ä To increase awareness, sponsors are encouraged to work with FDA, CDC, Organization of Teratogen Information Services, and other organizations ä ä FDA website will list known pregnancy registries

22. Research Design: Reporting Source ä ä Sources of baseline and follow-up information ä ä Subjects ä ä Health Care Providers ä ä Both

23. Research Design: Reporting Source-Subjects ä ä May minimize loss to follow-up ä ä Facilitates multiple follow-up contacts and enhance infant data collection ä ä Facilitates informed consent ä ä May need medical record validation ä ä May be more expensive due to more frequent and extensive follow-up

24. Research Design: Reporting Source - Health Care Providers ä ä Health Care Providers ä ä Convenient, good source of medical data ä ä Economical, requires fewer contacts ä ä Data collection on maternal and infant events may be incomplete ä ä Loss to follow-up may be substantial lack of motivation

25. Research Design - Patient Follow-up ä ä Patient follow-up: ä ä Describe follow-up procedures in protocol ä ä Update drug exposure & risk factor information ä ä Obtain results of any diagnostic tests ä ä Collect information on spontaneous abortions, elective terminations and the medical reasons for these events ä ä Consistent, similar follow-up for all women to avoid bias ä ä Specify criteria to define subjects that are pending and those lost to follow-up

26. Research Design: Study Outcomes ä ä Case definitions for all outcomes: maternal, labor & delivery, major categories of anomalies ä ä Confirm outcomes: autopsy & pathology results, birth and death infant records, expert evaluation of infant, long-term follow-up ä ä Feasibility of obtaining outcome data from different sources

27. Research Design: Miscellaneous ä ä Define outcomes of concern and hypothesis ä ä Define characteristics of the exposed population ä ä Define biologic impact of the treated medical condition(s) ä ä Describe what is known about drug exposure during pregnancy ä ä Anticipate likelihood of discontinuing treatment upon diagnosis of a pregnancy

28. Research Design: Comparators ä ä Selection of unexposed comparison group(s): ä ä Matching on medical condition ä ä Exposure to another product ä ä Multiple comparison groups

29. Research Design: Statistical Considerations ä ä Adequate sample size ä ä Estimate rates of suspected outcomes of scientific interest ä ä Estimate power

30. Research Design: Data Analysis ä ä Separate prospective and retrospective cases ä ä Pregnancy outcome, fetal abnormalities ä ä Describe subjects lost to follow-up, and compare to study subjects ä ä Calculate incidence point estimate and 95% confidence interval ä ä Compare to population background rates

31. Regulatory Reporting ä ä Registry reports are considered information derived during active solicitation of information from patients. ä ä Should be handled as safety information obtained from a study (1997 FDA Interim Report Guidance) ä ä FDA Postmarketing Safety Reporting Regulations are in the process of being updated.

32. Additional Information ä ä References ä ä Suggested Data Elements for Pregnancy Registries ä ä Sample Size Determinations by Adverse Pregnancy Outcomes