Guidance for Industry Establishing Pregnancy Registries

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

33. Thank You