Reproductive Health Drugs, Pregnancy Labeling Subcommittee Meeting March 28-29, 2000

1. Monitoring Drug Risks in Pregnancy: Regulatory Aspects Reproductive Health Drugs, Pregnancy Labeling Subcommittee Meeting March 28-29, 2000 Holli A. Hamilton, M.D., M.P.H. Pregnancy Labeling Team Office of Drug Evaluation IV Center for Drug Evaluation & Research

2. Overview • FDA and drug labeling • Pregnancy section of drug labels • How information is obtained for labeling

3. Introduction to Labeling • FDA regulates drugs and biologic products • Investigation and development • Marketing approval (drugs)/license (biologics) • FDA does not conduct clinical research • Review data provided by sponsors of studies • Final vetting at time of marketing application to assure quality and integrity

4. Introduction to Labeling(continued) • Label represents basis for market approval • Key data for medical professionals • Commercial sponsor owns the label • Legal document • Focal point for negotiations • Once marketed, company must • Report all safety data/toxicities

5. Labeling 101 • Drugs usually do not have “indications” for use in pregnancy • Products are approved for treatment of conditions listed under “Indications” • FDA does not regulate the practice of medicine • Pregnancy section adds information • Similar to Geriatrics

6. Labeling: Focal Point for Negotiations • NDA/PLA approval negotiations can involve committing to Phase IV studies • In addition, efficacy supplements for already approved drugs/biologics can establish the impetus for updating safety sections

7. Opportunities for New Data • Adverse event reporting system (AERS) • Case reports (spontaneous reports)/ Med Watch • Literature • Epidemiology Studies • Registries • Sponsor conducted • Observational studies most common • Estimation of frequency/rates of events

8. Postmarketing Safety InformationSpontaneous Reports • After approval, there are requirements for reporting safety data to FDA • Serious, unexpected events in 15 calendar days • Other events periodically depending on time product on market (e.g., quarterly for first three years and annually thereafter)

9. “Serious” Adverse Events(at any dose) • Death • Life Threatening • Disability (persistent or significant) • Congenital Anomaly • Hospitalization (initial or prolonged)

10. Not in the current label “Unexpected”

11. Limitations of Case Reports • No denominator to assess rate • Bias toward abnormal outcomes • Uncertain value for common events • eg, migraine, spontaneous abortion • Information often incomplete • Underreporting is problematic • e.g., knowledge, time, fear of reprisal

12. When are case reports helpful? • Biologically plausible event • e.g., pharmacology, confirms animal data • Pattern is suggested • Confounders ruled out • Dose, timing and other exposures known • Rechallenge/Dechallenge

13. Existing Pregnancy Section of Label • First addressed in regulations in 1979 • Goal to assist physicians prescribing for pregnant women • Simplify risk/benefit information • Letter categories A, B, C, D and X

14. “Pregnancy Categories” • Controlled studies in pregnancy (<1%) • Animal studies show no risk; or human data are reassuring • Human data lacking; animal studies positive or not done (66%) • Human data show risk; benefit may outweigh • Animal or human data positive; no benefit

15. Lack of Data • No information obtained on pregnant women in the premarketing phase • pregnant women are excluded from clinical trials • if a woman becomes pregnant while in a trial, she is dropped • Only information sources • Animal data • Postmarketing human data

16. Experience and Feedback • Most products have only animal data and positive findings are common (category C) • No requirement to study further or to seek more data!!! • Ensures changes from C will be rare • Erasure of animal findings nearly impossible • No incentive to update the information • SAES will only add more to toxicity profile

17. Use only in pregnancy when the benefit outweighs the risk!

18. Changes are coming…. • New model for pregnancy labeling • Narrative text • Shift in thinking about risk management • Step toward better data collection • Postmarketing reporting regulations are being harmonized

19. ICH E2C • November 1996 ICH Document “Guidance for Industry: E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs” (62 FR 27470, 5/19/97) • These recommendations are being incorporated into the US postmarketing regulations

20. ICH E2C (continued) The overall safety evaluation will be required to specifically address positive or negative experiences during pregnancy or lactation.

21. Risk Communication • What information belongs in labels? • Well documented serious adverse events • Prescribing information • Population based data providing measure of assurance

22. Speaking out too soon Negative image of drugs in pregnancy (fear) Unnecessary termination of wanted pregnancies Waiting too long to speak Violates public trust (anger & fear) Places additional patients at risk Scientific & Regulatory Decisions

23. Special Challenges: Pregnancy and Perinatal Exposures • Pharmacology often poorly understood • No knowledge of fetal or maternal metabolism or PK for most drugs • Population exposed is small • Rare events difficult to detect • Case reports tend to be rare • Barriers to spontaneous reports may increase

24. Conclusions • Science must underlie regulatory/public health decisions related to drugs in pregnancy. • The pregnant patient brings us into an area of medicine where the most certainty is desired, but there is least data upon which to assess risk.

25. Conclusions(continued) • Encourage new tools and creativity • Engage stakeholders, including patients, in discussion in this changing environment of risk management. • Essential to bring more data to risk assessments • Begin to consider as new drugs are developed