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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
•Overview
FDA and drug labeling Pregnancy section of drug labels How information is obtained for labeling
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
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
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
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
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
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)
“Serious” Adverse Events(at any dose)
Death Life Threatening Disability (persistent or significant) Congenital Anomaly Hospitalization (initial or prolonged)
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
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
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
“Pregnancy Categories”
A Controlled studies in pregnancy (<1%)B Animal studies show no risk; or human data are
reassuring C Human data lacking; animal studies positive or not
done (66%)
D Human data show risk; benefit may outweighX Animal or human data positive; no benefit
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
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
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
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
ICH E2C (continued)
The overall safety evaluation will be required to specifically address positive or negative experiences during pregnancy or lactation.
Risk Communication
What information belongs in labels?– Well documented serious adverse events– Prescribing information– Population based data providing measure of
assurance
Scientific & Regulatory Decisions
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
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
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.