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 Information Spontaneous 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)
Unexpected
Not in the current label
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 Pattern
plausible event
e.g., pharmacology, confirms animal data
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 outweigh X 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
Use only in pregnancy when the benefit outweighs the risk!
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.
Conclusions (continued)
Essential to bring more data to risk assessments
Begin to consider as new drugs are developed
Encourage new tools and creativity Engage stakeholders, including patients, in discussion in this changing environment of risk management.
