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)

“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 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

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)

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