# Presentation: 708531

## PhRMA Perspective on Clinical Pharmacology Research in Pregnant Women

- Maria Palmisano, MD
- Director, Clinical Pharmacology/Experimental Medicine
- Bristol-Myers Squibb

## Overview

- Identify the problem
- Identify the limitations of pharmacology
- Identify the concerns of industry
- Possibilities for the future

## The Problem

- Few prescription drugs are specifically labeled for use during pregnancy
- Most women take at least one prescription drug during pregnancy
- Physiologic changes occur during pregnancy that alter the pharmacokinetics of drugs and may also alter pharmacodynamic response to the drugs.
- Limited data are available from product labels and the literature to guide physicians’ dosing recommendations.

## What Possibilities Does Clinical Pharmacology Hold?

- Clinical pharmacology studies can provide information on pharmacokinetic parameters
- AUC, Tmax, Cmax, VD, Clearance, t1/2
- The use of biomarkers may allow examination of the relationship between plasma concentrations and efficacy
- Recommendations could be made for dose adjustment in pregnancy

## What are the Limitations?

- The physiologic changes that occur during pregnancy vary over the course of the pregnancy
- Changes occur in the absorption, distribution, metabolism and elimination of drugs by the mother
- The fetus and placenta are also involved in drug distribution, metabolism and elimination

- Clin. Pharm. 1997;33(5):328

## What are the Limitations?(continued)

- Fetal susceptibility to adverse outcomes related to drug exposure may vary based on gestational age
- Thalidomide, Accutane®
- ACE inhibitors

- Clin. Pharm. 1997;33(5):328

## What are the Limitations?(continued)

- Pharmacokinetic and pharmacodynamic information
- Provides only short term and very limited safety information
- Cannot provide comparative safety information to guide choices between therapeutic options

## Industry Concerns 

- Which drugs should be studied?
- When in a drug’s lifecycle should it be studied in pregnancy?
- Who should be studied & when?
- What control group should be included?
- What information should be obtained?
- How should studies be designed and data analyzed & communicated?

## Which Drugs Should be Studied?

- Spectrum of opinion ranges from none to all
- Drugs needed to treat complications or problems of pregnancy
- Drugs that are used to treat diseases that occur frequently in women in their childbearing years
- Drugs that are known teratogens should be excluded during the period of organ sensitivity

## When in a Drug’s Lifecycle Should it be Studied?

- Background
- At the time of marketing approval, drug exposure is often limited to several thousand subjects
- Pregnancy avoidance is frequently a requirement for participation in clinical trials
- Inadvertent exposures are often during1st trimester and of limited duration
- Postmarketing surveillance data are incomplete and may be limited to spontaneous reports of adverse outcomes rather than reflecting the extent of drug use in pregnant women

## When in a Drug’s Lifecycle Should it be Studied? (continued)

- Pharmacologic evaluation may be considered when:
- Drug safety and efficacy have been demonstrated in the general population
- The drug has a potentially significant therapeutic benefit in addition to broad usage in pregnant women
- Drug exposure not expected to pose undue risk to the mother or fetus
- Evaluation of older drugs and generics poses a dilemma

## Who Should be Studied & When?

- Studies could be performed in women already receiving the drug as therapy
- It may be necessary to collect PK/PD data at multiple time points during pregnancy and compare them with postpartum data
- Healthy gravid women would not usually be studied

## What Information Should be Obtained?

- Pharmacokinetics & Pharmacodynamics
- Standarized lab measurements
- Clinical efficacy
- Biomarkers
- Surrogate markers
- Demographics
- Gestational age
- Concomitant medications
- Weight

- Comparison to non-pregnant status
- Postpartum measurements
- Fetal exposures
- Other
- Co-morbid conditions
- Pharmacogenomic information
- Use of combinaton therapy

## How Should Studies be Designed and Data Analyzed & Communicated? 

- Study designs need to be carefully considered, including use of appropriate patient controls
- Data could be included in product labels or available through other sources
- There is a risk that PK/PD data might be over interpreted to be safety data

## Possibilities for the Future 

- When
- Indications where the disease is considered life-threatening
- Drugs indicated for a pregnancy-related condition
- Drug has significant therapeutic indication and usage in pregnant women

## Possibilities for the Future(continued)

- How
- Industry-sponsored studies or registries
- Alliances with professional organizations, academia, or teratology services
- May allow for broader patient enrollment, efficient utilization of resources such as PK sites, and experienced interviewers
- Allows for comparisons across therapeutics or within a drug class
- Support could take many forms ranging from providing validated bioanalytical assays to assistance with study design and data analysis to study funding

## Summary

- Drugs are used frequently during pregnancy
- Physiologic changes occur during pregnancy that alter the PK and PD of drugs
- PK data can be a guide for dosing but are not a substitute for safety data

## Summary (continued)

- Studies in pregnant women may be considered when:
- Drug safety and efficacy has been demonstrated in the general population
- Drug has potentially significant therapeutic benefit and usage in pregnant women
- Drug exposure not expected to pose undue risk to the mother or fetus

## Summary (continued)

- Studies should be considered in women who require drug therapy to treat a medical condition
- Pharmacologic data may need to be collected for a given drug at multiple points during pregnancy and in the postpartum period
- Further discussions are needed  to determine the optimal way of designing studies and analyzing and communicating data

## The Ideal Goal

- Evidence-based dosing guidelines that permit rapid estimation of appropriate dosing for individual patients at a specific stage of gestation and  given body weight
- Products indicated for pregnancy-related conditions
- Products that are used to treat underlying medical conditions during pregnancy