# Presentation: 228082

## FDA’s Pregnancy Initiatives: Assuring product safety and efficacy for pregnant women

**FDA’s Pregnancy Initiatives: Assuring product safety and efficacy for pregnant women**

**Susan F. Wood, Ph.D.**
**Kathleen Uhl, M.D.**
**Margaret Miller, Ph.D.**

## Science Board Presentation

**The OWH Mission **
**Clinical Trials and Women**
**The Problem**
**Revising the Pregnancy Labeling**
**Improving the Content through Rulemaking and Guidance**
**Research Activities**
**Issues for Discussion**
**	****	****	**

**Notes:**
The Food and Drug Administration is a regulatory agency with broad jurisdiction over many products that affect the health of women including pharmaceuticals, vaccines and blood products, medical devices and food.

**The Office of Women’s Health serves as a champion for women’s health inside and outside the agency.**

**Notes:**
In 1994, the FDA created a new chapter in its commitment to women’s health by creating the office of Women’s Health.  The Office serves as champion for women’s health both inside and outside the agency. 

 To meet its goals, OWH:
Ensures that FDA functions, both regulatory and oversight, remain gender sensitive and responsive;
Works to correct any identified gender disparities in drug, device, and biologics testing and regulation policy;
Monitors progress of priority women’s health initiatives within FDA;
Promotes and integrative and interactive approach regarding women’s health issues across all the organizational components of FDA; and
Forms partnerships with government and non-government entities, including consumer groups, health advocates, professional organizations, and industry, to promote FDA’s women’s health objectives.

## Clinical Trials and 

**Clinical Trials and **
**the Approval Process**

**Determines if the product is safe and effective**
**Determines proper doses**
**Identifies adverse effects**

**Notes:**
The gold standard for determining that a product works is the randomized clinical trials.  Clinical trials also provide useful information on product safety in terms of common adverse events and toxicity.  Including of women in clinical trials is needed to ensure that the product works in women and to determine the common adverse events or toxicity of the drug.  Clinical trials are not powered to detect rare adverse events even if these event are serious, much less any gender difference in rare and serious adverse events. 

## Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs

**Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs**

**Encourages the participation of women in clinical trials. **
**Recommends the collection and analysis of data for gender differences.**
**Recommendations to minimize risk of fetal exposure by eliminating pregnant women.**

**Notes:**
In 1992,tThe Government Accounting Office analyzed the gender, age and race distribution of all New Drug Application approved between January 1988 and June of 1991 to determine if women were adequately represented in clinical trials for new drugs.  The survey showed that women were adequately represented in clinical trials for most new drugs but for drugs used to treat cardiovascular disease women consistently made up less than 40 percent of the populations studied.  In 1993, FDA revised the 1977 guideline and stated that in general drugs should be studies in the full range of patient likely to receive the drug one it is marketed. The 1993 guideline also recommends that the pharmacokinetics of the drug be defined in both genders and that the effectiveness and adverse effects be analyzed by gender (Food and Drug Administration, 1993). While the 1993 guideline was written for drugs, the agency intended that these guideline apply also to biologics and medical devices.

## Pregnancy Activities: The Problem

**Prevailing belief that pregnant women are healthy. **
**Prevailing belief that pregnant women should avoid taking prescription drugs or use “older” medications with good safety profile.**
**Many pregnant women need prescription products to maintain their health and the pregnancy. **
**Prescription products are not tested in pregnant women and pregnant women are actively excluded from clinical drug trials.**

**Notes:**
As I mentioned early because of fetal safety concerns, pregnant women are rarely included in clinical trials...Unless the drug is being approved specifically for treating a condition that occur only in pregnant women. Pregnant women will not be included in the clinical trial. 
For many years the prevailing wisdom among health care providers was that pregnant women are young, health and  should simply avoid taking prescription products while pregnant. 
For those few women that might need medical treatment during pregnant one should relie on one or two older medications that had a long history of  during pregnancy.

## Issues for the Board

- Prioritization of products
- Facilitation of research
- Other approaches

## Current Pregnancy Section of Label (21 CFR 201.57)

**First addressed in regulations in 1979**
**Goal to assist healthcare providers prescribing for pregnant women**
**Unintended exposures not addressed**
**Focused on teratogenic effects**
**Letter categories A, B, C, D and X**

**Notes:**
The current pregnancy labeling section was added to the regulations in 1979.  The goal of the labeling section was to help health care providers in making prescribing decisions for pregnant women.  The regulations did not attempt to provide any guidance for practitioners regarding what to do following unintended exposures.  The current Pregnancy labeling sections focuses primarily focuses on the potential of a drug to cause teratogenic effects.  The agency developed 5 lettered categories which summarized the results of teratogenic finding (or the risk assessment) together with the intended use of the drug (potential efficacy). 

## “Pregnancy Categories”

**A: Controlled clinical studies in humans**
**B: Human data reassuring (animal positive) OR ****	****animal studies show no risk**
**C: Human data lacking; animal studies ****	****	****	****positive OR not done  (>65%)**
**D: Human data show risk, benefit may ****	****	****	****outweigh**
**X:  Animal or human data positive**

**Notes:**
Category A:  represented those products which  had adequate well-controlled studies in humans showing no risk to the developing fetus or mother
Category B are products where there is no evidence of risk in human either because there were adequate well-controlled  Human studies that failed to show an increase in risk despite a positive finding in animals or because in the absence of human data the animal studies showed no risk
Category C are products for which the risk can not be ruled out because human studies are lacking and the animal studies are either positive or lacking
Category D are products where there is positive evidence of risk but the benefit of taking the drug may outweigh those risks
Category X are products that are contraindicated in pregnancy because  Animal or human data positive and the drug has little or no benefit for the pregnant patient

## Limitations of Existing Pregnancy Section 

**Categories are overly simplistic**
**Not informative clinically**
**Categories combine risk assessment and risk management and benefit**
**Most products have only animal data and positive findings are common **
**Most products are Category C**
**No requirement or incentive to update with human experience **
**“****Warning” perceived as optimal**
**Ensures changes will be rare**

**Notes:**
With the existing pregnancy categories, about 2/3rds of all drugs fall into category C simply because of the lack of human studies. Most products have only animal data at  the time of approval and because developmental toxicity studies are designed to demonstrate an effect most studies show positive findings. 
Since there is no requirement to conduct further studies, seek more data or even update the label as human data becomes available, the category to which products are assigned at the time of approval tend to remain even after human data becomes available.

Most sponsors are not anxious to have their products used in pregnant women as so a warning tone is viewed at optimal Consequently, most labels give a global warning that the product should be used in pregnant women only when the benefit outweighs the risk 

## Changes are coming....

**The FDA Pregnancy Labeling Initiative**
**	****	**
**	****A label that adequately provides information necessary for health care practitioners and their patients to make informed decisions about the use of drugs in pregnancy. **

**Notes:**
The goal of FDA Pregnancy Labeling Initiative is to address all these areas and provide a label that adequately imparts the information necessary to prescribe for and counsel a pregnant patient 

## Revise the Regulations

**Change Content & Format of the**** ****Pregnancy Section of Labeling**
**Separate risk from benefit**
**Standardized descriptive text not letter system**
** ****Distinguish clinical advice from risk information**
**Provide information about risk from inadvertent exposure to drugs**
**Provide information for optimal dosing of mother**
**Include information on PK/PD changes**
**Provide information on unique maternal toxicity**
**Requirement to update labeling**
**Clinically relevant information added to label**

**Notes:**
Currently we are drafting a proposed rule that will revise the content and format of the pregnancy section of the label.  Under the new regulation we want to separate clinical advise on how to best use the drug in a pregnancy patient from the risk information.  We intend to move away from the letter categories and provide the information in verbal statements.  This information will be followed by the actual data with human data presented separately form animal data.  
Separately form the pregnancy labeling initiative is the new proposed regulations on postmarketing reporting.  Part of the regulations is the periodic safety updates reports.  The new rule will require companies to include an analysis of positive and negative experiences during pregnancy...and the new pregnancy regulation will require that any clinically relevant information be added to the label.

## Improving Label Content

**Research on the Mother**
**	****Ethical Issues****	**
**	****PK/PD studies on Antihypertensive **
**	**** ****medication used during pregnancy**
**Counterterrorism (CT) Projects**
**	****Fetal Safety**
**	****Maternal Dosing information**
**Pregnancy Registry Webpage**

## Ethical Issues

**DHHS 45 CFR Part 46**
**Subpart A**
**Basic HHS Policy for Protection of Human Research Subjects**
**Subpart B**
**Additional Protections for Human Fetuses, Pregnant Women and Human  In Vitro Fertilization**

**Notes:**
The federal regulations governing the protection of human subjects participating in federal funded research are found in 45 CFR Part 46.  Subpart A of this regulation governs the protection of all human subjects that participate in clinical trials that are federally funded. Subpart B of CFR part 46 contains the additional protections for human fetuses, pregnant women and In Vitro human fertilization research funded by the federal government. 

## Subpart A: Basic Protections

**Expedited Review for Minimal Risk**
**Anticipated harm or discomfort is not greater than that ordinarily encountered in daily life or during the performance of routine physical or psychological examination or tests**
**Full IRB Approval: IRB Ensures**
**Risks minimized and reasonable with benefits**
**Subject selection equitable**
**Informed consent**
**Protocol ensures safety and confidentiality**
**Protection of vulnerable subjects**

**Notes:**
Subpart A allows for expedited review for research on human subjects with minimal risk. Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical and psychological examinations or tests. 
If the research involves more than minimal risk, Full Institutional review board approval is needed to ensure that risks to the study participants are minimized. That these risks are reasonable in relation to the anticipated benefits. Selection of subjects is equitable.  Informed consent is obtained from all participants.  In addition the IRB ensures that the research plan ensure safety of subjects and confidentiality of results.  Additional safeguards are in place for vulnerable subjects such as children, prisoners, pregnant women, mentally disabled persons, and economically or educationally disadvantaged persons.

## Subpart B: Special Protections for Pregnant Women and Human Fetuses

**Pregnant women can give informed consent and engage in research studies if-**
**Studies have been conducted on animals and non-pregnant women,**
**Research meets the health needs of mother and risk to fetus is minimum necessary or minimal risk,**
**Research benefits the mother, fetus or general knowledge**
**If benefit is to fetus only, maternal and paternal consent are required for maternal participation.**

**Notes:**
Subpart B of CFR part 46 covers the additional requirements that must be met when conducting research on pregnant women that is funded by the federal government. The instructions to IRB have always recommended that when research is undertaken to meet the health problems of a pregnant woman, her needs generally take precedence over those of the fetus [45 CFR 46.207], except, perhaps, where the health benefit to the woman is minimal and risk to the fetus is high. If, for example, an experimental drug were considered necessary to improve a pregnant woman's condition, her consent alone would be sufficient to authorize its administration - even though it might have unknown or greater than minimal risk for the fetus. In reviewing such studies IRBs must attempt to ensure that the risk to the fetus is minimized, consistent with achieving the research objective.The regulation were much less clear in providing advise for the participation of pregnant women in studies that were aimed to improving general scientific knowledge.
Last year at about this time Subpart B was modified to limited the need for paternal consent to studies involving pregnant women that are aimed a benefiting the fetus only.  For all other research studies, the informed consent of the pregnant women is sufficient for her to participate in the study.
The revised Subpart B will eliminate the need for paternal consent in cases where the research is to benefit the pregnant women or the pregnant women and the fetuses.

## Physiological Changes in Pregnancy

**Physiological Changes in Pregnancy**

**Pregnancy changes fluid volume, **
**	****	****urine output, liver metabolism**
**Pregnancy changes may alter drug distribution and metabolism**
**PK/PD changes have not been **
**	****established for most drugs**

## FDA/DHHS/CoE Research Project

**Develop study protocols for conducting PK and PD measurements on prescription medication used in pregnant women**
**Collect PK/PD data from pregnant women currently undergoing therapy to develop better dosing guidelines and assess product safety**
**Prototype on how to collect needed information in an ethical and economical study**
**Incorporate useful information into product label**

**Notes:**
Unfortunately when deciding on the appropriate dose of medication for a pregnant patient, healthcare providers rarely have sufficient information. While current policies encourage the participation of women in clinical trials, pregnant women are still excluded from clinical trials of medications used to treatment conditions that occur outside of pregnancy.  Thus, even in situations where pregnant women require therapeutics, pharmacokinetic and pharmacodymnamic studies in pregnancy women are rarely done. To correct this situation, we develop an contract with the DHHS Centers of Excellence in Women’s Health to developing a standard study protocols to study PK and PD during pregnancy. FDA/OWH intends to fund research to  Collect PK/PD data from pregnant women currently undergoing therapy. to This information will be used to develop better dosing guidelines and assess product safety
Prototype on how to collect needed information in an ethical and economical study It was our intended to conduct studies that would develop useful prescribing information and that this information could be incorporated into product labeling. 

## PK/PD of Antihypertensive Medications used in Pregnancy

** ****Traditional PK characterization**
- Serial blood samples on a small cohort followed during 2nd and 3rd trimester and postpartum
- Atenolol to control hypertension
-  **Population PK design**
- Few blood samples from a large population of pregnant women
- Labetalol to control hypertension

**Notes:**
There are different ways to assess the pharmacokinetics of a drug.  Typically, PK characterization of a drug requires several serial blood samples collected over a period of time from eac of a few subjects during the 2nd trimester, 3rd trimester.

Alternatively, a population PK study using the most useful sampling time points derived from modeling data from non-pregnant women can be used as a tool for assessing PK profiles of the drug in the pregnant women.  Validated sparse sampling methods based on optimal sampling theory and limited sampling methods is needed to determine the optimal sampling times to best characterize PK parameters.  This approach allows collecting as few as two to four observations per subject for PK analysis.
To assess the changes that occur during pregnancy, sampling will continued through the post-partum period to estimate the non-pregnant state. Since lactation may also influence PK, sampling during the post-partum period should investigate drug disposition in women who lactate and non-lactating women.

## CDER/OWH Counterterrorism InitiativeDosing and Safety in Special Populations

## 	CT Research Projects

**	****CT Research Projects**
**Safety Studies **
- Assessment of **maternal** effects and **infant** outcomes using large automated healthcare data systems in women exposed to prescription medications during pregnancy.
**Dosing Studies **
- Assessment of Pharmacokinetics and Pharmacodynamics of Counter-Terrorism Medications in Special Populations

## Fetal Safety Studies 

**Vanderbilt University **
**Infant outcomes for ciprofloxacin (n=686), doxycycline (n=3962),amoxicillin (n=42,653) and azithromycin (n=1602) **
**Control Groups**
**Pregnant women exposed to ACE inhibitors**
**Pregnant women exposed to no antibiotics**
**Pregnant women exposed to erythromycin**
**Infant outcomes:**
** ****birth, 3 months and one year**
**Patient population**
**Tennessee Medicaid database**

## Research Projects with the DHHS Centers of Excellence

**Research Projects with the DHHS Centers of Excellence**
- 	PK/PD of drugs used to treat 			conditions of terrorism in special 		populations
- 		Pregnant and lactating women
- 		Investigate Fetal Outcomes
- 		Elderly

## University of WashingtonPK of amoxicillin in pregnant women Drug is renally excreted dose adjustment likelyUniversity of WisconsinFormation of the CoE Research Consortium	Proposed to study 3 drugs (ciprofloxacin, azithromycin, gentamicin) in pregnant, and lactating, patients needing medication for other infections

## Pregnancy Registries are One Tool to Improve Safety Information

**	****The most practical means to collect information on safety and experience during pregnancy**
**	**
**	****Enroll women after exposure but before birth outcome**

## Pregnancy Registries Home Page

- The US Food and Drug Administration
***Office of Women’s Health***

***Pregnancy Registries Home Page***

*Information about Pregnancy Registries*

- _Promoting Healthy Pregnancies_

- _What  is a Pregnancy Registry?_

- _How can you participate in a Pregnancy Registry?_

- Guide to Pregnancy Registries

**Promoting Healthy Pregnancies**

**To help women make informed and educated decisions about using medicines during pregnancy, it is necessary to determine the effect of these medicines on the unborn baby. Pregnancy Registry studies are one way to do this. If you are pregnant and currently taking medicine--or have been exposed to a medicine during your pregnancy--you may be able to participate and help in the collection of this needed information. *****This Website provides a list of pregnancy registries that are enrolling pregnant women.***

- _Information about Pregnancy Registries_
- What is a Pregnancy Registry?
- How can you participate in a Pregnancy Registry?
- _List of Pregnancy Registries enrolling pregnant women_
- _Learn more about taking medicines while you are pregnant_

**Whether or not you should continue taking medicine during pregnancy is a serious question. However, if you stop taking medicine that you need, this could harm both you and your baby. *****Unfortunately, this Website cannot give personalized health advice, so please speak with a health-care provider who knows you, your condition, and your medicine before making any decision about the use of medicine during pregnancy.***

*List of Pregnancy Registries enrolling pregnant women*

*Learn more about taking medicines while you are pregnant*

## Summary

**Pregnant women needing medicines have been overlooked**
**Efforts to correct situation**
- 	Regulations/Guidance
- 	Research
- 	Outreach

## Discussion Issues

**	**
**	**

**Given the complexity of this problem, how should the FDA prioritize it’s efforts?**
**How should the agency encourage others (industry, academia) to conduct research on pregnant women?**
**What other strategies could be effective for obtaining information on drugs used by pregnant women?**

**Discussion Issues**

**Notes:**
To help accomplish its mission, OWH has two programmatic areas: Outreach programs,  and scientific programs.

FDA’s major outreach program is Take Time to Care.  Under the umbrella of Take Time to Care, FDA develops and disseminates health information targeted toward women.  The first message developed under this program was “Use medicine wisely” which encouraged women to read the label; follow directions ask questions and keep a record of their medicine use.  By partnering with the National association of Chain Drugstores and 60 national organizations nationwide FDA delivered this message to women and their families. 

The Science program funds intramural and extramural research intended to identify and fill gaps in knowledge in women’s health and promote the transfer of scientific knowledge into evidence-based policies that improve the safety and effectiveness of FDA regulated products for women