18 october 20101 pregnant women & clinical trials: scientific, regulatory, and ethical...

18 October 2010 1

Pregnant Women & Clinical Trials: Scientific, Regulatory, and Ethical Considerations

Karen Feibus, MD, Medical Team LeaderPediatric and Maternal Health Staff (PMHS), Maternal Health Team, Office of New Drugs

CDER/FDASara F. Goldkind, MD, MA, Senior Bioethicist

Office of Good Clinical Practice, OC/FDA

Views expressed are those of the speaker and don’t reflect the official position of the FDA

18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women 2

Objectives

Explore ethical considerations for drug development research in pregnant women

Examine different ways to obtain data in pregnant women during various stages of the drug development process

Premarketing vs. postmarketing

Clinical trials vs. epidemiological studies

Enrolling pregnant women vs. continuation of women who become pregnant in a clinical trial

Study design considerations Informed consent

Outcomes measures

Pharmacokinetics

18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women 328 July 2010 Prescribing Risks in Women Veterans of Childbearing Age

3

What should I consider when prescribing for women of childbearing potential?

What is my patient’s underlying medical condition? Is pharmaceutical treatment essential for her long term health

and her daily quality of life?

Is her medical condition well managed on her current medications?

What are the reproductive/developmental risks of her medications?

What is this based on? Are there any other data available that are not in the drug labeling?

Are there other medications that treat her underlying condition that have better developmental risk profiles?

Are these alternatives appropriate for her?

Have I informed my patient about the reproductive risks of her medicines and discussed the relative risk/benefits of appropriate therapies?

If she was pregnant, what would I do differently?

18 October 2010 4

“I Don’t Know”

is not an acceptable or fair answer to these questions.


Basic Principles: an ethical and scientific foundation

Agree with the following principles outlined by Faden, Little, and Lyerly through the Second Wave*:

“Women need effective treatment during pregnancy”

“Fetal safety”: Data are needed on fetal safety Inadequately treated mother compromises fetal well being

“Reticence to prescribe needed medications: the cost of uncertainty”

What are the risks of not treating or under treating the mother’s condition?

“Issues of justice and access to the benefits of research participation”

*Lyerly AD, Little MO, Faden R. The second wave: Toward responsible inclusion of pregnant women in research. Int J Fem Approaches Bioeth 2008 Fall; 1(2): 5-22.



The most compelling reason to justify the inclusion of pregnant women in a greater number of biomedical studies is the need for evidence gathered under rigorous scientific conditions that place fewer women and their fetuses at risk than the much larger number of pregnant women who will be exposed to the medications once they come to market.

The next logical-and ethical-step is the enrollment and retention of pregnant women in clinical trials.”

*Macklin, R. The art of medicine: Enrolling pregnant women in biomedical research. The Lancet February 20, 2010; 375: 632-3.



Research in pregnant women should only be done where there is need, but once need is identified, exclusion of pregnant women must be justified.

CIOMS: Pregnant women should be presumed eligible for participation in

biomedical research.

Research in pregnant women should be performed only if: It is relevant to the particular health needs of a pregnant woman or her

fetus, or

It is relevant to the health needs of pregnant women in general, and

When appropriate, it is supported by reliable evidence from animal experiments, particularly as to risks of teratogenicity and mutagenicity.

Protocols should include a plan for monitoring pregnancy outcomes, including maternal health and short-term and long-term health of the child.

*The Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO), Guideline 17.


In drug regulatory science,Who are pregnant women?

Pregnant women are NOT a separate and distinct population except when a drug specifically treats a condition unique to pregnancy

Pregnant women are a dynamic subset of the adult and adolescent female populations who use drugs and biologics

It is important to ALWAYS consider whether, when, and how to study pregnant women in the drug development process

Adult and adolescent women

Pregnant women


Subpopulation differences:Pregnant women vs. non-pregnant women

Drug efficacy and safety can not be entirely extrapolated from non-pregnant women to pregnant women

Pregnancy physiology affects pharmacology Changes in total body weight and body fat composition

Expansion of plasma volume

Increase cardiac output

Changes in regional blood flow

Increase in GFR Altered GI motility

Decrease in Albumin

Changes in hepatic enzyme activity and drug metabolism by CYP450 system


Stages and phases:the clinical drug development process

When?When? Pre-marketing? Post-marketing?

How?How? Randomized controlled trial vs. cohort or case-control study Careful development program from the outset including statistical

analysis considerations

Who?Who? Pregnant women for whom the study drug offers potential direct benefit

Pregnant women already using the drug therapeutically Women who become pregnant while on study drug

Phase 1 Phase 2 Phase 3 Phase 4

Pre-marketing Post-marketing

Drug approvedfor marketing



Post-marketing studies in pregnant women

Most common and generally accepted approach because: Body of nonclinical toxicology data

Some clinical experience in nonpregnant women from premarketing clinical trials

Factors influencing study design Established efficacy may ethically preclude comparison to placebo

Extent and duration of use





Post-marketing studies in pregnant women

Pregnancy exposure registry

Prospective cohort study with an internal or external control group

Postmarketing requirements under the FDA Amendments Act of 2007

For drugs marketed for an extent of time

Database studies with mother/baby record linkage

Case control studies

Clinical trials

Placebo control or active control



Pre-marketing studies: questions to consider:

Are preclinical reproductive and developmental toxicity studies complete and adequate?

Are there positive findings of developmental toxicity in animals?

Are effective alternative therapies with better documented developmental toxicity profiles available?

What are the risk/benefit considerations for mother and fetus with regard to the drug and the condition it is intended to treat?






Pre-marketing studies: questions to consider:

Placebo control or active control with established therapy?

Do pregnant women have access to other effective therapies?

Are there planned PK assessments early in the study to ensure adequate systemic exposure to achieve efficacy (e.g., nested PK study in Phase 3 clinical trial)?

Does the protocol support retention of woman in the clinical trial if pregnancy occurs? (examples on slide 21)





Plan ahead: for pregnant women’s participation in clinical trials

Two potential scenarios:

Women who become pregnant during a clinical trial

Clinical trials that enroll pregnant women


Women who become pregnant while in clinical trials

When should a women who becomes pregnant while enrolled in a clinical trial be allowed to continue on study drug?

If the potential benefits of continued treatment outweigh the:

potential risks of ongoing fetal exposure to study drug,

risks of discontinuing maternal therapy, and/or

risks of exposing the fetus to additional drugs if the mother is placed on an alternative therapy

For example, malaria, tuberculosis, cancer


Women who become pregnant while in clinical trials

Consented as a nonpregnant woman

Contraceptive counseling

Potential embryo-fetal toxicity counseling

If become pregnant, need: Pregnancy management counseling New informed consent as pregnant study subject

Discuss alternative therapies and comparative therapeutic risks and benefits

Risk of ongoing fetal exposure to study drug vs. risk of fetal exposure to the study drug and the new alternative therapy.

Risk of untreated maternal disease


Enrolling pregnant women in clinical trials

Pregnant women with a medical condition requiring treatment may be involved in clinical trials if: Access to drug holds out the prospect of direct benefit to the

pregnant woman that is not otherwise available to her

Pregnant women have not clinically responded to other available therapies

Alternative therapies are not effective (e.g., drug allergy, drug intolerance, or drug resistance)

The risk to the fetus is not greater than minimal and important knowledge is acquired (which cannot be obtained by other means)

Adequate preclinical studies (reprotox) are complete

Pregnant women are prescribed the drug for therapeutic reasons


Addressing Challenges to Clinical Research in Pregnant Women

Recruitment and retention for studies conducted in both the premarket and postmarket settings

Identifying potential subjects Educating women

Lack of data on the use of medicines during pregnancy The values of research participation (pregnancy registries,

clinical trials) Sharing and securing personal information

Understanding factors that influence women’s likelihood to enroll and continue in clinical research during pregnancy

Overcoming fears and misconceptions in the research community


Artemether/lumefantrine treatment of malaria in pregnant women

Originally marketed outside the United States

Published and unpublished data on treatment of pregnant women with artemether/lumefantrine

FDA approved in 2009

Pregnancy labeling:

Safety data from an observational pregnancy study of approximately 500 pregnant women who were exposed to Coartem Tablets (including a third of patients who were exposed in the first trimester), and published data of over 1,000 pregnant patients who were exposed to artemisinin derivatives, did not show an increase in adverse pregnancy outcomes or teratogenic effects over background rate.

Clinical trials with PK, efficacy, and safety assessments


Study protocol considerationsfor pregnant women

Protocols should include the following:

Address informed consent Risk/benefit considerations with regard to fetal exposures and maternal

well being Therapeutic alternatives to clinical trial enrollment

Study endpoints and data collection mechanisms to capture maternal, fetal, and neonatal outcomes of interest

Gestational dating Gestational timing and duration of drug exposure Collection of ultrasound reports and results of other prenatal testing Records of maternal complications Pregnancy outcomes

Gestational age at delivery

Delivery complications

Condition of the neonate and complications in the neonatal period


FDA Guidances Pregnancy Exposure Registries:

Guidance for Industry, Establishing Pregnancy Exposure Registries, final published August 2002

Pharmacokinetics: Industry Guidance (draft), Pharmacokinetics in Pregnancy - Study

Design, Data Analysis, and Impact on Dosing and Labeling, draft published October 2004.

Final guidance in clearance – Pharmacokinetics During Pregnancy and the Postpartum Period.

Clinical Lactation Studies: Industry Guidance (draft), Clinical Lactation Studies-Study

Design, Data Analysis and Recommendations for Labeling, draft published February 2005.

Final guidance in clearance

Pregnant women and clinical trials: Industry Guidance, Pregnant Women in Clinical Trials: Scientific

and Ethical Considerations, draft in clearance


Contact information

[email protected]

Karen Feibus, MD, clinical team leader (301)796-0889 [email protected]

[email protected]

Sara F. Goldkind, MD, MS, Senior Bioethicist (301) 796-8342 [email protected]

18 october 20101 pregnant women & clinical trials: scientific, regulatory, and ethical...

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