Pregnant Women & Clinical Trials: Scientific, Regulatory, and Ethical Considerations Karen Feibus, MD, Medical Team Leader Pediatric and Maternal Health Staff (PMHS), Maternal Health Team, Office of New Drugs CDER/FDA Sara 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 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

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 28 July 2010 Prescribing Risks in Women Veterans of Childbearing Age Issues in Clinical Research: Enrolling Pregnant Women 3

is not an acceptable or fair answer to these questions. “I Don’t Know” is not an acceptable or fair answer to these questions. 18 October 2010

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

Basic Principles: an ethical and scientific foundation 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. 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

Basic Principles: an ethical and scientific foundation 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. 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

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

Stages and phases: the clinical drug development process Pre-marketing Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Drug approved for marketing When? Pre-marketing? Post-marketing? How? Randomized controlled trial vs. cohort or case-control study Careful development program from the outset including statistical analysis considerations 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 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

Stages and phases: the clinical drug development process Pre-marketing Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Drug approved for 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 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

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 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

Stages and phases: the clinical drug development process Pre-marketing Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Drug approved for marketing 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? 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

Stages and phases: the clinical drug development process Pre-marketing Post-marketing Phase 1 Phase 2 Phase 3 Phase 4 Drug approved for marketing 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) 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

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

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 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

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 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

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 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

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 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

Study protocol considerations for 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 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women

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

Issues in Clinical Research: Enrolling Pregnant Women Contact information PMHS@fda.hhs.gov Karen Feibus, MD, clinical team leader (301)796-0889 Karen.feibus@fda.hhs.gov gcp.questions@fda.hhs.gov Sara F. Goldkind, MD, MS, Senior Bioethicist (301) 796-8342 Sara.goldkind@fda.hhs.gov 18 October 2010 Issues in Clinical Research: Enrolling Pregnant Women