Pregnancy and the Pharmaceutical Industry

The Movement towards Evidence-Based Pharmacotherapy for Pregnant Women

Kristine E. Shields

• Publisher: Academic Press
• Year: 2019
• ISBN:
  9780128190746
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Pregnancy and the Pharmaceutical Industry: The Movement towards Evidence-Based Care for Pregnant Women explores the issues surrounding the decision to undertake clinical trials with pregnant women. There is currently a lack of data on the safety and effectiveness of medications used during pregnancy as it is impossible to extrapolate that information from drug studies on men and non-pregnant women. As a majority of pregnant women confront a medical condition during their pregnancy, from simple pain, to ongoing or new medical issues, this book quantifies the current absence of pregnant women in drug studies and identifies ethical issues, barriers, litigation fears and opportunities.

Those in the pharmaceutical industry, IRB members who approve or deny drug study plans, doctors, nurses and midwives working in obstetrics or involved in conducting studies at their institutions will find this book an essential resource.

• Explores the medical, ethical, scientific and legal rationales behind the inclusion of pregnant women in drug studies
• Describes how pharma and biotech companies can safely implement the new FDA guidance and begin to include pregnant women in drug testing
• Shares views from pharmaceutical industry insiders about company risks, reluctance to implement guidance, and the ultimate need to include pregnant women in studies

Part I

The background, the debate, and the ethics involved

Outline

• Chapter 1 Drug testing and pregnant women: background and significance
• Chapter 2 The rationales for and against inclusion
• Chapter 3 The ethics involved

Chapter 1

Drug testing and pregnant women: background and significance

Abstract

This chapter introduces the reader to the history of drug testing, drug safety, and the exclusion of pregnant women from clinical trials. Dr. Shields shows that the lack of knowledge that results from their absence hampers our ability to safely and effectively treat the four million US women who become ill, or die, during pregnancy each year. Increased morbidity, inadequate treatment, the unnecessary termination of wanted pregnancies, and maternal death are some of the consequences.

The author reviews the history of how the benefits of inclusion in research studies became more evident during the AIDS crisis in the 1980s. In the 1990s women of childbearing potential fought for inclusion. In the 2000s advocates for the inclusion of pregnant women in research studies are raising their voices. Improving evidence-based treatment for pregnant women may help improve the steadily worsening rate of maternal mortality in the United States.

Keywords

Pregnant women; drug testing; clinical trials; maternal mortality; evidence-based medicine; history; DES; thalidomide; AIDS; proponents of inclusion; birth defects; safety

The lack of drug studies in pregnancy constitutes a major public health problem.¹

Background of the issue

“Each year over 400,000 women in the US confront significant medical illness while pregnant.”² In addition to pregnancy-specific complications like gestational diabetes and preterm labor, medical conditions that occur in nonpregnant women occur in pregnant ones as well, including psychiatric illness, cancer, and infectious diseases. These conditions can have a devastating impact on the health of the pregnant woman and on the well-being of her fetus. The safe and effective treatment of medical conditions complicating pregnancy is challenged by a serious lack of information on the safety and effectiveness of the medications used to treat them. Women’s health care practitioners lament that the “current evidence base for the care of pregnant women facing illness is widely regarded as deplorable.”³

The most effective way to improve our knowledge of safe and effective pharmacotherapy during pregnancy is through clinical research. Yet, despite the recommendations of experts in the US, including the Food and Drug Administration (FDA),⁴ the Institute of Medicine (IOM),⁵ the Council for International Organizations of Medical Sciences (CIOMS),⁶ and the American College of Obstetricians and Gynecologists (ACOG),⁷ to include pregnant women in drug research studies, exclusion is the norm. Without information from research studies, clinicians and their pregnant patients must make treatment decisions based on traditions, educated guesses, and gut feelings. Is this really the best we can do?

In 1993, Dr. David Kessler, the FDA Commissioner at the time, stated that “many drugs are ultimately used during pregnancy without reliable data on their maternal and fetal effects.” He cited the recent discovery that angiotensin converting enzyme (ACE) inhibitors, first marketed 10 years earlier to treat hypertension, could cause fatal kidney defects in babies when used by pregnant women in their second and third trimester.⁸ FDA, he said, needed “to develop recommendations on this important topic that will facilitate the conduct of trials in pregnant women and result in more such trials.”⁹

In April 2018, 25 years after the Commissioner first spoke of the need for drug studies in pregnant women, FDA finally released a draft guidance document on the topic: Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials.¹⁰

Historical perspective

As with research practices in general, guidelines regarding women’s participation in research have evolved over time. Following the tragic outcomes related to the use of under-studied but regulatory agency-approved products by women in the 1950s and 1960s, particularly thalidomide and diethylstilbestrol (DES), federal regulations were changed to exclude women of childbearing potential from clinical trials.

Thalidomide was never FDA-approved in the US due to safety concerns, but was widely prescribed and sold over-the-counter as a sedative and antiemetic in West Germany (where it was first licensed), Canada, Australia—over 40 countries in total. It was used by pregnant women to prevent and treat nausea and vomiting. In 1962, two physicians, one in Germany and one in Australia, publicized their suspicions that thalidomide was the causative agent in over 10,000 babies born with limb and other organ malformations. Many other thousands of babies died before the drug was removed from the market. Thalidomide has since been reapproved for the treatment of erythema nodosum leprosum (leprosy), multiple myeloma, and other serious conditions and is prescribed in the US via a strict safety program to prevent inadvertent use by pregnant women.

Subsequent to the thalidomide disaster, FDA revamped their regulatory processes, mandating efficacy as well as safety data prior to approval, strengthening regulations to include developmental toxicity testing in at least two species of animals,¹¹ expanded patient informed consent procedures, and demanded increased transparency from drug manufacturers.¹²

DES was a synthetic estrogen approved by FDA for the prevention of miscarriage in 1947. It was prescribed to pregnant women with a history of spontaneous abortion (but was later discovered to be ineffective). In 1971, a report in the “New England Journal of Medicine” warned about a link between the use of DES during pregnancy in the 1950s and the development of a rare vaginal cancer in their daughters. It was later discovered that sons exposed to DES during pregnancy have an increased risk for genital anomalies like undescended testicles and epididymal cysts.¹³

In 1977, FDA issued guidelines that recommended the exclusion of women of childbearing potential from early phases of drug trials until safety and effectiveness were established, except in the case of life-threatening diseases. Public sentiment and litigation against drug manufacturers compounded the reluctance to include women of childbearing potential in drug studies. Women’s health advocacy groups argued that the exclusion assumed “that women cannot take steps to avoid becoming pregnant,” decided for women “that protecting the fetus outweighed other possible interests,” and was unethical based on the principle of autonomy.¹⁴ However, exclusion had become the norm.

The benefits of inclusion in research studies became more evident during the Acquired Immuno-Deficiency Syndrome (AIDS) crisis in the 1980s. Women began to question the accuracy of data derived from studies performed on men when applied to women. In addition, women with AIDS were angry that experimental drugs available to men in clinical studies were not available to them. They demanded a “right to choose for themselves whether to take on the health risks of drug research.”¹⁵ The realization grew that “policies designed to protect certain populations from research risk may actually expose these populations to a greater risk of another kind: a lack of data about their health.”¹⁶ Through activism and advocacy, regulations evolved until all women, even pregnant ones, were permitted to participate in clinical trials.

Since 1981, rules of ethics about biomedical and behavioral research have been codified in Health and Human Services Title 45 Code of Federal Regulations (CFR) Part 46 (Public Welfare) Subparts A, B, C, and D also known as “The Common Rule.”¹⁷ US policy regarding the inclusion of pregnant women in federally funded research is in Subpart B (see Table 1.1.).

Table 1.1

The common rule—subpart B.

TITLE 45—PUBLIC WELFARE PART 46_PROTECTION OF HUMAN SUBJECTS

Subpart B Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research

Sec. 46.204 Research involving pregnant women or fetuses

Pregnant women or fetuses may be involved in research if all of the following conditions are met:

(a) Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for assessing potential risks to p...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• List of figures
• List of tables
• Preface
• Epigraph
• List of abbreviations
• Part I: The background, the debate, and the ethics involved
• Part II: Quantitative and qualitative discoveries
• Part III: Uniting the regulators, the industry, and the advocates
• Appendix I. FDA draft guidance—Pregnant women: scientific and ethical considerations for inclusion in clinical trials
• Appendix II. Executive summary: task force on research specific to pregnant women and lactating women
• Bibliography
• Index