Pharmacy Students Can Improve Gender Equity in Clinical Research

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Pharmacy Careers, Fall 2022, Volume 16, Issue 2

Pharmacists can provide their knowledge to female patients but also ensure women are adequately represented in research.

Clinical trials are essential for health care professionals and consumers to learn more about a new drug, especially its safety and efficacy. Despite a history of lower female participation in clinical trials, health professionals and researchers have made significant changes in the 21st century to include women. Having diverse clinical trial participants who accurately represent the entire population is vital to providing knowledgeable health care for everyone. In particular, pharmacists and pharmacy students have a duty to improve women’s participation in clinical trials so we can provide our patients with the safest medical decisions.

A Brief History of Women's Inclusion in Clinical Trials

Women’s participation in clinical research has come a long way. In the 1970s, very few women were in the medical and science fields. In 1977, the FDA’s policy recommended excluding women of childbearing potential from phase 1 and phase 2 drug trials. However, excluding women from these early stages led to a shortage of data on how specific drugs affected pregnant women.1 In 1989, the National Institutes of Health (NIH) announced that researchers should include women and racial and ethnic minority individuals in clinical trials.1

In late 1989, the NIH established the Office of Research on Women’s Health, andthe first female NIH director, Bernadine Healy, MD, launched the Women’s Health Initiative soon after.1 In 1993, the NIH inclusion policy finally became federal law.1 This law requires various requirements for NIH-funded research, such as the cost not being an acceptable reason for excluding women and racial and ethnic minority individuals from participation.1 The FDA Office of Women’s Health (OWH) was established in 1994, with a focus on promoting the inclusion of women in clinical research by engaging researchers and informing the public on critical issues surrounding women’s health.1 The OWH has introduced changes in regulatory policy and improved the safety and inclusion of FDA-regulated products for women.1

Some may wonder why there is a lack of female participation in clinical trials. In addition to a history of unethical research, women often encounter lack of transportation, interference with work and family obligations, exhaustion from constant travel and medical testing, and financial burdens.2 Providing childcare and transportation may help increase participation. The logistical and financial needs of the participants should be addressed, and communication between staff and participants needs to be improved. In addition, expanding advertisement in salons, stores, churches, and on social media can improve women’s participation.2,3 Finally, including female physicians in clinical trials and providing transparent communication can recruit more female participants for clinical trials.4 These strategies will help improve overall participation in clinical trials.

Current Regulatory Effort

Scientists and regulators are continuing to take significant steps to include women in clinical trials. The FDA has several projects to include more women in clinical trials and continues to educate and train their staff on reporting, analyzing, and communicating data by subpopulation. The FDA also partners with the NIH to identify best practices to overcome barriers.

In addition, the FDA has the Critical Path Initiative, with the goal of modernizing drug development with various tools and techniques.2 For example, using biomarkers and pharmacogenomics can help discover potential safety and efficacy and identify any subpopulation differences.

The FDA also has the Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data. This plan focuses on 3 aspects: quality, participation, and transparency. Quality-related efforts work on improving collection, reporting, and analysis of demographic subgroup data. Participation efforts involve identifying any barriers for member enrollment in the subgroups and implementing programs to encourage enrollment. Finally, transparency improvements involve making data from the demographic subgroups more accessible.2

To improve transparency, the FDA has a user-friendly website called Drug Trial Snapshots (DTS).2 It provides information about subpopulation involvement in pivotal clinical trials for newly approved drugs and whether any differences in benefits or risks of drug use by subpopulation were observed. The website also discusses drug use, adverse effects, efficacy, safety, and demographic data.

Lack of Representation Has Real-World Effects

Some conditions, such as iron deficiency and rheumatoid arthritis, have higher prevalence in women, making their representation in clinical trials even more essential.5 Women made up an average of 63% of participants in trials supporting 40 novel drugs approved to manage conditions that are not sex specific, according to a commentary published in Med.5

DTS published a 5-year summary (2015 to 2019) for 231 novel drug approvals, showing 51% of international clinical trial participants and 56% of American trial participants were women.5 DTS also provided a report that demonstrated how female and male participants were broken down for general therapeutic areas. The analysis demonstrated that fewer women were enrolled in trials for infectious diseases and cardiovascular diseases.5 This finding is particularly concerning because heart disease is the leading cause of death for women in the United States.5

On the other hand, the OWH conducted a decadal review to examine women’s participation in pivotal cardiovascular trials from 2005 to 2015 and found that women were well represented in trials for atrial fibrillation and systemic hypertension. However, they were underrepresented in trials studying therapies for heart failure, coronary artery disease, and acute coronary syndromes.5 This underrepresentation is ultimately a setback for women’s health, because it can lead to a lower number of women referred for cardiovascular screening.

An individual’s sex has been shown to affect both the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug. Levels of endogenous sex hormones, weight, muscle mass, body fat, and other factors can all affect the PK and PD of the drug. In one study, researchers found the same dose of the drug zolpidem caused twice the drug levels in women compared with men because of differences in metabolism.2 The study results also found that women who smoked the same number of cigarettes as men were 20% to 70% more likely to develop lung cancer.2

Diseases also present differently between men and women. For example, sexually transmitted diseases affect women differently with regard to symptoms and various long-term complications.2 Study results show some cardiac drugs that prolong the QT interval can induce torsade de pointes, a form of tachycardia common in women.6

Results have also shown that women have higher levels of cytochrome P450 isozyme 3A4, an endogenous enzyme used to metabolize drugs. Approximately 50% of drugs on the market are metabolized by this enzyme.6 Therefore, proper pharmacokinetic studies in both men and women are important to ensure drugs do not reach toxic levels in the body.

To provide personalized and safe care for patients, inclusion of both sexes is imperative in clinical research. This will allow researchers to detect differences in drug responses between male and female participants due to biological and hormonal differences between them.

The Debate Around Pregnant Patients

Some researchers still express concerns about including pregnant women in clinical trials. There are approximately 4 million births per year in the United States,7 so it makes sense for pregnant women to be included in clinical trials to improve knowledge about how drugs affect this large population. However, safety is a concern.

Researchers often avoided including women in clinical trials because of concerns about the effects of hormonal fluctuations on trial outcomes and, more importantly, possible fetal exposure to drugs and long-term damage to women’s germ cells. In the past, the FDA prohibited women of childbearing age from being recruited in early phases of research, but women are now empowered and encouraged to make their own risk-benefit choices about their pregnancies and overall health. Pregnant women need to manage chronic disease states, such as diabetes and hypertension, but clinicians know drugs are safe for pregnant women with these disease states only through clinical trials.

Various physiological changes occur in the body when women are pregnant, which can lead to changes in the PD and PK of drugs. The FDA considers it ethically justifiable to include pregnant women with a disease or medical condition requiring treatment in clinical trials in the premarketing and postmarketing settings.7 In these settings, adequate nonclinical studies, including studies on pregnant animals, need to be completed. In the premarketing setting, such as for investigational drugs, there also needs to be direct benefit to the pregnant woman and/or fetus that is not available outside the research setting. In the postmarketing setting, which includes FDA-approved drugs, there needs to be an established safety database for nonpregnant women in clinical trials.

Researchers have adopted several strategies to avoid potential negative fetal exposure. First, researchers must inform female participants about the potential risk of fetal toxicity and potential effects on fertility in the informed consent document and investigator’s brochure. To avoid potential fetal exposure, researchers can ensure participants are unlikely to get pregnant by providing a reliable method of contraception. Finally, researchers may reduce the risk of fetal exposure through study design, meaning they will administer treatment during or immediately following a women’s menstrual period or after obtaining a negative pregnancy test result.

Student Pharmacists Can Play a Role

The inclusion of women in clinical trials has a direct effect on whether women are screened and referred for proper treatments. Therefore, continued investigation and studies on sex-based biology, different health care needs, and reduction in health disparities are essential factors to consider for future trials. In addition, expanding and continuing agencies’ leadership and support to ensure women are properly represented in trials for novel drugs and therapeutic areas can have a huge impact. Because women take 60% of all medications, we need clinical trials to evaluate potential adverse reactions and drug-drug interactions.

Pharmacists are supposed to be drug experts in the medical field, and just like physicians, pharmacists take an oath to do no harm. We can do this only if we have enough knowledge and information from clinical trials to help us make the best medical decisions for women’s health. However, without research about female participants, pharmacists cannot properly treat patients and maintain the integrity of the profession and safety of patients.

Student pharmacists can also play a vital role in clinical trials. As student pharmacists, we can help pharmacists administer drugs to participants and monitor for any adverse events or contraindications of the drug. Student pharmacists can also ensure the safety of each participant is a top priority.

In addition, students may assist the clinical research coordinator (CRC) in maintaining the integrity and safety of the study. As an assistant to the CRC, pharmacy students can help the primary investigators conduct study activities such as maintaining accurate drug accountability, obtaining informed consent, recruiting participants, collecting and reporting adverse events, maintaining compliance with the institutional review board (IRB), and educating the participants. By understanding and taking an active role in clinical research, students can make a big contribution in preventing disease progression and advocating for public health.

Most students also work in pharmacies and know firsthand how certain disease states and medications affect patients. To recruit participants, students can inform patients about upcoming clinical trials, especially patients from the community who are not well represented in clinical trials, such as women. If student pharmacists enjoy their roles in clinical trials, they can also work toward becoming members of the IRB. As IRB members, they may oversee research at the research site and protect the rights, welfare, and safety of the participants. In addition, they will have the opportunity to collaborate with different health care professionals to provide study protocol, ensure safety, and improve equity in clinical trials.

ABOUT THE AUTHORS

Sarah John is a 2024 PharmD candidate at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She currently works in a community pharmacy and hospital pharmacy setting. She is president of the Temple University chapter of Phi Lambda Sigma, international vice president of the American Pharmacists Association, and vice president of the Pediatrics Pharmacy Association Group at Temple University.

Vanessa Bravo is a 2024 PharmD candidate at the Temple University School of Pharmacy in Philadelphia, Pennsylvania. She works at a local community pharmacy and is currently pursuing a master's degree in global clinical and pharmacovigilance regulations along with her pharmacy degree. She is secretary of the Temple University chapter of the Professional Society for Pharmacoeconomics and Outcomes Research and communication ambassador for Temple University's Pennsylvania Pharmacists Association.

REFERENCES

1. History of women’s participation in clinical research. National Institutes of Health. Accessed August 27, 2022. https://orwh.od.nih.gov/toolkit/recruitment/history

2. Liu KA, DiPietro Mager NA. Women’s involvement in clinical trials: historical perspective and future implications. Pharm Pract (Granada). 2016;14(1):708. doi:10.18549/PharmPract.2016.01.708

3. Successfully including women in clinical trials: a guide for researchers. National Institute on Drug Abuse. Updated October 2011. Accessed August 27, 2022. https://nida.nih.gov/sites/default/ les/womens-brochure_1025-004_508.pdf

4. Coakley M, Fadiran EO, Parrish LJ, Gri th RA, Weiss E, Carter C. Dialogues on diversifying clinical trials: successful strategies for engaging women and minorities in clinical trials. J Womens Health (Larchmt). 2012;21(7):713-716. doi:10.1089/jwh.2012.3733

5. Vasisht KP, Nugent BM, Woodcock J. Progress and opportunities for women in clinical trials: a look at recent data and initiatives from the U.S. FDA. CellPress. May 15, 2022. Accessed July 15, 2022. https://www.cell.com/med/pdf/S2666-6340(21)00159-8.pdf

6. Miller MA. Gender-based differences in the toxicity of pharmaceuticals—the Food and Drug Administration’s perspective. Int J Toxicol. 2001;20(3):149-152. doi:10.1080/109158101317097728

7. FDA. Pregnant women: scienti c and ethical considerations for inclusion in clinical trials. April 2018. Accessed July 13, 2022. https://www.fda.gov/files/drugs/published/Pregnant-Women--Scientific-and-Ethical-Considerations-for-Inclusion-in-Clinical-Trials.pdf