Addressing Barriers to Clinical Trial Participation for Transgender People With Cancer to Improve Access and Generate Data

Introduction

Current estimates indicate that at least 1.6 million transgender people live in the United States and that more than 400,000 will be diagnosed with cancer in their lifetimes.^1-3 Transgender people experience systemic oppression, poverty, violence, and discrimination in medical settings; all these factors and others may lead to late-stage cancer diagnoses.^4,5 Consequently, transgender people may experience worse survival outcomes compared with their cisgender counterparts.^5-8

Clinical trials are the mechanisms that enable the collection of data to characterize the safety and effectiveness of new treatments. Clinical trials are also an important component of quality oncology care because they provide access to cutting edge investigational therapeutics and, in some instances, may provide an alternative to available treatments, which may be of limited clinical benefit. Transgender people have interest in contributing to treatment advances through participation in clinical research.⁹ Given the importance of clinical trials, it is critical to identify barriers that may both prevent transgender people and other sexual and gender minority (SGM) people with cancer from participating in clinical trials and limit our understanding of the experiences of transgender people in cancer clinical trials.

Background

Methodologic issues with data collection.

Historically, the terms sex and gender have been used interchangeably in medicine and medical research and in federal regulations, including those regulations that govern federal public health agencies and clinical data repositories such as ClinicalTrials.gov. This practice may incorrectly imply concordance between sex assigned at birth and gender.¹⁰

Gender is a concept that reflects a person's internal sense of themselves and their identity (eg, man, woman, nonbinary, etc). Throughout this article, the term gender is used to refer to a person's identity. An individual's sex assigned at birth is the designation usually made at birth typically by assessing a newborn's external genitalia. Sex assigned at birth has often been considered to describe factors including but not limited to X and Y chromosomes, reproductive anatomy and physiology, and gender. Scholars have described that sex assigned at birth may not be sufficient to adequately characterize an individual's reproductive anatomy, hormone levels, or gender as each of these factors may not be routinely assessed and may change over the course of a person's life. For example, an individual may be, based on the appearance of external genitalia at birth, assumed to have a specific karyotype in the absence of testing to confirm this assumption. In addition, people may undergo surgeries and/or endogenous estrogen or testosterone levels may fluctuate naturally over time or because of therapeutic interventions or other factors.^11-15

Rather than using the variables sex and gender interchangeably, more accurate and inclusive clinical trial data collection and reporting practices that decouple these concepts are preferred to facilitate the generation of more nuanced data. For example, information could be collected on anatomy as is relevant to the disease and/or treatment being studied, physiologic factors such as current hormone levels, and gender as defined by trial participants themselves. Consequently, the collection and reporting of data in clinical care and research would appropriately reflect reproductive anatomy, hormonal milieu, and gender as distinct variables. This approach would also facilitate much needed efforts aimed to better characterize outcomes for patients who are SGM and may serve as the basis for addressing the specific needs of these patient populations in both routine clinical care delivery and clinical research.

The authors well recognize the ongoing discussions related to what constitutes the best practices for collecting and reporting data on reproductive anatomy, sexual orientation, and gender for research, clinical care, and administrative purposes. Recently, a National Academies of Science, Engineering, and Medicine expert panel was convened to review the current evidence and make recommendations regarding collection of data regarding intersex status, gender, and sexual orientation; the ensuing report recommended using a two-step measure that queries gender and sex assigned at birth, among other recommendations.¹⁶

Structural barriers to high-quality oncology care for transgender people.

The societal stigma and discrimination that transgender people face can lead to decreased access to and participation in cancer clinical trials. Specifically, stigmatization that predisposes transgender people to interpersonal violence, unstable housing, lack of access to quality health care, poverty, unemployment, and participation in underground economies such as sex work may pose significant barriers to accessing health care including clinical trials. These factors increase the risk of mental distress and exposure to infections (eg, human papilloma virus, hepatitis, and human immune deficiency virus) and may also increase cancer incidence, morbidity, and mortality among transgender people. Structural factors along with intersecting social determinants of health can reduce access to health care and cancer screenings for transgender people, leading to late presentation for oncologic care and to later-stage cancers at the time of diagnosis.⁵

Structural barriers also adversely affect clinical trial participation.¹⁷ Qualitative research suggests that transgender people are motivated to participate in trials that (1) are led or staffed by transgender researchers, (2) benefit transgender communities, (3) provide resources that address financial barriers, and (4) are integrated into health care and/or are recommended by trusted clinicians.^18,19 In addition, trials that are designed to minimize the conduct of invasive procedures that can be triggering for patients with higher exposure to physical violence may also further increase interest in clinical trial participation.^19,20

Institution-level barriers may also hinder access to clinical care and clinical research. Transgender people are less likely to seek care at institutions where they experience stigmatization and may discontinue care after negative experiences with oncology clinicians.²¹ Many National Cancer Institute–designated cancer centers lack antidiscrimination policies related to gender identity and expression,^22-24 yet such policies along with grievance policies are needed to ensure the safety of transgender people.^22-24 Thoughtful consideration should also be given to organizations and other institutions that an institution may partner with to ensure that their policies protect the safety of transgender people. For example, although partnering with a community-based organization that addresses social determinants of health may increase trust and increase access to care and clinical research, such an alliance may be counterproductive if the community-based organization is not welcoming of transgender people. Institutional policies that allocate financial resources to support transportation reimbursement and provide access to food and health literacy training can address these formidable barriers at the institutional level. Institutions could also prioritize telehealth interventions and ensure that trial materials are accessible to all patients regardless of educational background or primary language.²⁵ As institutions consider the tools and approaches to promoting more flexibility in the conduct of clinical research, they could take into consideration approaches that decrease retraumatization for people who have experienced violence. Trauma-informed care or mechanisms to avoid invasive procedures (eg, self-swab Pap tests) would decrease barriers. In addition, well-defined institutional practices are needed to engage transgender communities to develop recruitment and retention strategies across the clinical research continuum and develop metrics for advancing inclusive research.^18-20 Institutions that employ transgender investigators and/or clinical research staff and utilize community-based participatory research are highly effective at recruiting transgender people, including transgender people of color to participate in clinical trials. Strategies such as these may be useful when incorporated into cancer clinical trials.^17,26-30 Cultural humility training may improve the ability of trial staff to be nonstigmatizing although the efficacy of training may be limited.^31,32

Clinical trial protocol language that implicitly and explicitly excludes transgender people.

As previously described, medical language often contains presumptive links between sex assigned at birth, gender, and reproductive anatomy (eg, the presumption that an individual who identifies as a man has a prostate or that such an individual cannot become pregnant).^33-35 As a result, the language used in clinical trial protocols and consent documents often excludes transgender people and renders their experiences and identities invisible. Linking gender to specific cancer types as an eligibility criterion automatically excludes some participants. For example, inclusion criteria such as men with prostate cancer or women with ovarian cancer would exclude women and nonbinary people with prostate cancer and men and nonbinary people with ovarian cancer, respectively. Replacement of references to gender with criteria that are based on disease or risk of disease, reproductive anatomy, or pregnancy potential as an example could improve clinical trial access and visibility of transgender people in health care settings (Appendix Table A1, online only).

Demographic categories that are inclusive of transgender people and that allow participants to choose from gender identity categories (eg, agender, bigender, genderfluid, genderqueer, gender nonconforming, nonbinary, and two-spirit), avoid terms such as female to male and male to female, and allow participants to select all that apply and include free text-responses are needed.^12,36 In addition, reporting practices should reflect more inclusive terms to enable characterization of transgender individuals' experience in health care settings and in clinical research.

HIV.

Because of overlapping axes of poverty, violence, and barriers to health care, transgender people in the United States have higher rates of HIV than the general US population.⁵ This is particularly true for Black and Latinx transgender people, with nearly one in two Black transgender people and one in four Latinx transgender people in the United States living with HIV.^4,37 Thus, blanket clinical trial exclusions for people living with HIV may disproportionately exclude transgender people, particularly Black and Latinx transgender people. The reasons for eliminating these exclusions have been elucidated widely in recent medical scholarship, and the US Food and Drug Administration has provided industry guidance supporting the inclusion of individuals with well-controlled HIV in cancer clinical trials.^38-42 Exclusions on the basis of HIV status should be based on sound evidence of the potential risks of the investigational therapy in patients with HIV infection, and, for medical products with a theoretical increased risk, data should be collected to fully characterize this risk.^43-45

Interventions that change hormone levels.

Hormone therapy, including estrogen and testosterone, are standards of care that may be used to align a person's anatomy and physiology with their gender. Use of exogenous hormone therapy improves mental health for transgender people who desire it and, in conjunction with desired surgeries, is associated with decreased suicidality.^46-50 Exclusion of potential participants on the basis of former or current hormone therapy may preclude the evaluation of medical products in transgender populations. In some cases, clinical trial criteria are ambiguous regarding whether people on hormone therapy can safely participate, which can lead investigators to not offer clinical trials to transgender people or discourage transgender people from inquiring about clinical trials.

Discussion

Barriers to cancer clinical trial participation exist for transgender people, and multilevel, multistakeholder action is needed to eliminate them. Recognizing these issues, the Oncology Center of Excellence at the US Food and Drug Administration convened a symposium on November 18 and 20, 2020, to (1) discuss barriers to cancer clinical trials for transgender and other SGM people with cancer and (2) explore ways to address these barriers in the context of oncology drug development. Participants' perspectives informed the recommendations presented in this article. First, policies and practices that promote interchangeable use of sex and gender, or that do not adequately provide for a more comprehensive evaluation of reproductive anatomy and gender as distinct concepts, can exacerbate disparities. Exclusion from clinical trials—by either protocol design or implicit messaging—can adversely affect early access to cutting-edge cancer therapeutics, in some cases when no effective standard-of-care options are available. Restricted access to clinical trials raises challenges in understanding how clinically relevant factors may affect safe and effective use of new treatments in this population. Inclusion of transgender people in clinical trials along with more comprehensive data collection can help provide data and information to describe clinical outcomes in the context of hormone levels, reproductive anatomy, sexual orientation, and transgender identity that could be useful in assessing the generalizability of the trial's results on the basis of objective factors. A framework for inclusion of transgender people in cancer trials is shown in Table 1; this framework may be a reasonable step toward delivering more inclusive care to transgender individuals with cancer, including in the context of clinical research.

TABLE 1.

Framework for Inclusion of Transgender People in Oncology Trials

APPENDIX

TABLE A1.

Sample Changes to Prostate Cancer Clinical Trial Eligibility Criteria

AUTHOR CONTRIBUTIONS

Conception and design: Ash B. Alpert, Jamie Renee Brewer, Spencer Adams, Lexis Rivers, Sunshine Orta, Charles Kamen, Richard Pazdur, Julia A. Beaver, Lola Fashoyin-Aje

Collection and assembly of data: Ash B. Alpert, John R. Blosnich, Susanne Miedlich, Don S. Dizon

Administrative support: Richard Pazdur

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Addressing Barriers to Clinical Trial Participation for Transgender People With Cancer to Improve Access and Generate Data

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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