1
Introduction
The U.S. Food and Drug Administration (FDA) has approved dozens of hormone therapy products for men and women, including estrogen, progesterone, testosterone, and related compounds (FDA, 2019). These products are approved to, among other things, address hormonal changes associated with aging or other endocrine-based health concerns (ASA, 2006; de Villiers et al., 2016; Stuenkel et al., 2015). By the end of the twentieth century, hormone therapy became one of the most prescribed drug treatments for women in the United States (Brett and Burt, 2001).
In response to the growing popularity of hormone therapy, the National Institutes of Health in the 1990s launched the Women’s Health Initiative (WHI), a comprehensive, prospective study, to test whether hormone therapy would prevent heart disease and to examine overall health risks and benefits of FDA-approved hormone therapy (Hays et al., 2003; Stefanick et al., 2003). In the years since, researchers have published more than 100 findings related to a broad spectrum of health risks and benefits associated with the use of hormone therapy in postmenopausal women (WHI, 2020). Early analysis and science communication efforts for WHI, coupled with FDA’s limited indications for use of hormone therapy and requirements for boxed warnings of potential adverse effects, have had a lasting effect on clinician- and patient-related concerns regarding the use of hormone therapy (Barlow, 2014; Thompson et al., 2017). (See Chapter 8 for additional discussion.)
In recent years, certain health care providers and patients have turned to custom-compounded drugs as an alternative treatment for hormone-related health concerns. These treatments, often marketed as “bioidentical”
or “natural,” are commonly referred to as compounded bioidentical hormone therapy (cBHT) (Gass et al., 2015).1,2 Evidence suggests that millions of men and women may use cBHT and that there may be thousands of potential compounded hormone formulations that patients can purchase with a prescription. Media influences and targeted marketing approaches and claims have led many patients and certain prescribers to perceive cBHT preparations as safer and more effective alternatives to FDA-approved hormone products (Fishman et al., 2015; Thompson et al., 2017). However, compounded preparations are exempt from certain federal requirements for pharmaceuticals and are not required to demonstrate safety and efficacy.3 In addition, some patients have a mistaken belief that bioidentical hormone therapy (BHT) medications are only available through custom preparation at compounding pharmacies (Files et al., 2016), even though FDA has approved several bioidentical hormone products at different doses and with various routes of administration (FDA, 2019).
In light of the fast-growing popularity of cBHT preparations, the safety, effectiveness, and use of these medications has become a substantial public health concern for various stakeholders, including medical practitioners, patients, health advocacy organizations, and federal and state public health agencies.
STUDY CHARGE
To explore the complex issues surrounding cBHT, FDA in fall 2018 requested the National Academies of Sciences, Engineering, and Medicine (the National Academies) appoint an ad hoc committee to assess the clinical utility of treating patients with cBHT. The resulting Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy was charged to review the uses of cBHT preparations and the available evidence that would support marketing
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1 As a consequence of cBHT marketing strategies, the term bioidentical is often misinterpreted by the general public. The committee intentionally includes the term when referencing certain types of hormone therapies, with the rationale that bioidentical serves as an important identifier for many compounded hormone therapies, and including the term may be a useful means of more effectively communicating the report conclusions to the general public. It should be noted, however, that the committee’s use of the term bioidentical should not be interpreted as an endorsement.
2 For the purposes of this report, the word replacement was removed from the term bioidentical hormone therapy to avert implications that the goal of hormone therapy is to replace hormone concentrations to the levels present in young adults. The official National Academies’ language regarding the committee and its task still maintains the use of the original term.
3 Federal Food, Drug, and Cosmetic Act. 21 U.S. Code Chapter 9.
claims of the safety and effectiveness of cBHT preparations.4 The committee was asked to assess whether the available evidence suggests that these preparations have clinical utility and safety profiles warranting their clinical use, and it was asked to identify patient populations that might benefit from cBHT preparations in lieu of FDA-approved BHT. The committee’s Statement of Task is presented in Box 1-1.
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4 While the terms effectiveness and efficacy are similar, they are not the same. The effectiveness of a drug refers to its therapeutic effect in real-world settings. The efficacy of a drug refers to the therapeutic effect in controlled clinical settings—such as phase 2 or phase 3 randomized clinical trials. This difference is critically important. Given the limited efficacy data for cBHT preparations, the committee considered clinical studies of effectiveness, in addition to clinical studies of efficacy, in its examination of clinical utility of cBHT preparations. Owing to its broader application to the body of research reviewed, the term effectiveness is used more generally across the report.
STUDY SCOPE
The committee systematically reviewed the available evidence relevant to each component of the clinical utility definition, within the limits of the committee’s resources, study timeline, and study scope. The committee maintained a prioritized focus on cBHT preparations of interest to the study sponsor (NASEM, 2019). These included cBHT preparations containing estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone (DHEA), pregnenolone, progesterone, testosterone, testosterone cypionate, and/or testosterone propionate, many of which serve as the hormonal ingredients within the most commonly prescribed cBHT formulations (see Chapters 5 and 6). Other hormone therapies commonly available through compounding, such as thyroid medications or human growth hormone, are not covered in this report.
The report looked solely at compounded drugs prepared within the regulatory framework outlined in the compounding provisions of the Federal Food, Drug, and Cosmetic Act;3 hormones sold as dietary supplements (e.g., vitamin D) were not considered relevant to this report. Additionally, the report focuses on the use of cBHT resulting from traditional prescriber–pharmacist–patient triads, although there is limited discussion of online purchases and office stock where pertinent.
Based on the physiological effects and indications of the steroid hormones the committee reviewed, the primary focus of this report is on the use of cBHT preparations to treat menopause or male hypogonadism symptoms. The committee acknowledges that men of various ages use compounded bioidentical testosterone formulations for improvement in physical appearance and/or athletic or physical performance enhancement, resulting in the potential for nonclinical abuse. The committee reviewed evidence supporting the use of cBHT in men in this report, but given the reported magnitude of use of cBHT in women (McPherson et al., 2019), the report places a greater focus on this patient population.
KEY DEFINITIONS
Clinical utility is a multidimensional, context-dependent term for which no standardized definition exists. However, based on review of the literature, including peer-reviewed articles, consumer surveys, and formal position statements and guidelines, the committee developed, for the purposes of this report, its own definition of the term. Here, clinical utility is defined as a multidimensional construct that reflects evidence about safety, effectiveness, and therapeutic need.5 Patient preference is also a component of
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3 Federal Food, Drug, and Cosmetic Act. 21 U.S. Code Chapter 9.
5 In the context of this report, therapeutic need relates to the treatment of menopausal and male hypogonadism symptoms.
clinical utility, reflecting patients’ individual decision making based on how each person accepts benefits and risks. Evidence-based decisions regarding the clinical utility of a test, treatment, or medical intervention may evolve over time with additional studies (NASEM, 2016). See Box 1-2 for an overview of main themes of clinical utility and Box 1-3 for key definitions of terms used in this report.
STUDY APPROACH
To address the study charge, the National Academies appointed a 12-member committee of experts to address objectives in the Statement of Task (see Appendix D for biographical sketches of the committee members and staff). The committee met in person five times and held four half-day virtual meetings. In addition to its closed-session meetings, the committee held five public information-gathering sessions and evaluated the
peer-reviewed literature and gray literature (e.g., research reports, books for a lay audience) on topic areas relevant to the study’s charge.
In recognition of the limited information available addressing the use, safety, effectiveness, and patient perspectives of cBHT, the committee also made concerted efforts to collect and review relevant anecdotal, survey, and
(when possible) quantitative data from national stakeholders to supplement its research efforts. For example, relevant data were submitted by the following:
- FDA
- Professional Compounding Centers of America
- National Association of Boards of Pharmacy
- Select state boards of pharmacy
- A state attorney general’s office
- Representatives of 503A compounding pharmacies and 503B outsourcing facilities
- An editor-in-chief of a leading compounding journal
- Nonprofit medical and pharmaceutical societies and organizations
- Compounding advocacy organizations
- Nonprofit wellness organizations
- Women’s health advocacy groups
- Medical prescribers and researchers of cBHT
In addition, the committee reviewed submitted testimonies from thousands of patients who use cBHT.
The committee used the compiled, multitiered evidence base to formulate findings, conclusions, and actionable recommendations to inform FDA on the clinical utility of cBHT and its use in the treatment of patients. Box 1-4 provides details of the committee’s supplemental information-gathering process. (See Appendix A for additional details of the study approach.)
REPORT ORGANIZATION
The remainder of this report provides a more thorough discussion of cBHT in response to the Statement of Task. Chapter 2 provides an overview of the history of compounding, reviews its complexity as an art and a science, and provides a summary of the current compounding market. Chapter 3 provides an overview of the regulatory framework for compounded mediations and includes a discussion on the development, evaluation, and approval of FDA-approved drug products to highlight differences in regulatory processes to ensure safety and effectiveness. Chapter 4, serving as important context for the remainder of the report, provides an overview of the synthesis, structure, and biochemistry of steroid hormones, and clarifies the term bioidentical hormone.
Chapter 5 provides an extensive review of the available cBHT preparations and, where relevant, discusses FDA-approved BHT products to provide relevant comparisons of formulation procedures and quality testing.
Chapter 6 examines the available evidence on the bioavailability of the hormones included in cBHT preparations. Chapter 7 outlines the key findings and conclusions that resulted from the committee’s literature review on the safety and effectiveness of hormone ingredients commonly used in cBHT preparations. This chapter also addresses the importance of adverse event reporting, a critical component in assessing the safety of publicly available medications. Chapter 8 reviews the evidence related to the current use of cBHT by patients, including the overview of the current clinical guidance for use, patterns and trends of use, and psychosocial factors that affect patient preference. The final chapter, Chapter 9, summarizes the major report conclusions supported by the evidence presented in Chapters 2 through 8 and delves into the committee’s overall conclusion regarding the clinical utility of cBHT for treating patients. This final chapter also presents the committee’s six recommendations to the stakeholders of the report.
REFERENCES
Ahn, J.-K., Y. Kim, and K.-H. Choi. 2019. The psychometric properties and clinical utility of the Korean version of GAD-7 and GAD-2. Frontiers in Psychiatry 10(127).
ASA (American Society of Andrology). 2006. Testosterone replacement therapy for male aging: ASA position statement. Journal of Andrology 27(2):133–134.
Bagheri, A., J. Beasley, P. Sardina, E. Johnston, L. Ganguzza, J. Padikkala, and E. Gianos. 2019. Evaluating the utility of a diet quality screener in clinical practice to improve quality of preventive care (p07-002-19). Current Developments in Nutrition 3(Suppl 1).
Barlow, D. H. 2014. Understanding the impact of the women’s health initiative. Menopause 21(7):683–684.
Brett, K. M., and C. W. Burt. 2001. Utilization of ambulatory medical care by women: United States, 1997–98. Vital Health Statistics 13(149):1–46.
Canter, D. J., J. Reid, M. Latsis, M. Variano, S. Halat, S. Rajamani, K. E. Gurtner, Z. Sangale, M. Brawer, S. Stone, and S. Bardot. 2019. Comparison of the prognostic utility of the cell cycle progression score for predicting clinical outcomes in African American and non-African American men with localized prostate cancer. European Urology 75(3):515–522.
Challener, D. W., L. J. Prokop, and O. Abu-Saleh. 2019. The proliferation of reports on clinical scoring systems: Issues about uptake and clinical utility. JAMA 321(24):2405–2406.
de Villiers, T. J., J. E. Hall, J. V. Pinkerton, S. Cerdas Pérez, M. Rees, C. Yang, and D. D. Pierroz. 2016. Revised global consensus statement on menopausal hormone therapy. Climacteric 19(4):313–315.
FDA (U.S. Food and Drug Administration). 2019. Orange Book: Approved drug products with therapeutic equivalence evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm (accessed November 4, 2019).
FDA. 2020a. Approved drug products with therapeutic equivalence evaluations (Orange Book). https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book (accessed March 26, 2020).
FDA. 2020b. Biosimilars. https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/biosimilars (accessed March 26, 2020).
Files, J. A., L. N. Kransdorf, M. Ko, J. M. Kling, P. S. David, S. Pruthi, R. Sood, D. Creedon, Y. H. Chang, and A. P. Mayer. 2016. Bioidentical hormone therapy: An assessment of provider knowledge. Maturitas 94:46–51.
First, M. R., V. R. Peddi, R. Mannon, R. Knight, C. L. Marsh, S. M. Kurian, J. C. Rice, D. Maluf, D. Mandelbrot, A. Patel, J. David, C. Schieve, D. Lee, P. Lewis, J. J. Friedewald, M. M. Abecassis, and S. Rose. 2019. Investigator assessment of the utility of the trugraf molecular diagnostic test in clinical practice. Transplantation Proceedings 51(3):729–733.
Fishman, J. R., M. A. Flatt, and R. A. Settersten, Jr. 2015. Bioidentical hormones, menopausal women, and the lure of the “natural” in U.S. anti-aging medicine. Social Science and Medicine 132:79–87.
Gass, M. L., C. A. Stuenkel, W. H. Utian, A. LaCroix, J. H. Liu, and J. L. Shifren. 2015. Use of compounded hormone therapy in the United States: Report of the North American Menopause Society survey. Menopause 22(12):1276–1284.
Grosse, S. D., and M. J. Khoury. 2006. What is the clinical utility of genetic testing? Genetics in Medicine 8(7):448–450.
Hays, J., J. R. Hunt, F. A. Hubbell, G. L. Anderson, M. Limacher, C. Allen, and J. E. Rossouw. 2003. The Women’s Health Initiative recruitment methods and results. Annals of Epidemiology 13(9 Suppl):S18–S77.
Ishikawa, K., R. I. Kohno, E. Hasegawa, S. Nakao, S. Yoshida, and K. H. Sonoda. 2019. Preoperative estimation of distance between retinal break and limbus with wide-field fundus imaging: Potential clinical utility for conventional scleral buckling. PLOS ONE 14(2):e0212284.
Johansen Taber, K. A., K. A. Beauchamp, G. A. Lazarin, D. Muzzey, A. Arjunan, and J. D. Goldberg. 2019. Clinical utility of expanded carrier screening: Results-guided action-ability and outcomes. Genetics in Medicine 21(5):1041–1048.
Lee, J. J., J. Y. Verbakel, C. R. Goyder, T. Ananthakumar, P. S. Tan, P. J. Turner, G. Hayward, and A. Van den Bruel. 2019. The clinical utility of point-of-care tests for influenza in ambulatory care: A systematic review and meta-analysis. Clinical Infectious Diseases 69(1):24–33.
Lesko, L .J., I. Zineh, and S. M. Huang. 2010. What is clinical utility and why should we care? Clinical Pharmacology & Therapeutics 88(6):729–733.
McCormack, R. T., and P. R. Billings. 2015. Clinical utility: Informing treatment decisions by changing the paradigm. NAM Perspectives. Discussion Paper, National Academy of Medicine, Washington, DC.
McPherson, T., P. Fontane, and R. Bilger. 2019. Patient experiences with compounded medications. Journal of the American Pharmacists Association 59(5):670–677.
Michel, L. L., L. Sommer, R. González Silos R, J. Lorenzo Bermejo, A. von Au, J. Seitz, A. Hennigs, K. Smetanay, M. Golatta, J. Heil, F. Schütz, C. Sohn, A. Schneeweiss, and F. Marmé. 2019. Prediction of local recurrence risk after neoadjuvant chemotherapy in patients with primary breast cancer: Clinical utility of the MD Anderson Prognostic Index. PLOS ONE 14(1):e0211337.
Miller, M. B., F. Atrzadeh, C. A. Burnham, S. Cavalieri, J. Dunn, S. Jones, C. Mathews, P. McNult, J. Meduri, C. Newhouse, D. Newton, M. Oberholzer, J. Osiecki, D. Pedersen, N. Sweeney, N. Whitfield, J. Campos, ASM Clinical and Public Health Microbiology Committee, and the ASM Corporate Council. 2019. Clinical Utility of Advanced Microbiology Testing Tools. Journal of Clinical Microbiology 57(9):e00495-19.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2016. Biomarker tests for molecularly targeted therapies: Key to unlocking precision medicine. Washington, DC: The National Academies Press. https://doi.org/10.17226/21860.
NASEM. 2018. Returning individual research results to participants: Guidance for a new research paradigm. Washington, DC: The National Academies Press. https://doi.org/10.17226/25094.
NASEM. 2019. PowerPoint presented on behalf of FDA to the Committee during the open session of Meeting One. March 5, 2019 (available through the National Academies Public Access File).
Oh, K. H., K. D. Suh, Y. H. Lee, S. Y. Lee, M. Y. Chang, and S.-K. Mun. 2019. Clinical utility of cervical vestibular-evoked myogenic potentials in predicting residual dizziness after benign paroxysmal positional vertigo. Clinical Neurophysiology 130(1):95–100.
Osumi, H., E. Shinozaki, K. Yamaguchi, and H. Zembutsu. 2019. Clinical utility of circulating tumor DNA for colorectal cancer. Cancer Science 110(4):1148–1155.
Setlur Nagesh, S. V., V. Fennel, J. Krebs, C. Ionita, J. Davies, D. R. Bednarek, M. Mokin, A. H. Siddiqui, and S. Rudin. 2019. High-definition zoom mode, a high-resolution X-ray microscope for neurointerventional treatment procedures: A blinded-rater clinical-utility study. American Journal of Neuroradiology 40(2):302–308.
Soh, S. B., and T. C. Aw. 2019. Laboratory testing in thyroid conditions—pitfalls and clinical utility. Annals of Laboratory Medicine 39(1):3–14.
Stefanick, M. L., B. B. Cochrane, J. Hsia, D. H. Barad, J. H. Liu, and S. R. Johnson. 2003. The Women’s Health Initiative postmenopausal hormone trials: Overview and baseline characteristics of participants. Annals of Epidemiology 13(9 Suppl):S78–S86.
Stuenkel, C. A., S. R. Davis, A. Gompel, M. A. Lumsden, M. H. Murad, J. V. Pinkerton, and R. J. Santen. 2015. Treatment of symptoms of the menopause: An Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism 100(11):3975–4011.
Teutsch, S. M., L. A. Bradley, G. E. Palomaki, J. E. Haddow, M. Piper, N. Calonge, W. D. Dotson, M. P. Douglas, and A. O. Berg. 2009. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: Methods of the EGAPP working group. Genetics in Medicine 11(1):3–14.
Thompson, J. J., C. Ritenbaugh, and M. Nichter. 2017. Why women choose compounded bioidentical hormone therapy: Lessons from a qualitative study of menopausal decision-making. BMC Women’s Health 17(1):97.
Vlahos, R. 2019. Clinical utility of pulmonary function and blood biomarker measurements. Respirology 24(1):13–14.
WHI (Women’s Health Initiative). 2020. Welcome. https://www.whi.org (accessed February 3, 2020).
Zago, M. P., J. E. Wiktorowicz, H. Spratt, S. J. Koo, N. Barrientos, A. Nunez Burgos, J. Nunez Burgos, F. Iniguez, V. Botelli, R. Leon de la Fuente, and N. J. Garg. 2018. Potential utility of protein targets of cysteine-s-nitrosylation in identifying clinical disease status in human chagas disease. Frontiers of Microbiology 9:3320.
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