Summary

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. These products have been reviewed for safety and efficacy and are indicated for treatment of symptoms resulting from hormonal changes associated with menopause or other endocrine-based disorders.

In recent decades, an increasing number of health care providers and patients have turned to custom-formulated, or compounded, drug preparations as an alternative to FDA-approved drug products for hormone-related health concerns. These compounded hormone preparations are often marketed as “bioidentical” or “natural” and are commonly referred to as compounded bioidentical hormone therapy (cBHT).^1,2 In recent surveys, millions of men and women have reported using compounded hormone therapy, and today there is a broad array of compounded hormone

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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, replacement was removed from the term BHT 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.

formulations available for purchase, accounting for an estimated 26 to 33 million prescriptions that cost upwards of $2 billion annually. 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. Because compounded preparations are exempt from certain federal requirements for pharmaceuticals, these custom-compounded preparations are not required to demonstrate safety or effectiveness before they are dispensed to patients. In addition, many patients may believe that bioidentical hormone medications are only available through custom preparations at compounding pharmacies. However, FDA has approved several bioidentical hormone therapy (BHT) medications at different doses and with various routes of administration.

OVERVIEW OF COMPOUNDING

Compounding is the process of combining, mixing, or altering ingredients to create a medication tailored to the needs of a patient. Compounded drugs can provide therapeutic alternatives for patients with medical needs that cannot be met by available FDA-approved drug products. For example, compounding can provide customized formulations to (1) create alternate dosage strengths or forms or (2) omit components of FDA-approved drug products to which a patient has an allergy. Compounding can also fill gaps in cases where manufactured drugs are in short supply or have been discontinued. The process of compounding can produce sterile or nonsterile preparations, and it is conducted within a wide range of pharmaceutical and medical settings. Patient populations that have traditionally benefited from customized compounded formulations include pediatric patients, people living with chronic pain, people at the end of life, and people with certain specific medical conditions for which an FDA-approved drug product is not available.

Compounding can occur in community pharmacies, physicians’ offices, and hospital pharmacies, collectively known as 503A compounding pharmacies. Traditionally, this practice of compounding was a small-scale, ad hoc, and patient-specific process, and the minimal regulations and oversight applied to the practice reflected that. However, recent years have seen an expanded supply of and demand for compounded medications, as well as the emergence of large-scale compounding pharmacies that produce and sell greater volumes of compounded preparations in preset formulations, sometimes across state lines. This change in the compounding landscape prompted Congress to create a separate category of compounding facility—called an “503B outsourcing facility”—that is subject to an increased level of federal oversight, although not as strict as FDA oversight for

manufactured products. (See below for an additional discussion of the inadequate regulation and oversight of compounding pharmacies and outsourcing facilities.)

CLINICAL UTILITY OF CBHT

In light of the fast-growing popularity of cBHT preparations, the clinical utility of these compounded preparations is a substantial public health concern for various stakeholders, including medical practitioners, patients, health advocacy organizations, and federal and state public health agencies. In fall 2018, FDA requested the National Academies of Sciences, Engineering, and Medicine (the National Academies) to appoint an ad hoc committee to examine the clinical utility of cBHT drug preparations, with a prioritized focus on preparations containing estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone (DHEA), pregnenolone, progesterone, testosterone, testosterone cypionate, and/or testosterone propionate. The resulting Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy was charged with reviewing the uses of cBHT preparations and the available evidence that would support marketing claims of the safety and effectiveness of cBHT preparations.³ The committee was also asked to assess whether the available evidence suggests that these preparations have clinical utility and safety profiles warranting their clinical use and to identify patient populations that might benefit from cBHT preparations in lieu of FDA-approved BHT.

Over the course of the study, the committee held nine meetings, five of which were information-gathering sessions open to the public. In addition to the evidence collected at its public meetings, the committee also conducted reviews of 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

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³ 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 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 data on efficacy for cBHT preparations, the committee also considered clinical studies of effectiveness 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.

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 pharmacy societies and organizations; compounding advocacy organizations; nonprofit wellness organizations; women’s health advocacy groups; and medical prescribers and researchers of cBHT. In addition, the committee reviewed submitted testimonies from thousands of patients who use cBHT.

CLINICAL UTILITY: SAFETY, EFFECTIVENESS, THERAPEUTIC NEED, AND USE OF CBHT

The primary focus of this report is on the term clinical utility. 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.⁴ Patient preference is also a component of clinical utility and reflects patients’ individual decision making, based on variable acceptance of benefits and risks.

Clinical Utility of cBHT: Safety and Effectiveness

The committee assessed components of clinical utility, safety, and effectiveness of cBHT by examining peer-reviewed evidence relevant to the 10 prioritized steroid hormones evaluated for this study. The committee also reviewed the public health protections offered by the current federal and state-level oversight of compounded preparations, as well as the reported number, types, and severity of adverse events related to use.

From the hundreds of submitted patient and prescriber testimonies, the committee determined there are a vast number of anecdotal claims and patient reports on the safety and effectiveness of cBHT. On the other hand, in the committee’s review of the available peer-reviewed evidence, the committee found a substantial dearth of safety and efficacy data, including little or no high-quality pharmacokinetic data to inform evidence-based conclusions on the safety and effectiveness of cBHT preparations. These custom formulations have little or no data documenting absorption, distribution, and metabolism in the body, raising concerns about their safety

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⁴ In the context of this report, therapeutic need relates to the treatment of menopausal and male hypogonadism symptoms.

and underscoring the uncertainty about the reproducibility of the intended physiological effects of cBHT preparations.

The committee also determined that while some observational studies report data on the safety and effectiveness of cBHT, there are few well-designed, double-blind, randomized, placebo-controlled trials. The vast majority of the relevant studies reviewed had severe methodological limitations, the most common being the lack of standardized measures (e.g., assessments of hormone level, randomizations, participant exclusion and inclusion criteria, reporting measures) and minimal details on participant-specific dosing regimens, formulations, and dosage forms of the treatment arms, and where relevant, control arms of the study. Studies that lack this detail limited the interpretation and generalizability of the study results, and hindered the committee’s ability to draw meaningful conclusions about the safety and effectiveness of cBHT.

The committee recognizes that for the large patient population using cBHT, it is difficult, if not impossible, for clinicians to provide equal evidence-based guidance on the safety or effectiveness of each unique formulation. That being said, the safety and effectiveness data are still required for understanding risks and benefits for all therapeutics, and they are fundamental to the practice of medicine in this country. Given the lack of high-quality, well-controlled data, the committee could not draw definitive overall conclusions on the safety or effectiveness of cBHT preparations. There is, however, some evidence to suggest that estriol may be effective in treating certain menopausal-related symptoms, including vasomotor symptoms and vaginal atrophy; however, as with the other hormones reviewed, the data do not support the claims of superior safety or efficacy of cBHT preparations compared to FDA-approved BHT products.

Of critical importance, the lack of data should never be interpreted as a marker of safety and/or effectiveness (i.e., the absence of evidence of harm is not the same as the evidence of absence of harms). In general, the contraindications for cBHT are expected to be similar to those of FDA-approved hormone products of the same class.

Given the lack of high-quality clinical evidence to demonstrate safety and effectiveness, there is a public health concern regarding prescribing, compounding, dispensing, and use of cBHT. Current federal and state oversight of the formulation, marketing, dispensing, surveillance, and adverse event reporting of compounded preparations are insufficient to identify and then communicate the risks assumed by patients when using cBHT. For example, while nonprofit scientific organizations such as the United States Pharmacopeia (USP) have issued national standards and guidance for individuals who compound, there is limited or inconsistent oversight of procedures related to formulation, testing for safety and effectiveness, and dispensing of compounded medications. In part, this has led to a lack of

standardization of best practices for compounding and dispensing cBHT preparations, resulting in significant state-by-state and even pharmacy-by-pharmacy variability in the compounded medications and related health information dispensed to patients.

In addition, unlike for FDA-approved BHT products, 503A compounding pharmacies and 503B outsourcing facilities are not required by federal regulations to include comprehensive product labels, similar to those required for FDA-approved products, or standardized package inserts for compounded preparations. These exemptions provide opportunities for ambiguous instructions for use, incomplete listing of active and inactive ingredients, or an omission of potential contraindications, all of which creates the potential for patients and prescribers to be inadequately informed about possible safety concerns related to the use of these medications.

Clinical Utility of cBHT: Therapeutic Need

FDA-approved BHT products are primarily indicated to treat vasomotor symptoms and symptoms of vulvar and vaginal atrophy associated with menopause, and for men, to treat symptoms of male hypogonadism or testosterone deficiency. However, collected testimony from marketing claims and cBHT advocates assert that cBHT is effective and safe for treating a broad spectrum of indications outside of those for FDA-approved BHT products, including antiaging concerns (e.g., longer, fuller hair and smoother skin), sexual health, joint pain, general chronic pain, insomnia, cardiovascular diseases, and various mental health disorders.

To examine the evidence base to support the indication claims for cBHT, the committee reviewed available clinical guidance and published position statements issued by professional medical associations and societies (e.g., American Medical Association, Endocrine Society, North American Menopause Society) and other evidence-based clinical resources. Overall, the clinical guidance expresses concerns regarding the quality, safety, and effectiveness of cBHT preparations and cautions against their use in lieu of FDA-approved BHT options.⁵ The committee was also unable to identify

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⁵ It should be noted that medical associations, societies, and other relevant health organizations that issue clinical guidance are often supported, in part, by the pharmaceutical industry. Furthermore, many of the co-authors of the issued guidance conduct medical research that may be funded, in part, by the pharmaceutical industry. All aspects of the pharmaceutical ecosystem (including FDA-approved and compounded drugs) should be extremely mindful of the great responsibility entrusted to them by the public to disclose all conflicts of interest (real and perceived) and to uphold esteemed medical and scientific ethics, values, and standards. After considering the disclosed conflicts of interest for the authors of the clinical guidance reviewed in this report, the study committee had sufficient confidence to allow the guidance to serve as an important piece of evidence used to inform its report conclusions.

any specific life-threatening medical conditions that necessitated the use of cBHT preparations.

In its review of evidence, the committee was able to identify clinical guidance that acknowledges certain uniquely specific situations for which there may be potential use for cBHT preparations. These situations can be organized into three specific categories: the avoidance of select components in FDA-approved products (e.g., because of allergies), testosterone use in women to treat female sexual dysfunction, and gender dysphoria.

Avoidance of Select Components of FDA-Approved Products

Allergies to ingredients in FDA-approved BHT products are a reported rationale for patient use of cBHT preparations. Although mentioned in clinical guidance as a potential rationale for cBHT use, clarification on the specific allergies that occur in response to FDA-approved BHT products is extremely limited in the literature. A review of anecdotal testimonies suggests that potential intolerances to FDA-approved BHT products include sedative side effects, gastrointestinal issues, or skin sensitivities to transdermal patches.⁶ However, FDA’s product database includes a range of available FDA-approved BHT formulations to help circumvent these concerns, and, with few exceptions, would allow patients the flexibility to avoid ingredients that may serve as potential allergens or switch dosage forms (e.g., from an oral medication to a transdermal patch) while having the assurance of safety and efficacy afforded by the FDA approval and oversight processes.

Female Sexual Dysfunction and Gender Dysphoria

Patients with female sexual dysfunction (FSD) and gender dysphoria are two indications for which there are no FDA-approved BHT products.^7,8 Often, both indications are treated with off-label use of FDA-approved BHT products. The committee was unable to identify any clinical guidelines that recommend the use of compounded hormone treatments, of any hormone, to treat FSD (including hypoactive sexual desire disorder or female

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⁶ Anecdotally, a commonly discussed exception is when a potential patient with a peanut allergy would be in need of a single-agent progesterone product.

⁷Female sexual dysfunction (FSD) is a complex condition associated with diagnostic classifications including hypoactive sexual desire, sexual arousal disorder, orgasmic disorder, or sexual pain disorder.

⁸ A Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) recognized diagnosis that is “a noticeable incongruence between the gender the patient believes they are, and what society perceives them to be” (see the American Psychiatric Association’s DSM-5, 2013).

sexual interest/arousal disorder) or gender dysphoria, in lieu of off-label use of FDA-approved BHT products.

Clinical Utility of cBHT: Patient Preference

Patient preference is perhaps the most complex consideration in the committee’s definition of clinical utility. As discussed above, clinical guidance suggests there may be some clinical utility of cBHT, in lieu of FDA-approved products, in limited, specific situations. And yet, the suggested volume, scope, and clinical rationales for use of cBHT do not align with the evidence-based clinical recommendations from the medical community, contributing to a growing concern that cBHT is prescribed for reasons outside of a demonstrated unique therapeutic need.

Informed primarily by anecdotal testimonies and a few qualitative studies, the committee examined the factors seeming to have the greatest influence on patient preference for cBHT preparations. Based on a limited number of studies, patients (largely women) taking cBHT are thought to be simultaneously “pushed away” from FDA-approved BHT and “pulled toward” cBHT by conflicting psychosocial forces. Specifically, the committee identified several factors that may influence preference for cBHT including the early analysis and science communication efforts related to the Women’s Health Initiative study; FDA requirements for labeled indications and boxed warnings for certain FDA-approved BHT products; cBHT marketing; physician practices and perspectives; patient mistrust of the health care industry and commercial pharmaceutical industry; interest in the “natural” movement; and prescription costs.

The committee knows little about how patients are first introduced to cBHT as a treatment option; however, available sources suggest that many rely on media outlets (e.g., social media, books, television commercials) to educate themselves about cBHT. In addition, research uncovered that certain patient motivations, influenced by marketing strategies, “pulling” them toward cBHT were beliefs that cBHT was “natural,” as well as safer than FDA-approved BHT, and that these motivations were often influenced by marketing strategies used by advocates and suppliers of compounded medications. Additionally, there is evidence that many physicians are uncertain about whether cBHT is or is not an FDA-approved product. This implies there are inadequacies in prescribers’ continuing education efforts, as well as in science communication and health literacy. Given the inadequate labeling of compounded preparations, there are concerns about how well vital information regarding potential risks and benefits is communicated to patients and prescribers. In the absence of safety and effectiveness data of cBHT, aspects of patient preference should not be the sole driver for use.

THE CLINICAL UTILITY OF CBHT AND RELATED CONSIDERATIONS FOR PRESCRIBERS

Given the paucity of data on the safety and effectiveness of cBHT, the committee concludes there is insufficient evidence to support the overall clinical utility of cBHT as treatment for menopause and male hypogonadism symptoms. The committee determined there is substantial patient interest and apparent use of cBHT to treat menopause and male hypogonadism symptoms. The limited oversight and surveillance of the large amount of clinical use of cBHT, including when, why, and which cBHT preparations are prescribed, is a concern. Nonetheless, within the body of evidence reviewed, there are potentially a few specific medical circumstances for which there may be clinical utility of cBHT, such as for patients who have an allergy to specific ingredients in an FDA-approved drug product or patients who require a dosage form not currently available as an FDA-approved drug product. Should further data from high-quality, well-controlled clinical trials become available, such evidence could be evaluated and the clinical utility of cBHT preparations could be reassessed.

Considerations for Medical Practitioners and Providers

Acknowledging, on the one hand, the substantial interest in and use of cBHT, and on the other, a lack of evidence to support the clinical utility of cBHT, the committee recognizes important professional obligations for stakeholders (i.e., physicians who prescribe and pharmacists who compound and fill these prescriptions) to uphold. These obligations include respecting patient autonomy—meaning the right of patients to choose—while at the same time ensuring that patients’ decision making is informed by the best available evidence and supported with shared decision making.

Based on the precautionary principle, medical practitioners prescribing hormone therapy have a duty to engage in practice informed by evidence-based clinical guidelines and to educate patients to ensure that their decision making is informed by evidence-based health information. Health literacy and its reliance on evidence is foundational to autonomous patient decision making, and patients must have ready access to the best available evidence that is easy to understand and use as they weigh the risks and benefits of therapeutic options. In consideration of these obligations, concerns arise from areas of potential liability for prescribers of cBHT, which may include the invalidation of malpractice insurance, personal liability, or possible criminal charges.

Pharmacists and other qualified compounders have a professional obligation to follow USP’s recommended standards and protocols to ensure safe manufacturing and dispensing of all medications in order to minimize

safety concerns. They also have an obligation to provide clear directions for use, have a clear rationale for each ingredient used in the medication, as well as include evidence-based information about the medication’s potential adverse effects.

RECOMMENDATIONS

There is a dearth of evidence to support many of the marketed claims for the clinical utility of cBHT as a treatment of menopausal and male hypogonadism symptoms. Based on its examination of cBHT’s clinical utility, the committee recommends restricted use of cBHT, assessments of its difficulty to compound, and additional education, oversight, and research.

All clinical trials or observational studies related to the safety, effectiveness, and use of cBHT should register with and be approved by an appropriate institutional review board, as well as obtain informed consent from all patients and study participants.

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