9
Clinical Utility and Recommendations
This committee was charged with summarizing findings and making recommendations with respect to the clinical utility of treating patients with compounded bioidentical hormone therapy (cBHT) preparations—including a review of whether the available evidence of their safety and effectiveness supports use of cBHT preparations to treat patients, and whether there are special populations that might need cBHT preparations, in lieu of available U.S. Food and Drug Administration (FDA)-approved products. In this final chapter of the report, the committee summarizes its key findings and conclusions regarding the clinical utility of cBHT preparations, and notes the critical importance of evidence-based clinical guidance and its use by clinicians to support positive health outcomes for patients.
WHAT DOES “CLINICAL UTILITY” MEAN?
As discussed in Chapter 1 of this report, clinical utility is a multidimensional, context-dependent term for which no standardized definition exists. Given this, the committee turned to the literature, position statements and guidance issued by professional medical societies and associations, stakeholder testimony, and submitted resources to gain a better understanding of the potential components of clinical utility and the varied contexts in which to consider the use of the term.
Literature references to clinical utility point to a range of clinical- and scientific-based examples that reflect the various components of the term (e.g., Ahn et al., 2019; Bagheri et al., 2019; Canter et al., 2019; Challener
et al., 2019; First, 2019; Grosse, 2006; Ishikawa et al., 2019; Johansen Taber, 2019; Lee, 2019; Lesko, 2010; McCormack, 2015; Michel, 2019; Miller, 2019; NASEM, 2018; Oh et al., 2019; Osumi, 2019; Setlur, 2019; Soh, 2019; Teutsch et al., 2009; Vlahos, 2019; Zago et al., 2018). Based on insights from the literature, an entity that is said to have clinical utility has been described as being able to:
- Optimize treatment and short- and long-term health outcomes
- Affect diagnostic testing processes
- Assist with patients’ decision making
- Offer psychological benefits to the patient, including improved health literacy
- Improve society
Furthermore, the evidence describing the components of clinical utility is not confined to randomized controlled trials; rather, it takes into account a broad range of factors (e.g., Lesko, 2010; Miller, 2019). These components include
- The current standard of care
- The care setting
- Costs of care and tests
- The nature of what is being evaluated for clinical utility
In its review of clinical utility, however, the committee is aware that these examples were not necessarily all-inclusive and that the term clinical utility may potentially encompass additional components not necessarily reflected in existing definitions. In consideration of this guidance, for the purpose of this report, the committee has defined clinical utility as a multidimensional construct that reflects evidence about safety, effectiveness, and therapeutic need.1 Patient preference is also a component of clinical utility, and it reflects patients’ individual decision making based on variable acceptance of benefits and risks. In its approach to examine the clinical utility of prescribing cBHT to patients, the committee systematically reviewed the available evidence relevant to each component of this definition.
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1 In the context of this report, therapeutic need relates to the treatment of menopausal and male hypogonadism symptoms.
THE CLINICAL UTILITY OF CBHT AND RELATED CONSIDERATIONS
Table 9-1 provides an overview of the committee’s major conclusions related to the clinical utility of cBHT. In summary, evidence suggests the current use of cBHT exceeds the small potential therapeutic need for cBHT. The committee concluded there are insufficient data to support that cBHT preparations are as safe as or safer than FDA-approved hormone therapy, and that inadequate oversight and reporting of adverse events are a public health concern. Similarly, the committee concluded there are insufficient data to support that cBHT preparations are as effective as or more effective than FDA-approved hormone therapy. Therefore, in consideration of clinical utility, current volume use of cBHT appears to reflect patient and prescriber preference for cBHT. Marketed claims, as well as celebrity endorsements, likely influence the use of, or patient preference for, cBHT. In addition, collected testimonies suggest there is widespread misunderstanding of the regulation, safety, and effectiveness of cBHT, and that these gaps in knowledge undermine accurate consideration of risks and benefits of cBHT use. Taken together, the evidence suggests that factors, including marketing claims, general misinformation, a mistrust of the pharmaceutical and health care industries, and cost may influence patient perspectives on overall clinical utility of cBHT.
Through anecdotal testimonies and a few qualitative studies, the committee was made aware of the strong preferences for individualized treatment among certain individuals who use cBHT; however, safety and effectiveness are foundational to assessing its overall clinical utility. Given the paucity of data on the safety and effectiveness of cBHT, the committee made the following conclusion:
However, 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 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
TABLE 9-1 Summary of Key Conclusions Related to the Clinical Utility of cBHT Preparations
| Components of Clinical Utility | Key Conclusions from the Report |
|---|---|
| Safety and effectiveness |
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| Components of Clinical Utility | Key Conclusions from the Report |
|---|---|
| Therapeutic need |
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| Patient preference |
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from well-controlled clinical trials become available, such evidence could be evaluated and the clinical utility of cBHT preparations could be reassessed.
Considerations for Health Care Practitioners and Clinicians
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 that there exist 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, physicians who prescribe hormone therapy, both FDA-approved drug products and compounded preparations, have a duty to engage in practice informed by evidence-based clinical guidelines and to educate patients to ensure their decision making is
based on evidence-based health information and is supported by techniques of shared decision making. Health literacy and its reliance on best available 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. Considering 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 standards issued by the United States Pharmacopeia to ensure safe preparation and dispensing of all compounded medications in order to minimize safety concerns. They also have an obligation to provide clear directions for use, disclose a clear rationale for the inclusion of each ingredient used in the medication, and 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 for 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.
Recommendation 1: Restrict the use of compounded bioidentical hormone therapy (cBHT) preparations.
Prescribers should restrict the use of cBHT preparations to the following: documented allergy to an active pharmaceutical ingredient or excipient of U.S. Food and Drug Administration (FDA)-approved drug product, or a documented requirement for a different dosage form. Patient preference alone should not determine the use of cBHT preparations.
In general, the potency of cBHT doses should not exceed those of FDA-approved hormone therapy products because of potential safety concerns. Any use of cBHT, including therapy for gender dysphoria, should align with established clinical guidance and require documentation of shared decision making and rigorous monitoring for long-term risks.
Prescribers and compounding pharmacists should clearly explain the limited evidence-based information about the safety and effectiveness of cBHT preparations. They should inform patients that compounded preparations are not FDA approved.
Recommendation 2: Review select bioidentical hormone therapies and dosage forms as candidates for the U.S Food and Drug Administration (FDA) Difficult to Compound List.
The Pharmacy Compounding Advisory Committee should review the following bioidentical hormone therapies as candidates for FDA’s Difficult to Compound List: estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone, pregnenolone, progesterone, testosterone, testosterone cypionate, and testosterone propionate. These candidates have safety and efficacy concerns related to the lack of bioavailability data and product-to-product variability as a result of drug formulation differences, stability, and quality control.
The Pharmacy Compounding Advisory Committee should consider all compounded bioidentical hormone therapy preparations formulated in pellet dosage form as candidates for FDA’s Difficult to Compound List.
Recommendation 3: Improve education for prescribers and pharmacists who market, prescribe, compound, and dispense compounded bioidentical hormone therapy (cBHT) preparations.
To ensure the appropriate clinical use of cBHT, the committee recommends the following for prescribers:
- State medical boards, the Federation of State Medical Boards, and medical professional societies and associations (e.g., American Medical Association [AMA], Endocrine Society, North American Menopause Society) should advocate for a state-level certification for individuals who are seeking to begin or continue to prescribe cBHT. Formal clinical education should be offered in parallel to continuing medical education courses.
- Nonprofit professional societies and organizations within the medical sectors (e.g., AMA) should expand and promote evidence-based guidelines and best practices for clinicians who prescribe or compound cBHT preparations. These guidelines should include not only evidence-based conclusions on the potential benefits and risks, but also practical steps of when to consider cBHT in lieu of U.S. Food and Drug Administration (FDA)-approved products, which potential formulations should be considered, and the contraindications associated with the treatment.
To ensure the appropriate clinical use of cBHT, the committee recommends the following for prescribers and pharmacists:
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State boards of pharmacies, National Association of Boards of Pharmacy, Pharmacy Compounding Accreditation Board, local and regional schools of pharmacies, and nonprofit professional societies and organizations within the medical and pharmaceutical sectors with a particular focus in epidemiology and women’s health (e.g., American Association of Colleges of Pharmacy, AMA, Endocrine Society, North American Menopause Society) should develop pathways to support and incentivize the attainment of more in-depth training on complex compounding of hormone preparations. These courses should do the following:
- Be conducted by schools of pharmacy or nonprofit professional societies and organizations within the medical and pharmaceutical sectors.
- Include a review of the compounding process, including complexities of formulation science.
- Examine the current peer-reviewed, evidence-based conclusions on the safety and effectiveness of commonly prescribed cBHT preparations.
- Review the potential risks and reported adverse effects associated with the use of cBHT and FDA-approved products with the same active ingredients.
- Describe potential conflicts of interest that exist within the prescribing, compounding, and treatment sectors of pharmaceutics.
- Additional continuing medical education courses hosted by for-profit organizations should not substitute for this training.
Recommendation 4: Additional federal and state-level oversight should be implemented to better address public health and clinical concerns regarding the safety and effectiveness of compounded bioidentical hormone therapy (cBHT).
The National Association of Boards of Pharmacy (NABP) and state boards of pharmacy should expand and improve their oversight and review of 503A compounding pharmacies to ensure that adequate quality standards are maintained and documented for every cBHT preparation dispensed. This increased oversight should include the following:
- All 503A compounding pharmacies should provide a standardized insert for dispensed cBHT preparations. The insert should:
- Include a detailed description of the preparation’s formulation, including all active pharmaceutical ingredients and the excipient(s) used, and use of the established name of the drug.
- Clearly note that the preparation has not been U.S. Food and Drug Administration (FDA) approved for use and that
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rigorous bioavailability data, such as that available on FDA-approved products, are not available.
- Include indications and guidance for use (administration), dosage strength and form, statement of compliance to current good manufacturing practices or United States Pharmacopeia (USP) standards, beyond-use date, contraindications, side effects, caution for potential adverse effects, and instructions on how to report adverse events.
- Include information on the person responsible for the quality and safety of the dispensed cBHT preparation, such as the establishment’s supervising pharmacist or other designated individual, and the name and contact information for the pharmacy.
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- All cBHT preparations dispensed from 503A compounding pharmacies should include boxed warnings for potential adverse effects for compounded prescriptions that include estrogens (estradiol, estriol, estrone) and androgens (testosterone), like those used in FDA-approved drug products with boxed warnings to educate the user about potential health risks.
- All 503A compounding pharmacies should increase their surveillance capacity by monitoring, recording, and annually reporting the types, formulations, payer, and dispensing rates of cBHT preparations. Data on the volume and types of cBHT dispensed should be submitted annually to a central repository within NABP and made available for public access.
- All 503A compounding pharmacies should be required to monitor and report all adverse events of cBHT preparations to state boards of pharmacy and simultaneously to MedWatch and the FDA Adverse Event Reporting System. Annual adverse event reports for nonsevere and non-life-threatening events should also be submitted. These reports should include information on the frequency, type, and severity of adverse events related to the use of cBHT.
- All states should uniformly and immediately adopt USP <795> and <797> standards to ensure the quality of dispensed sterile and nonsterile cBHT preparations. USP <795> and <797> should be considered minimum standards, and regulators should apply additional standards where needed to reduce patient risk.
FDA should continue to incorporate public health considerations into its regulation of the manufacturing, testing, and dispensing of cBHT by 503B outsourcing facilities. These considerations should include
- Expand the requirement for 503B outsourcing facilities to provide information on the bioavailability and effectiveness of common
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cBHT preparations (e.g., Bi-est, Tri-est, all sterile preparations including pellets), in addition to their current focus on quality, purity, and sterility.
- All 503B outsourcing facilities should use a standardized insert for dispensed cBHT preparations. In addition to the current requirements, the insert should include
- A detailed description of the preparation’s formulation, including all active pharmaceutical ingredients and inactive ingredients (e.g., excipients) used.
- Clearly note that the preparation has not been FDA approved for use, and that rigorous bioavailability data, such as that available on FDA-approved products, are not available.
- Include indications and guidance for use (administration), dosage strength and form, statement of compliance to current good manufacturing practices or USP standards, beyond-use date, contraindications, side effects, caution for potential adverse effects, and instructions on how to report adverse events.
- All cBHT supplied by 503B outsourcing facilities should include boxed warnings for potential adverse effects for compounded prescriptions that include estrogens (estradiol, estriol, estrone) and androgens (testosterone), like those used in FDA-approved drug products with boxed warnings to educate the user about potential health risks.
- Modify the standard MedWatch form to adequately collect and track adverse events data related to cBHT use, including but not limited to:
- All active pharmaceutical ingredients and excipients in the cBHT formulation.
- Potential drug–drug interactions.
Recommendation 5: Collect and disclose conflicts of interest.
Prescribers and compounders of compounded bioidentical hormone therapy (cBHT) may have conflicts of interest arising from financial relationships (e.g., ownership or investment interests held in specific cBHT formulations or companies), and such conflicts should be transparent, publicly available, and disclosed to patients at the point of care. In addition, state licensing boards should collect and archive information on such financial relationships in a publicly accessible repository.
Recommendation 6: Strengthen and expand the evidence base on the safety, effectiveness, and use of compounded bioidentical hormone therapy (cBHT) preparations.
As the field of personalized medicine continues to expand, interest in compounded medication is likely to grow. Ensuring the safe and appropriate dosing of cBHT formulations requires the evaluation of the bioavailability of all active ingredients included in the preparation.
To develop a comprehensive evidence base on the potential health benefits and risks of specific cBHT preparations, public agencies (e.g., National Institutes of Health) and philanthropic funding agencies should establish, provide, or increase funding for clinical, epidemiologic, and health services research to address gaps in the evidence base.
Other stakeholders, including the U.S. Food and Drug Administration (FDA), the United States Pharmacopeia, 503A compounding pharmacies and 503B outsourcing facilities, state medical boards, state boards of pharmacy, nonprofit professional societies and organizations within the medical and pharmaceutical sectors, pharmaceutical industries, and clinical and public health research groups should advocate for and support these research initiatives. Stakeholders should also develop a strategic plan to support precompetitive research projects and activities.
Prioritized research objectives should include, but not be limited to, the following:
- Data collection and surveillance.
- Accurate and consistent collection of adverse event data for each cBHT preparation, by formulation and compounder.
- Accurate determination of volume, scope, and financial costs of prescribed cBHT preparations in the United States.
- Clinical research on safety and efficacy.
- Conduct additional well-controlled trials (with or without active comparators) for commonly prescribed cBHT preparations and dosage forms, including formulations that include estrone, estradiol, estriol, progesterone, or testosterone, to examine effects on safety and symptoms associated with perimenopause and menopause.
- Generate bioavailability data for all active ingredients in the most commonly prescribed cBHT preparations to inform safe and effective dosing practices. Studies that include FDA-approved hormone therapy products with comparable active ingredients and dosage forms may help to inform clinical practice.
- Develop observational studies of genetic and lifestyle variation (smoking, alcohol, diet) in cBHT responses, including adverse events.
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.
