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 (e.g., the 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 FDA, USP, 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.

To read the full report, please visit nationalacademies.org/cBHT

EDITOR'S COMMENTS ON RECOMMENDATION 6

As is quite evident, the committee continues to develop their recommendations from an FDA New-Drug-approval point of view. The value of personalized medicine is that each individual is treated as an individual and not as a population. The value of the report is severely compromised by this approach, as it is inconceivable that all the variations in dosage forms, strengths, etc. could ever be tested as recommended because the costs would be in the billions of dollars...and for what end? Just a few comments here:

• Safety and Efficacy: Estradiol, Estriol, Estrone, Progesterone, and Testosterone have been widely accepted clinically as effective and safe since the 1940s (almost 80 years of safe and effective use both as manufactured and compounded products).
• Patient Titration: Compounding is unique since a dosage can be adjusted to obtain the desired clinical effect in each individual patient while minimizing any potential side effects. This is why so many patients prefer cBHT as compared to manufactured products available only in limited dosage forms and strengths. A patient is titrated by adjusting/changing the dose and/or dosage form as needed by the prescribing physician and patient response.
• A comprehensive data base might be beneficial but what is the cost:benefit ratio of spending inordinately large sums of money to collect data coming from a wide range of participants that may not be valid when trying to categorize it and develop conclusions. Without a defined goal, this may be a meaningless task.
• Adverse event data reporting is already recommended but in many situations the prescribing physician is the only individual with which this is discussed by the patient. The compounding pharmacist receives a new and maybe slightly changed prescription without always knowing the reasons.
• Of what value and to whom would the data collection of volume, scope, and financial costs of prescribed cBHT preparations be beneficial? I don't believe this would be of much value to prescribers, compounders, or patients.
• Bioavailability data is important but not critical, especially with the close "prescriber-patient-pharmacist" relationship involved in cBHT. Bioavailability issues, if they occur, are resolved based on the patient's response and the close prescriber-patient-pharmacist relationship. If something is not working, it is investigated and resolved. Conclusion 6-1 of the Report even states that "The immense number of potential combinations of different hormones, excipients, dosage forms, and strengths, as well as the lack of uniformity of cBHT preparations, make determining definitive bioavailability of those preparations difficult.
• Regarding the comment "observational studies of genetic and lifestyle variation..." may have already been extensively studied since Estradiol, Estriol, Estrone, Progesterone, and Testosterone FDA-approved products have been in use for almost 80 years. Whether or not the data would be any different or not with cBHT since the same drugs are involved is questionable. If this has not been studied but is considered important, "Why hasn't it been studied?"

In summary, the purpose of the report (commissioned by the FDA), the contracting of the project to NASEM (paid for by the FDA), the composition of the committee (backgrounds, conflicts of interest, etc.), composition of invited speakers and the final report really are of little or no value, especially since the basis of the recommendations are to generally comply with New Drug requirements, which are impossible with personalized medicine at the individual patient level.