In late 2018, FDA entered a contract with the National Academies of Sciences, Engineering, and Medicine (the National Academies) to examine the clinical utility (effectiveness), safety and uses of compounded bioidentical hormone therapy (cBHT).  A high-level committee was formed and examined in detail the clinical utility of cBHT drug preparations, especially those containing estradiol, estrone, estradiol cypionate, estriol, dehydroepiandrosterone (DHEA), pregnenolone, progesterone, testosterone, testosterone cypionate, and/or testosterone propionate.  After over a year of study the committee published “The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use (2020)” which can be found here (for purchase or a free pdf document).  The report lists editors, committee members and their affiliations, study staff and reviewers.

Even though FDA has approved dozens of hormone therapy products that have gone through the regulatory processes and extensively reviewed for safety and efficacy, many healthcare providers and patients have moved to custom-formulated/compounded drug preparations for hormone-related health matters.  These compounded preparations are often marketed as “natural” or “bioidentical” alternatives to approved products.  The uses of these preparations are estimated at 26 to 33 million prescriptions, and costs in excess of $2 billion annually.

The committee defined clinical utility as a multidimensional construct that searches for evidence about safety, effectiveness, therapeutic need, and patient preference concerning benefit to risk balance.  In its search for evidence, the committee evaluated findings from peer-reviewed literature, held open listening sessions to obtain input from stakeholders, heard presentations by researchers, clinicians, health advocates, representatives from government agencies, attorneys, and members of professional medical and pharmacy societies.  Additionally, the committee received extensive correspondence from stakeholders, compounding (503A) pharmacists, and members of a coalition of (503B) pharmacists.  The committee made concerted efforts to collect relevant anecdotal, survey, and quantitative data from national stakeholders and reviewed submitted testimonies from thousands of patients who use cBHT.

After review of the collected data and information, the committee determined there are many anecdotal claims and patient reports on the safety and effectiveness of cBHT, but little or no data documenting absorption, distribution, and metabolism in the body.  This raises concerns about the safety of these products and underscores the uncertainty about reproducibility of the intended physiological effects.  Based on the review of the peer-reviewed evidence, the committee found a dearth of safety and efficacy data, including little or no high-quality pharmacokinetic data to make conclusions on the safety and effectiveness of cBHT preparations.

In its reviews, the committee was able to identify three specific situations for which there may be potential use for cBHT preparations: 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.

Because the committee found that there is a dearth of evidence to support many of the marketed claims for the clinical utility of cBHT, it recommends the following:

(1) Restrict the use of compounded bioidentical hormone therapy (cBHT) preparations;

(2) Review select bioidentical hormone therapies (found in the report) and dosage forms as candidates for the U.S. Food and Drug Administration (FDA) Difficult to Compound List;

(3) Improve education for prescribers and pharmacists who market, prescribe, compound, and dispense compounded bioidentical hormone therapy (cBHT) preparations through Federal, State and Trade Associations;

(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); cBHT preparations dispensed from 503A compounding pharmacies should include boxed warnings for potential adverse effects; 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; 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; all states should uniformly and immediately adopt USP standards to ensure the quality of dispensed sterile and nonsterile cBHT preparations; Expand the requirement for 503B outsourcing facilities to provide information on the bioavailability and effectiveness of common cBHT preparations; use a standardized insert including a boxed warning for potential adverse reactions; listing of active and inactive ingredients and note that the preparation is not FDA approved; and modify the MedWatch form for adequately collecting and tracking adverse events data related to cBHT use, including but not limited to active pharmaceutical ingredients and excipients in the formulation.

(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

(6) strengthen and expand the evidence base on the safety, effectiveness, and use of compounded bioidentical hormone therapy (cBHT) preparations.

The committee concluded overall that, because of the fast-growing social popularity of cBHT preparations and lack of supporting data, the clinical utility of these compounded preparations is a substantial public health concern for medical practitioners, patients, health advocacy organizations, and federal and state public health agencies.  Current federal and state oversight of the formulation, marketing, dispensing, surveillance, and adverse event reporting of compounded preparations is insufficient to identify and then communicate the risks assumed by patients when using cBHT.

FDA will evaluate this report and hopefully address the recommendations in future Guidances, changes to existing regulations, and add this to their priorities for Compounding Oversight.