Legal and political
“Editors’ Overview: The existence of compounded bioidentical hormones and compounding pharmacies in the USA are at imminent risk of disappearing as never before. In 2002, prior to the WHI, 18 million American women–40% of those in menopause–were receiving hormonal treatment, the vast majority of which was with Premarin and Prempro. At that time, these were the most popular and profitable pharmaceutically manufactured drugs of all time. The false and terrifying scare mistakenly presented in the WHI, that there was an increased risk of breast cancer, heart attack, and stroke, exploded out into the public and healthcare professional worlds. Even the WHI study itself was falsely reported, Premarin was associated with a 0.76 relative risk (RR), thus a lower risk than non-treated women. Prempro had a 1.26 RR, declared statistically insignificant within the WHI–but the report was still published and over the objections of some of the study committee members. a HRT usage and sales plummeted to the low millions. By the time there was some recovery with the resumption of treatment, over half of the menopausal women receiving hormones were now being treated with compounded bioidentical hormones (cBHRT).6a, 6b, 6c This colossal loss of market share to the pharmaceutical manufacturers and the startling rise of popularity of cBHRT is opined by many to be the trigger to the pharmaceutical manufacturers to urge the FDA to put pressure on the healthcare professionals dispensing and prescribing cBHRT.4 The FDA receives the lion’s share of its funding from the pharmaceutical industry. There was a significant effort by the FDA in 2008 to undermine the compounding pharmacists. A massive show of support from American women led to protections–and losses–to the proponents of cBHRT. The protections seemed apparent…and, simultaneously, the laws enacted put substantial financial burdens on compounding pharmacists. Fast forward to 2018 where the FDA tasked and funded the National Academy of Science, Engineering and Medicine (NASEM) to do a study on the cBHRT (described below). This process, right out of the gate was assessed as a “stacked deck” by knowledgeable physicians, compounding pharmacists, attorneys, and lobbyists (see below). The 12 members of the NASEM committee, PhD’s and MD’s, had zero experience prescribing, dispensing or scientifically studying cBHRT. The FDA appeared to have an agenda and had a major influence throughout the process on the proceedings, conclusions, and reports of the Committee–contrary to US law. And, as predicted by proponents of cBHRT, the recommendations of the Report have the teeth to begin the demise of cBHRT for healthcare providers, American women, and men. The report basically comes down to recommending this final outcome! 2 Fortunately, there has been a very robust response by compounding pharmacists, (APC: a4pc.org, compounding.com), the Alliance for Natural Health (ANH: https://anh-usa.org), a coalition of healthcare professionals: physicians, compounding pharmacists, scientists, attorneys, lobbyists, and more (cbhrtcoalition.org), and lay public (wethewomen.org). We are together mounting multiple efforts with great commitment and intention, to protect these vital treatment measures that make such a monumental difference in millions of women and men’s lives, in the USA and all over the world. Please join us. Please see below for a sampling of the information, actions, and science related to cBHRT. Please join us. We do not want to lose these precious hormones, and, we so easily could. Please join us.
Here is a sampling of relevant information:
- Recommendation 1: Restrict the use of compounded bioidentical hormone therapy (cBHT) preparations….to 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.
- 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.
2. FDA Response to NASEM Report
- Quoting from the FDA Website, paragraph 2: “Based on its research and analysis, NASEM determined there was a lack of rigorous evidence of safety and effectiveness from well-designed or properly controlled clinical studies. NASEM found information about the safety and effectiveness of cBHT came mostly from low-quality data, such as anecdotal claims, patient reports, and prescriber testimonies. Further, there is limited federal and state-level oversight of the quality and use of cBHT preparations. Given the lack of high-quality clinical evidence and minimal oversight of cBHT, NASEM concluded that their widespread use poses a public health concern.”
- As a reminder:
- This NASEM Committee was tasked and funded by the FDA
The FDA receives major funding from the pharmaceutical industry4
- The pharmaceutical industry had the most popular and profitable prescription drugs of all time
- Premarin and Prempro—18 million American women were being treated—until the Women’s Health Initiative (WHI) study in 2002 (falsely) reported increased risk. Hormone treatment of women cascaded, 80% of women stopping hormone treatment.. By a 2017 study, there was recovery to women being treated to approx. 5 million.
- Issue: more than half of these women are being treated with compounded bioidentical hormones.
- Many believe this loss of market share is the principal reason that the FDA has been on a multifaceted program to eliminate compound
- This NASEM Committee was tasked and funded by the FDA
3. Responses to the NASEM report and the FDA Followup:
- “This report is evidence of yet another public attempt by FDA to discredit critical and life-sustaining compounded hormone therapies in the eyes of the public in favor of FDA-approved hormone therapies”
- The Report is just the latest chapter in a long battle initiated by FDA against compounders that specialize in cBHRT and the physicians and patients they serve. From its inception, the Study was not independent and demonstrated extraordinary bias, including gender bias.
- FDA unfairly and inappropriately influenced the NASEM Committee’s conclusions and recommendations to discredit cBHRT because it is not FDA-approved. The Federal Food, Drug, And Cosmetic Act (“FDCA”) via the Drug Quality Security Act (“DQSA”) exempt compounds like cBHRT from the new drug approval process, meaning FDA cannot evaluate compounded medication for its perceived clinical utility (i.e., for safety and effectiveness). FDA cannot, therefore, circumvent its governing federal statute and effectively force cBHRT through new drug approval via this commissioned Study.
- The Study was predicated on multiple forms of bias. In a review of who comprised the NASEM Committee, the materials the NASEM Committee chose to consider, and the organizations that provided data for the Study, it is clear that the scales were tipped far in favor of Big Pharma. The NASEM Committee also heavily relied on studies that it claimed demonstrated “methodologic rigor,” which have traditionally used the male body as the default and excluded women, and are therefore rooted in striking gender bias. These multiple forms of bias seriously call into question the credibility of the Report and the NASEM Committee’s conclusions and recommendations.
- FDA’s adoption or use of the Report violates FACA. FACA requires the membership of an advisory committee to be fairly balanced, and it also prohibits a federal agency from managing or controlling an advisory committee. In this case, the FDA heavily influenced the NASEM Committee and its conclusions and recommendations that the FDA, in essence, managed and controlled NASEM Committee. Jane Axelrad’s involvement, as well as the active measures the FDA took to control the outcome of the study, demonstrate the FDA’s undue influence over the NASEM Committee and its results. Accordingly, FDA may not adopt the Report without violating FACA.
- …we strongly discourage FDA from engaging the Pharmacy Compounding Advisory Committee (“PCAC”) for any evaluation of whether a bioidentical hormone in any form, including pellet form, should be a candidate for FDA’s Difficult to Compound List. It appears that PCAC itself is in violation of FACA for failing to be fairly balanced in the points of view represented and the functions it performs and is therefore in no position to be evaluating whether hormone therapies or categories thereof should be included on FDA’s Difficult to Compound List. Further, should PCAC place certain bioidentical hormones and pellets on the Difficult to Compound List, this will have devastating effects on the health and wellbeing of the millions of patients treated with cBHRT.
- FDA unfairly influenced the NASEM Committee to achieve its goals of discrediting cBHRT. FDA steered the NASEM Committee to conclude that cBHRT has no clinical utility and may be too difficult to compound. FDA did so in the following key ways: (1) by influencing the NASEM Committee’s definition of “clinical utility” in such a way that it effectively forces compounds through the new drug approval process, a process from which compounds are statutorily exempt; (2) by furthering its public campaign designed to discredit cBHRT; and (3) by indirectly encouraging the dominance of presenter and Report reviewer Jane Axelrad—who, as the former FDA lead on compounding for 21 years, is FDA on compounding issues
- Additionally, the NASEM Committee’s definition of “clinical utility” allows FDA to practice medicine—which the Agency is well aware it cannot do. As set out above, at FDA’s influence, the NASEM Committee defined “clinical utility” as a construct that reflects evidence about, among others, “therapeutic need.”12 The NASEM Committee clarified that “[i]n the context of this report, therapeutic need relates to the treatment of menopausal and male hypogonadism symptoms.”13 In other words, at the request and sponsorship of FDA, the NASEM Committee is evaluating whether a certain medication (i.e., cBHRT) treats two specific disease states—this is the practice of medicine, and the practice of medicine lies wholly outside the scope of FDA’s purview. Physicians—not FDA—are to determine which medication is appropriate to prescribe to best treat their patients. In commissioning NASEM to examine the “clinical utility” of treating patients with cBHRT, FDA effectively inserted itself into the decision-making process between a physician and his or her patient and called into question physicians’ judgment as to the use of cBHRT for treatment. Numerous courts have held that FDA does not have the legal authority to regulate the practice of medicine and even FDA has, in the past, acknowledged that it has no such authority.
- Rachael Pontikes 2nd submission to the FDA
- Before the Study even began, FDA provided one-sided information to NASEM on compounded medications, particularly hormone medications, that profoundly shaped the NASEM Committee’s position on cBHRT;
- As the Study began to materialize, FDA played a role in determining who should serve on the NASEM Committee and who NASEM should rely on as cBHRT subject-matter “experts”;
- [None of these professionals on the NASEM Committee treated women in menopause with cBHRT as part of their professional endeavors]
- [there are specific conflicts of interest in those advising the Board]
- During the course of the Study, FDA and the NASEM Committee consistently collaborated over substantive aspects of the Study; and
- Finally, FDA was given the opportunity to review and comment on the Report before it was published—a Report that was supposed to be advice independent from FDA.
- APC Alliance for Pharmacy Compounding: The APC has been putting forth a prodigious effort to address the NASEM/FDA pressure.Intheir immediate response9 to the NASEM report they had several key points:
- The NASEM study committee was populated by esteemed healthcare professionals, but there was not a pharmacist with patient-facing experience, much less a pharmacy compounder, in their number. Neither was there a physician with substantive experience in bioidentical hormone therapy. Likewise, the peer reviewers for the study included few compounders – but did include one former FDA employee (and current FDA contractor) who is a long-time, well-known opponent of pharmacy compounding.
- Although compounded drugs are exempt from the new drug approval process because they are prepared to meet individual patient needs, the foundation of NASEM’s analysis seems to focus on the absence of new-drug-caliber studies of compounded meds. The report makes an illogical leap by effectively deeming cBHT unsafe unless it can mirror drug manufacturing in terms of safety and effectiveness data, labeling, AE reporting, pharmacokinetic data, and scale of clinical trials.
- NASEM said it based its recommendations in large part on a review of literature, but identifies only 13 studies as having, in the judgment of the committee, suitable “rigor and relevance” – these, out of literally hundreds of studies out there, not to mention abundant patient outcomes data that could and should have been considered and weighed.
- The report calls for restricting the use of cBHT to patients with allergies to FDA-approved drugs, despite the fact that many FDA-approved therapies may not meet the dosing needs of patients – a point not addressed by the report’s recommendations.
- The recommendations seem to suggest that a prescriber’s medical judgment and a patient’s preferences should play no role in determining a proper course of treatment – a stunning assertion that is applied to no other aspect of medicine or pharmacy care. Women’s needs are much more complex than the cookie-cutter approach offered by current FDA-approved drugs. Individualized therapy is the result of a balanced approach between prescriber, patient, and pharmacist assessing each patient’s unique needs.
- The NASEM study seems to suggest that states that do not adopt USP <795> and <797> chapters in whole, without question or amendment, are somehow under-regulating compounders, yet it provides no evidence of patient harm that has resulted in states that adhere to different standards.
- The report cites concerns over bioavailability. However, many compounders or prescribers perform saliva or serum testing to confirm cBHT is appropriate therapy. Yet how many prescribers routinely check levels of FDA-approved products?
- The report sends mixed messages. Individualized therapy is a part of the FDA’s newly established goal of creating personalized therapies to target each patient. Factors such as age, weight, genetics, past medical history all contribute to appropriate treatment and dosage selection. Yet these NASEM recommendations seem to assert that FDA-approved drugs are always superior to compounded therapies.
- The Berkley Research Group Analysis of NASEM report:
- “The Panel Put Policy-Making Before Patient Need: An Independent Analysis of the FDA-Commissioned NASEM Report…”
In the United States, the Food and Drug Administration (“FDA”) oversees the approval, marketing, and labeling of prescription drugs. However, it is the right and the duty of the physician to prescribe what he or she thinks is best for the patient. In its Code of Medical Ethics, the American Medical Association (AMA) states:
“The practice of medicine, and its embodiment in the clinical encounter between a patient and a physician, is fundamentally a moral activity that arises from the imperative to care for patients and to alleviate suffering. The relationship between a patient and a physician is based on trust, which gives rise to physicians’ ethical responsibility to place patients’ welfare above the physicians’ own self-interest or obligations to others, to use sound medical judgment on patients’ behalf, and to advocate for their patients’ welfare.”
Consistent with this principle, U.S. law prohibits the invasion of the FDA into the purview of the physician, as the FDA is not purposed to regulate the practice of medicine or to otherwise interfere with a doctor’s care of a patient. It is well-recognized that flexibility and respect for physicians’ autonomy in caring for patients is “crucial for (doctors] to be able to judge what is best for each individual patient and to provide effective medical care of the highest quality.” Indeed, as recently as November 2020, the AMA “confirm[ed] its strong support for the autonomous clinical decision-making authority of a physician,” and reaffirmed that it “strongly opposes the FDA’s intrusion into the practice of medicine by making decisions for individual care.”
Despite its mandate to respect prescribers’ autonomy, the FDA recently commissioned a report setting forth recommendations that constitute an intrusion into a physician’s ability to practice medicine and to meet his or her patient’s needs. On July 1, 2020, the National Academies of Sciences, Engineering, and Medicine (“NASEM”) published The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Efficacy, and Use (the “NASEM Report” or the “Report”), wherein NASEM received a directive from the FDA to “assess the clinical utility of treating patients with compounded bioidentical hormone therapy (“CBHT”). Specifically, the FDA commissioned
As detailed throughout this white paper, cBHT is used for a variety of medically necessary reasons by patients across the U.S. Continued access to CBHT is critical to patient health and well-being.
While there are opportunities for improving BHT compounding practices, such as establishing clearer guidelines for patient monitoring, the NASEM Report does not provide an accurate or complete lens through which these opportunities can be evaluated. Rather, the NASEM Report offers a biased perspective of CBHT, promulgated by a Committee with practically no patient-facing experience with hormone therapy and guided by a regulatory body with a clear interest in either bringing compounding under its purview or effectively prohibiting the practice of CBHT altogether.
Moreover, as a practical matter, it is unlikely that the concerns of the FDA and those in opposition to CBHT will be addressed through the implementation of the Committee’s recommendations. Most physicians and pharmacists-like any other professional-understand that it is in their own best interest to offer the best possible care to patients as a practical matter. To do otherwise would result in both financial and reputational loss, as it would be in violation of their professional oaths and could have significant ramifications (e.g., the loss of their professional licensure). Laws at the state and federal level mitigate the risk of improper or dangerous business practices. State boards of medicine and pharmacy establish requirements and guidelines for safely treating patients and compounding treatments, respectively. While it may be tempting to seek to regulate every aspect of the health care continuum, it is important to recognize that there will always be bad actors. Try as it might, the FDA cannot prevent individuals from committing a crime or unintentionally causing harm. However, if the Committee’s recommendations are implemented, the FDA will adversely affect the safe practice of medicine and the well-being of CBHT patients nationwide.
In sum, NASEM’s recommendations seek to severely restrict-or eliminate entirely-the ability of the physician to prescribe cBHT to his or her patients. In turn, the restriction on the physician’s ability to prescribe cBHT would limit the patient’s choices for treatment. When a patient’s choices are limited, so too is his or her path to wellness.
We therefore recommend that patient need must take priority over policy-making.
We recommend that FDA not rely on or consider the NASEM Report and instead work to ensure that prescribers, patients, and pharmacists may continue to collaborate on treatment options that work best for the individual patient in a manner that is safe and effective. More specifically, we recommend that:
- FDA should work collaboratively with medical and pharmacy compounding industries to address concerns around labeling and adverse event reporting for compounded therapies.
- Developing a system in which patients are consistently provided with information specific to their prescription medication should be encouraged, including developing product monographs for ingredients used in compounded treatments. The system should ensure that patients receive up-to-date, accurate, and consistent information about their prescription medications.
- The current adverse event reporting system and process should be evaluated for improvements to ensure compounded therapies are being addressed. Improvements to this system, if necessary, should broadly address concerns with CBHT and other compounded therapies.
- FDA should sponsor or encourage sponsorship of educational campaigns directed to medical providers, pharmacists and/or patients focusing on the benefits and risks of CBHT compared to commercially available hormone therapies. Such educational programs should provide fair-balanced benefit and risk information in a manner that is respectful of the doctor-patient relationship.
- FDA should develop and/or improve upon systems to encourage adherence to Code of Ethics for prescribers and pharmacists. Appropriate use of CBHT should be encouraged. Patients are not served if cBHT is not being appropriately used (i.e., overuse and/or underuse).
- Compounding pharmacies should be expected to comply with USP Standards related to the preparation of compounded prescriptions. State Boards of Pharmacy should assess their current requirements and monitoring and enforcement efforts around compliance with USP Standards.