Potential Variances Between Preparations

Unlike with FDA-approved hormone products, the process of formulating a compounded prescription is entirely compounder specific. That is, the content and quality of the final preparation depends completely on what is described in the Master Formulation Record (MFR) as chosen or described by the compounder.^3,4 Compounder-specific factors that may influence quality and performance of the final preparation include the choice of active and inactive ingredients, ingredient testing, available compounding equipment, compounder skill, quality systems, facility cleanliness, and environmental controls. Per United States Pharmacopeia (USP) standards, once completed, the compounded preparations should undergo an abbreviated release inspection that should at a minimum include a visual inspection of the formulation, but it may also include quality checks developed and reviewed solely by the compounder (USP, 2012, 2014).⁵

While important, the recommended postcompounding inspection process is superficial, in that these steps do not ensure that the compounded preparation contains the purported amount of active ingredient or can deliver the active ingredient to the patient and the site of action. Because of these limitations, different compounders may use different processes to compound an identical prescription, and as a result, cBHT preparations ordered with identical prescriptions and labeled with the same name will likely vary between compounders. Indeed, FDA has received adverse event reports that reveal harmful variations in compounding (FDA, 2020a; see Chapter 7).

Inadequate Labeling Requirements

Labels for compounded preparations are not required to provide guidance for patients about safe use.⁶ This is in contrast with requirements for FDA-approved hormone products to provide labeled instructions for patients on the proper use and storage of the product and warnings about possible risks.⁷ For 503A compounding pharmacies, the decision to provide labels for compounded preparations is up to the compounder. As a result, and as presented at the study's open session meetings, dispensed cBHT preparations often do not include the boxed warnings, warnings, contraindications, and detailed instructions for use similar to those included with FDA-approved hormone product labeling, despite containing the same active ingredients (NASEM, 2019c). (See Box 5-1 and Table 5-1 for additional discussion on labeling of FDA-approved hormone products.) Although the federal statutes establishing 503A and 503B compounders specifically exempted them from federal labeling provisions on adequate directions for use,⁸ there is no clear clinical rationale for excluding information on the potential risks associated with the use of hormone medication, particularly for those that contain estradiol and testosterone.

BOX 5-1

Labeling of FDA-Approved Hormone Products and Boxed Warnings.

Inadequate Data Collection

In addition to concerns related to labeling, there are also concerns related to data collection. Specifically, once an MFR is created, there is no central registry where the MFR must be submitted, and there is no requirement for independent outside review, as is the case for FDA-approved products. Unlike with FDA-approved products, compounded preparations do not have a National Drug Code and are not listed in any conventional shared drug product database. In contrast, basic characteristics of FDA-approved products, including active ingredients, strength, and dosage form, are described in multiple public databases, including the Orange Book (FDA, 2020b), RxNorm (NLM, 2019), International Nonproprietary Names (WHO, 2018), and others. This further underscores that compounded preparations are unique to the compounder that prepares them, and that for identical prescriptions, the final compounded preparations may differ between compounding establishments.

Box

Conclusion 5-1.

Available Dosage Forms and Routes of Administration

To support the committee's research efforts, Reed Smith LLP submitted a briefing document that contained a list of common cBHT dosage forms.¹⁰ Although this list may not be comprehensive, it describes at least 32 different types of dosage forms of cBHT formulations. In contrast, there are only 13 FDA-approved bioidentical hormone therapy dosage forms available (see Table 5-2).

Of the 10 hormone ingredients of focus for this report, all are available in cBHT preparations except for estradiol cypionate.¹¹ Table 5-3 provides a summarized list of the different dosage forms available for single active ingredient cBHT preparations, as identified by the committee in its review, and compares them to available dosage forms of FDA-approved single active ingredient BHT products. In summary, the committee found that the single ingredient cBHT preparations are available in a wide variety of dosage forms and strengths, while comparatively there are fewer FDA-approved hormone products available for each of the routes of administration. For example, there are at least 13 different cBHT progesterone dosage forms, including oral (capsule, capsule sustained release, lozenge, oil, tablet), topical (cream, gel, solution, spray), injection (oil, pellets, suspension), rectal (enema), and vaginal (capsule, suppository) preparations, as compared to four different FDA-approved BHT progesterone dosage forms, including oral (capsule), topical (gel), injection (solution), and vaginal (insert). Furthermore, estriol cream and pellets containing estradiol or progesterone only exist as compounded preparations.

Conversely, there is no compounded estradiol or testosterone patch, testosterone film, or estradiol ring, perhaps a result of the complexity of manufacturing these FDA-approved dosage forms (FDA, 2018b, 2019d). Of the 10 hormone ingredients of focus for this report, only 3—DHEA, estriol, and pregnenolone—are not available as injections or implants. The three hormone salts, estradiol cypionate, testosterone cypionate, and testosterone propionate, are water insoluble and are found almost exclusively in depot oil-based injection products. These three preparations are not commonly found in other types of cBHT dosage forms, and as such are not listed in the summary Table 5-3 below. In addition, estrone and pregnenolone were only ever combined with at least one other active ingredient in the cBHT formulations found, and therefore, are also not included in Table 5-3.

Available Doses

For each of the dosage forms listed in Table 5-3, the compounding process generates preparations of varying strengths, adding to the number of total possible cBHT preparations available for use. For example, in considering formulations with single and multiple active ingredients, the committee identified hundreds of different formulations and strengths for cBHT preparations (see Appendixes F and G).¹²

To serve as an illustrative example, Figure 5-1 above compares the variety of progesterone capsule strengths against the two FDA-approved capsule strengths. The preparations with low doses of progesterone pose a clinical concern: low dose progesterone has not been found to protect the endometrium and reduce the risk of endometrial cancer induced by unopposed estrogen (Stute et al., 2016). At the committee's open session meeting in November 2019, invited panelist, Dr. Pamela Smith (Center for Personalized Medicine), described these low doses of progesterone as ineffective and something she would not prescribe (NASEM, 2019b). Nonetheless, these doses are still available and marketed to patients for use. In addition, high progesterone doses (> 200 mg) are also available in cBHT preparations, but have never been tested for safety or efficacy in FDA-approved drug products, thus raising a different set of safety concerns.

FIGURE 5-1

Comparing the strength of various compounded progesterone capsule formulations to two FDA-approved capsule strengths. SOURCES: Committee generated, using information derived from peer-reviewed literature on the use of cBHT (e.g., IJPC, 2018), cBHT preparation (more...)

In summary, compared to compounded formulations, there are fewer FDA-approved dosage forms and strengths, and in many cases there is no comparable FDA-approved drug product. Therefore, even with the limited data available to the committee, it can be assumed that there are likely tens of thousands of different cBHT preparations (dosage forms and doses) available for patient use. This includes the wide array of different dosage forms, single active ingredient preparations, multiple active ingredient preparations, and an extensive range of different active ingredient doses and dose combinations.

Multihormone cBHT Preparations

Part of the appeal of compounding bioidentical hormones is that multiple hormones can be combined into a single dosage form that does not exist in a single FDA-approved drug product. In fact, of the 741 formulations identified by the committee, 289 were formulations containing more than one active pharmaceutical ingredient (API). While it may be convenient for patients to have multiple hormones combined into a single formulation, thereby reducing their medication burden, it remains unclear whether the combinations of these hormones are necessary or sufficient to elicit the desired effects, allowing the potential for patients to be exposed to undue risk without deriving any additional benefit. Moreover, the practice of combining multiple APIs in a single formulation is a complex process requiring careful consideration of drug–drug interactions as well as the compatibility of all the active and inactive ingredients in the dosage form (Pourkavoos, 2012).

In contrast to the wide variety of available multihormone cBHT preparations, there is only one FDA-approved fixed-dose combination bioidentical hormone product, Bijuva (TherapeuticsMD, 2018). The limited FDA-approved option is likely a result of the narrow conditions under which FDA approves products with two or more active ingredients. Unlike cBHT preparations, which may combine any number of hormones without first demonstrating safety or effectiveness, FDA-approved drug products that combine multiple drugs must not only provide evidence of safety and efficacy, but they must also demonstrate the combination improves the safety over any of the individual drug components alone (see Box 5-2).¹³

BOX 5-2

FDA Policy and Guidance on Products Combining Multiple Drugs.

In addition, within the new drug application or abbreviated new drug application submitted for all FDA-approved drug products is a description of the manufacturing and quality processes involved,¹⁴ including the “Chemistry, Manufacturing, and Controls” (CMC) section.¹⁵ The CMC section is an extremely detailed set of documents with far more information than in an MFR. For example, the CMC section will include active and inactive ingredient potency reverification, container labeling, stability testing, and detailed manufacturing processes to control for quality attributes (Sheinin and Williams, 2002). FDA encourages that the CMC manufacturing process be further refined via the quality-by-design process through which quality is built into the drug product by identifying and controlling critical process parameters and attributes of the APIs, excipients, and final drug product. In drug manufacturing, this usually involves extensive drug product testing across batches, as well as strict control of process parameters as well as API and excipient attributes to minimize product variability (Yu et al., 2014). This is a more intensive process than what can be captured by a 503A compounding pharmacy or 503B outsourcing facility, but it provides a necessary comparative context.

Complex Characteristics of Active Ingredients Used in cBHT Preparations

The challenges of formulating the 10 APIs covered in this report represent a complex topic that has been described in great detail over many decades (Goodman Gilman et al., 1990), and the breadth of those challenges is beyond the purview of this report. However, this topic provides useful context for the committee to consider in its examination of the clinical utility of cBHT preparations.

In all formulation processes, it is important to consider the “formulatability” of APIs, meaning how easily the API can be made into a stable dosage form capable of consistently delivering it to the sites of action in the body. As a class, steroid hormones are recognized as presenting formulation difficulties, in part because of their poor water solubility (Benet et al., 2011), potential to be metabolized in vivo (Miller and Auchus, 2011), active uptake by cellular transporters (Hammes et al., 2005), and potential variablility (FDA, 2012; see Table 5-4).

To provide a closer look at the complexity of formulating APIs, the following sections discuss six API characteristics that must be considered during formulation to more reliably deliver hormones to the active site: particle size, polymorphism, solubility, purity, in vivo metabolism, and formulation stability. A related concept, formulation release rate, will also be discussed.

Formulation Stability

FDA-approved drug manufacturers must test their products for API stability within the formulation and for their ability to safely release hormones over time.²⁰ Demonstrating API stability in a formulation is of obvious importance. For example, if a dissolved API crystalizes out of solution in a topical cream, it may decrease the bioavailability of the hormone, decreasing the effectiveness of the cream (Garnero et al., 2018). This scenario can happen simply because the cream loses water over time if it was not in a well-sealed package. As a second example, for many formulations, the order of ingredient mixing, inclusion of solubilizers, and other process variables are critical for formulation stability. This is especially the case for topical preparations, as microstructures are formed between ingredients within the dosage form (Jeong et al., 2003). Simple two or three ingredient topical formulations or use of a single premixed commercial base may not be adequate to produce a formulation with suitable stability. For comparison, Box 5-4 lists the 10 inactive ingredients incorporated into Estrace Cream, which are all required for prolonged product stability.

BOX 5-4

Inactive Ingredients in Estrace Cream, an FDA-Approved Drug Product.

In contrast, 503A compounding pharmacies are not required to demonstrate that APIs are stable in formulations for the life (i.e., expiry date or beyond-use date) of their products. Neither are compounders required to measure hormone release rates from cBHT preparations. For example, at a November 2019 open session meeting, Dr. Gary S. Donovitz (BioTE Medical, LLC) who uses a 503B outsourcing facility to prepare testosterone pellets for use in their practice was asked during an open session meeting whether their group tested the pellets to determine the rate of testosterone release over time. Dr. Donovitz expressed that his practice does not conduct such testing, but instead examines the peak serum testosterone levels in patients, using certain target ranges for optimization (NASEM, 2019c).

All of the factors reviewed in this section must be taken into account when developing drug formulations with hormone APIs. Formulations require rigorous testing and improvement over time, before knowing that they can reliably, over time, deliver hormones through the skin, gastrointestinal tract, and tissues. However, the materials, methods, and quality standards followed differ among pharmacies when preparing cBHT preparations, even when filling identical prescriptions.

Examples of Complexity: Formulations, Dosage Forms, and Potency

As a formulation's complexity increases, so does the potential for product failure. For example, Bi-est (formulated with estradiol and estriol, in varying amounts) and Tri-est (formulated with estradiol, estriol, and estrone, in varying amounts) are commonly prescribed cBHT formulations.²¹ An even more complex formulation is “Arousal Cream,” which contains six active ingredients. Unless formal stability studies on these complex formulations are conducted and disclosed, there is cause for concern regarding the stability and bioavailability of every multi-ingredient compounded preparation.

The level of potency is also an important consideration. For compounded preparations, USP has established a ±10 percent potency deviation range for most compounded preparations (USP Compounding Expert Committee, 2014). Yet, differences in the potency of cBHT preparations have been documented between compounding pharmacies. For example, when compared with product labeling, estradiol capsule potency varied from –26 percent to +5 percent, estradiol cream potency varied from –11 percent to +1.4 percent, progesterone capsule potency varied from –9 percent to +31 percent, and progesterone cream potency varied from –5 percent to +12 percent of the label (Stanczyk et al., 2019). For reference, FDA-approved products typically must maintain potency within a ±10 percent range from the label (Blessy, 2014) to maintain safety and effectiveness (FDA, 2004).

Illustrative Example of Complex cBHT Preparations: Hormone Pellets

Hormone pellet therapies are complex formulations that must be prepared to exacting specifications in order to safely, reliably, and repeatedly deliver a uniform amount of hormone over time. Pellets are implanted subcutaneously and are expected to release hormone(s) at a controlled uniform rate, typically over weeks to months (McCullough, 2014). As such, they are controlled release dosage forms, which makes them different from the more routinely compounded “immediate release” therapies such as topical creams, oral capsules, or immediate release injections.

The committee found multiple examples of cBHT pellets for estradiol, testosterone, and progesterone, available in varied strengths (see Appendix F).²² In regard to the scope of available pellet therapies, the testosterone replacement market alone has been described as a multibillion dollar industry (McCullough, 2014).

Several factors affect the ability of a pellet to reliably release hormone(s) over time, including content uniformity and pellet size and shape (length, width, surface area). Content uniformity is how well the hormone(s) and inactive ingredients are mixed together. As pellets slowly dissolve over time, and thereby slowly release hormone(s) over time, any pockets of hormone crystals (e.g., from a nonuniform mixture) within the pellet may deliver an unintended bolus of hormone(s) to the body.

For most pellets, the size, shape, and surface area of the pellet must be uniform among all pellets of the same dose, and the pellet surface area must be proportional between different dose pellets. That is because the dose delivered is proportional to the surface area of the pellet (McCullough, 2014). Whether compounded or FDA approved, testosterone pellets for men are usually implanted in sets of 10 or more (Glaser and York, 2019; McMahon et al., 2017), and each is expected to deliver hormone(s) at the same rate (McCullough, 2014). Small deviations in length or width will change the rate of hormone delivery. Note that pellets are much smaller than the products a pharmacist typically prepares. For example, a Testopel pellet is 3 mm wide and 8 mm long (McCullough, 2014), which is about the size of a single grain of rice. To dispense a pellet in response to a patient prescription, a pharmacist would have to own and know how to operate special equipment that can mix, dry, extrude, package, and sterilize the pellets. Such equipment is simply not found in the majority of pharmacies. It also cannot be made “on demand.” Also, to be sure the pellets are of uniform size, the pharmacist would have to be able to measure small differences in length and width, on the scale of ≤ 0.3 mm, among same dose pellets.

To prepare pellets simply requires special compounding equipment that is only found in pharmaceutical manufacturing facilities. Also to test a batch of pellets to show they are the correct size, shape, have proper content uniformity, and deliver hormones at a uniform prespecified rate, requires both complex physicochemical testing (specialized dissolution testing) and analytical test methods. Again, such testing is only available in specialized pharmaceutical analytical testing facilities.

Because hormone pellets deliver hormones slowly over an extended period of time, including up to 2 to 5 months (Glaser and York, 2019; McCullough, 2014), specialized bioavailability study designs are required to show how reliable and consistent the delivery happens in humans. That is, pellets require the types of bioavailability study designs applied to depot injection products, which deliver active ingredients over weeks and months. As will be discussed in Chapter 6, compounded preparations are not required to be tested for bioavailability. Also the standard in vitro batch release tests do not capture information required to have assurance that a hormone pellet can safely and uniformly deliver hormones over long time periods. This may explain why there is evidence of significant adverse reactions, indicative of hormone overdose, in groups of patients who have received hormone pellet therapy (Jiang, 2019).²³ For example, a higher incidence of mood swings, breast tenderness, hair pattern changes, acne, weight gain, and dyslipidemias were reported in woman who received compounded pellets containing estradiol or testosterone, when compared with woman receiving an FDA-approved hormone product. Also in the same study, woman receiving pellet products had significantly higher and more variable serum concentrations of estradiol and testosterone, when compared with woman receiving an FDA-approved product (Jiang, 2019). There is also evidence of compounding pharmacies substituting inactive ingredients into pellet products (e.g., a cholesterol base for a steric acid base), which would completely change the release characteristics of the pellet,²⁴ a formulation change that could clearly put patients at risk.

Difficult to Compound

Given the complexity of the compounding process as discussed above, the Federal Food, Drug, and Cosmetic Act (FDCA) asks FDA to develop regulations identifying drugs and drug categories that “present demonstrable difficulties for compounding” and to establish a Difficult to Compound List, which would preclude the use of listed drugs in compounded preparations.²⁵ When considering whether or not a drug is difficult to formulate, both the active ingredient and the dosage form should be considered. Relevant to this report, most of the cBHT APIs and certain cBHT formulations exhibit one or more of the complexities discussed in the criteria for the Difficult to Compound List (see Box 5-3).

BOX 5-3

Difficult to Compound List.

Box

Conclusion 5-2.