Special Feature

The Bioidentical Hormone Conflict

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

The adverse publicity following publications from the Women's Health Initiative was a multibillion dollar bonanza for compounding pharmacies providing postmenopausal hormones. Bioidentical hormones are now the focus of a political, financial, and legal conflict. Bruce Patsner, MD, JD, MBA, research professor in the Health Law & Policy Institute at the University of Houston Law Center, has written what is in my view a masterful analysis of the problem, with suggestions for its resolution.1

The History of the Conflict

The operations of a pharmacy are regulated in the individual states by state boards of pharmacy, in a system similar to the regulation of medical practice. The first federal law regulating drugs, the Federal Food, Drug & Cosmetic Act, was passed in 1938, at a time when most drugs were compounded according to a doctor's prescription. The American Pharmaceutical Association defines pharmacy compounding as the preparation of a prescription drug that is "individualized" to the needs of the patient. This changed after World War II with the development and growth of the pharmaceutical industry. The Kefauver-Harris Amendment in 1964 extended the FDA role to include safety and efficacy.

In the 1990s, the FDA began to regard the drugs coming from compounding pharmacies as falling under the "new drug" regulations, and, therefore, the FDA had jurisdiction over the marketing and promotion of those drugs. The pharmacy world was immediately challenged; there was no way that an individual pharmacy could carry out the kind of clinical studies required for the approval of new drugs. Thus, the pharmacists immediately realized that all compounded drugs would be illegal. At the same time, the FDA was a bit ambivalent, acknowledging that there were examples where the individual needs of a patient required the compounding of a drug, e.g., the creation of a liquid preparation when none was available. This was before compounding took to the Internet for marketing and promotion.

In 1992, the FDA issued its Compliance Policy Guide on Compounding, reserving a right for "selective enforcement," as a compromise between believing it was correct in assuming that compounded drugs represented new drugs and admitting that some patients required compounding. The pharmacy profession immediately rejected the idea that the FDA had any regulatory jurisdiction over pharmacies. The 1997 Food and Drug Modernization Act attempted to clarify the situation. An amendment was added to the existing laws stating that compounded drugs were not "new drugs," but at the same time the act prohibited the marketing of compounded drugs.

The pharmacy profession sued the FDA, arguing that a restriction on advertising and promotion of compounded drugs was unconstitutional, a restriction of free speech. The District Court ruled against the FDA in 1999. The FDA appealed and lost again in the 9th Circuit Court of Appeals, which further invalidated the entire 1997 Act. In 2002, the U.S. Supreme Court upheld the Circuit Court decision.

The FDA issued a new Compliance Policy Guide in 2002, stating that selective enforcement would hinge on 3 major factors: 1) a potential adverse effect of a drug; 2) whether drugs were compounded from non-FDA-approved components; and 3) whether compounded drugs were similar to drugs already removed from the market for safety reasons. At this point, the FDA affirmed that it did not want to infringe on the traditional practice of compounding, the preparation of a drug according to a doctor's prescription to fit an individual patient's requirements.

Wyeth Pharmaceuticals filed a Citizen Petition with the FDA in October 2005 requesting that the FDA take action against several compounding pharmacies that are primarily Internet-based. The petition's major allegation was that these pharmacies were essentially manufacturing new drugs and should be subject to new drug regulations. On Jan. 9, 2008, the FDA announced it would take action against 7 pharmacies providing prescription bioidentical hormones, and issued warning letters that potentially could be followed by seizures of drugs and injunctions against production.

The Current Landscape

Now, where are we? Currently, the FDA is caught between a rock and a hard place. The FDA would like to regard compounded drugs as "new drugs," but the legal precedent has now been set by the courts: Compounded drugs are not "new drugs." This was reaffirmed in a 2006 decision in the U.S. District Court for Texas. The FDA would further like to regard the giant compounding pharmacies, especially those operating over the Internet, as manufacturers, like pharmaceutical companies, but again, the court decisions have prevented the FDA from requiring compounding pharmacies to meet "new drug" standards. The "new drug" argument just isn't working.

"Bioidentical" and "natural" are often used in concert. Strictly defined, the hormones must be precisely the same as normal endogenous estradiol or progesterone. To argue that products are not "artificial," begs the issue because even if the source is a steroid molecule derived from plants, chemical and manufacturing processing is still required. These terms obviously have marketing value, and no one can deny that the terms are used to imply greater safety, even greater efficacy. The situation is further compounded (pun intended) because it is likely that most patients assume that the marketed bioidentical and natural hormones have been demonstrated by appropriate studies to be effective and safe. Of course this is not the case, although it seems like an obvious conclusion to view Product A and Product B to be the same if they are the same molecule. The problem is that compounding pharmacies are not required to compare the formulation with the performance of an approved product, nor is there any way for a patient to be assured that the dosage is correct (that the drug contains what it is supposed to contain).

The large compounding pharmacies meet the "individualization" requirement that usually comes from a clinician-patient interaction by promoting salivary measurements of hormones, as interpreted by one of their employed clinicians to produce tailored hormone choices and doses. Assessment of this approach by researchers, as well as organizations such as the American College of Obstetricians and Gynecologists and the Endocrine Society, have concluded that the variations in salivary sex steroid levels from individual to individual and from specimen to specimen preclude clinical interpretation. For most patients, laboratory testing is not necessary in hormone decision making. As Patsner says, this is "pseudo-individualization." Individualization is a process that requires a clinician-patient interaction.

The politicization of this issue is well underway. See the Project F.A.N.S. (Freedom of Access to Natural Solutions) web site at www.projectfans.org. This organization and web site are headed by a physician who has his own Hotze Health & Wellness Center in Houston, TX, that promotes the "safer, natural bioidentical hormones."

A New Approach

The American Pharmacists Association and the National Association of Boards of Pharmacies define compounding as the steps required to provide a drug in response to a clinician's prescription according to an individual patient's needs, and the preparation of drugs in anticipation of a demand. Therefore, there are 3 people involved: the patient, the clinician, and the pharmacist. This is in contrast to the production of large amounts of a drug for a national market of unknown users. The American Pharmacists Association further says that if an FDA-approved product is commercially available that meets a patient's needs, it should be the drug provided.

The key to the position of the pharmacists is the contention that there are circumstances, decided by the patient, that makes the use of commercial products not a good choice. This seems reasonable, but it is also reasonable that this decision requires the involvement of the clinician because ultimately a prescription is still required. The traditional view of compounding, therefore, is one of personal relationships with patient, clinician, and pharmacists. This becomes a totally different story when a large Internet pharmacy responds to thousands of prescriptions with no knowledge of the patients. What happened to the "individualization" aspect of compounding? Is it practicing medicine by the pharmacy to have a registered clinician employed by the pharmacy to interpret hormone levels and adjust doses?

Clinicians are appropriately frustrated by the claims made that bioidentical compounded drugs have greater efficacy and safety. Signature Compounding Pharmacy (www.signaturepharmacy.com) says that natural hormone replacement therapy is safe, sensible, effective, and free from side effects caused by synthetic hormones. Of course, to claim that these products are free from side effects, to say that they protect against cancer, is a position unencumbered by data. This is a profit-driven, nonregulated market—doesn't that sound familiar?

The Wyeth petition will not meet its objective because the requests in the petition mirror the arguments already struck down by the courts, basically that compounded drugs should be regarded as new drugs and regulated in the same manner as commercial products. A new approach is needed. Bruce Patsner argues that it should be accepted that bioidentical drugs from the big compounding pharmacies do not meet the definition of compounding supported by the pharmacist's own organization, the American Pharmacists Association—a personal relationship of patient, clinician, and pharmacist addressing an individual's needs. The FDA can argue that the big operations are not legitimate compounding, but big commercial operations directed to unknown consumers.

Patsner also argues that the most vulnerable point is the false safety and efficacy claims. The contention should not be that the safety and efficacy claims are inaccurate, because the pharmacies can always compose their words to avoid legal assaults. The point of attack should go back to the pharmacist's published credo: If a commercial, approved product is available to meet the patient's needs, a compounded product is not indicated. Replacing a commercial product with a "natural," untested, unregulated product is not the same thing as prescribing a compounded product when no commercial product will meet the individual's needs.

Patsner summarizes his argument by saying that the large compounding pharmacies are not true compounders because they advertise and promote their products as replacements for commercially available, approved, and tested drugs, and that the attempt at "individualization" uses an unsubstantiated method that marginalizes clinicians.

It is worth pointing out that this whole issue wouldn't be a problem of such a large magnitude without the involvement of physicians. There are clinicians who put the dollar ahead of good sense, and there are clinicians who don't want to take the time to counter the Internet advertisements. For this reason, it is necessary for the FDA to find a way to exert appropriate regulation.

Reference

  1. Patsner B. Pharmacy compounding of bioidentical hormone replacement therapy (BHRT): A proposed new approach to justify FDA regulation of these prescription drugs. Food Drug Law J 2008;63:459-491.