From the North American Menopause Society

Nashville, Tenn—Fueled by a growing population of women reaching menopause, regulatory and scientific uncertainty, and—depending on the viewpoint—elements of hucksterism, controversy has enveloped the burgeoning practice of hormone therapy based on designer products produced by compounding pharmacists.

Generally (and incorrectly) referred to as bioidentical hormone therapy, compounded prescription hormones moved from a supporting role in hormone replacement therapy (HRT) to center stage in 2004, when actress Suzanne Somers published The Sexy Years, a memoir describing how custom-made hormones had relieved her menopausal symptoms and questioning the safety and efficacy of so-called conventional HRT.

The book added an accelerant to a simmering debate over the regulatory, scientific, and legal status of bioidentical hormone therapy. The FDA presumes to have regulatory authority over compounded hormones, Bruce Patsner, MD, JD, a former FDA medical officer, said at a continuing medical education program held in conjunction with the North American Menopause Society (NAMS) annual meeting. However, federal courts have sided with the compounding industry, ruling that states have authority over bioidentical hormone therapy.

Compounding Pharmacies
The FDA has been frustrated by its inability to deal with the "obviously bogus health claims promoted by compounding pharmacies," said Dr Patsner, of Walter Reed Army Medical Center and the American University College of Law, both in Washington, DC. The compounding industry has thrived in the existing regulatory limbo.

Compounding pharmacies do not have to submit to the FDA's new drug application (NDA) process. And they regularly use direct-to-consumer promotions that include false and misleading claims for which "there is not a nanoshred of evidence" to support, Dr Patsner stressed. Patient testimonials frequently are offered as proof of a compounded hormone therapy's safety and efficacy.

But compounding has a long and well-accepted history in the practices of medicine and pharmacy. "Regardless of how the regulatory framework plays out, let's not lose the forest amidst the trees," said Dr Patsner. "Compounding of prescription drugs is a legal activity. It always has been, and it's always going to be."

Providing a voice for compounding pharmacists, Loyd V. Allen, Jr, PhD, RPh, acknowledged that he takes issue with "some of what is going on out there." But he insists that the compounding industry is "working to get it changed." He also maintains that most compounding pharmacists are reputable practitioners who have the needs and concerns of patients and physicians uppermost in their mind.

"The whole role of the compounding pharmacist is to individualize drug therapy at the request of the physician or patient," said Dr Allen, chief executive officer of the Midwest Institute of Research and Technology in Edmond, Okla, as well as editor-in-chief of the International Journal of Pharmaceutical Compounding.

Natural or Not?
The controversy begins with the terminology, explains Dr Patsner. The word "bioidentical" is not in any dictionary. The Rocky Mountain GYN & Hormone Center website (www.rockymountainobgyn.com) describes bioidentical hormones as natural hormones rather than the synthetic hormones that have "added side chains like methyl and acetate groups." The site claims that bioidentical hormones are created from the sources that are found in nature.

NAMS describes bioidentical hormones as "those that are chemically identical to the hormones produced by women," such as various estrogens, progesterone, and testosterone. And although many patients and physicians think the term "bioidentical" refers to all-natural, custom-made hormones, the recipe for many so-called bioidentical hormone therapies often includes nonhormonal ingredients that are necessary to "hold everything together" (www.menopause.org\\bioidentical.htm).

Several FDA-approved bioidentical hormone products are available by prescription and are federally regulated and tested for purity, potency, efficacy, and safety, including 17-beta-estradiol (eg, Estrace, Climara), estrone (eg, Ortho-Est, Ogen), and micronized progesterone (Prometrium, Prochieve 4%). "There are FDA-approved hormone therapies that are structurally identical to those produced by a woman's ovaries," said Lila Nachtigall, MD, of the New York University School of Medicine.

Nevertheless, the term is mainly used for hormone recipes made from a prescription by a compounding pharmacist, such as Biest (estriol and estradiol) and Triest (estriol, estradiol, and estrone), which are not approved by the FDA.

Regulatory Limbo
In 1997, Congress passed the FDA Modernization Act, which included a subsection that exempted compounded drugs from the NDA process. It also imposed advertising restrictions on compounded drugs. But in 1998, 8 pharmacies in 7 states sued the FDA, contending that the advertising restriction was an unconstitutional breech of their First Amendment rights.

The 9th Circuit Court sided with the pharmacies, ruling that the restrictions were too vague. The circuit court further ruled that the advertising clause could not be split from the rest of the subsection. This ruling was subsequently upheld by the Supreme Court in a 5-to-4 decision.

The Supreme Court decision effectively left the FDA in regulatory limbo, said Dr Patsner. The agency still maintains it has regulatory authority over compounding pharmacies, "but, the fact is, it has not been able to do it. Even if we wanted to, we don't have the resources necessary to regulate this industry."

Lack of Evidence
From a scientific perspective, compounded hormones have virtually no supporting research, Dr Patsner continued. Authors of a review of bioidentical HRT concluded that compounded hormones "have no proven advantage over conventional hormone therapies, and their use is not supported by evidence regarding pharmacokinetics, safety, and efficacy" (Menopause. 2004; 11:356-367).

"No large, randomized, placebo-controlled trials support increased efficacy or safety of compounded bioidentical versus commercial hormone therapy," said Dr Nachtigall.

Dr Allen disagreed with the opinions expressed by other experts at the meeting, insisting that the compounding industry is subject to considerable oversight. He pointed out that state pharmacy boards, the US Pharmacopeia, and several federal agencies have established standards that compounding pharmacies must meet.

The Final Word?
Despite the current controversy, the demand for compounded drugs will continue to grow, said Dr Allen. New drug delivery systems, the continued evolution of nanotechnology, and a better understanding of pharmacogenomics and its application to medical and pharmacy practice are just some of the factors that will help maintain or increase the demand for compounded drugs.

"I think we may see more compounding in the future involving drugs that are produced at the behest of physicians on the basis of a patient's particular genetic makeup," he said.

"Eventually, we're going to have bad outcomes with these products," Dr Patsner said. "State attorneys general are going to step in. They are not going to be hampered by federal First Amendment requirements. There are state laws on false claims and fraud. Compounding pharmacies are much more vulnerable to state regulation."