Ginger Constantine of Wyeth (WYE) Pharmaceuticals is always suspicious when she comes across pamphlets at her local pharmacy promoting hormone replacement therapy based on "bio-identical" drugs -- compounds whose ingredients are touted as replicating the body's own hormone secretions. Such products are often touted as safe and natural alternatives to Wyeth's menopause treatments, Premarin and Prempro. "The word 'safe' is what bothers me," says Constantine, throwing up her hands in disgust. "How can they make those claims?"
Constantine, Wyeth's vice-president for women's health, plays a leading role in an increasingly raucous drama involving bio-identical drugs, which consumers -- especially women -- are turning to in droves. The treatments are produced by specialty pharmacists called compounders, who form a shadow industry that has largely dodged the scrutiny of the U.S. Food & Drug Administration. They market their concoctions without subjecting them to the rigorous clinical trials normally required for prescription medicines.
Compounding pharmacists don't attract much attention when they stick with their traditional role as the tailors of the pharmaceutical market. Say a patient needs a particular drug but is allergic to the dye that's in the pills. A compounder can make up a batch that doesn't contain the dye, at the order of the physician. Historically, the FDA has permitted such activity, leaving the task of monitoring pharmacies' manufacturing practices to state regulators. But now, Wyeth and women's health experts complain that compounders are manufacturing commercial quantities of drugs and mass-marketing them, allegedly violating FDA regulations and endangering patients.
Critics of the compounding pharmacists suffered a setback in late May. A U.S. district court judge in Texas commented from the bench that the FDA cannot regulate compounded drugs as if they are new products. Though his final ruling is not expected until July, compounders consider it a victory. Exults Susan Merenstein, a compounding pharmacist in Pittsburgh: "This is big. This is really big." L.D. King, executive director of the International Academy of Compounding Pharmacies, says: "This clarifies that compounding is legal."
That may be a hasty conclusion. As the bio-identical movement grows, so do worries about its wares. A document on the FDA's Web site estimates there are now more than 3,000 compounding pharmacies filling 30 million prescriptions a year. The compounders "are running drug companies under the guise of pharmacies," says Edward John Allera, an FDA specialist at the Washington law firm Buchanan Ingersoll. "It's a serious public health problem." The FDA declined to comment for publication. Meanwhile, the controversy has attracted congressional attention. Senator Edward M. Kennedy (D-Mass.) is studying the sector, and could possibly draft legislation calling for tougher federal restraints.
The most common bio- identical hormones are estrogens and progesterones designed to relieve symptoms of menopause. Compounding pharmacies make them from ingredients that come from plants such as Mexican yams. They sell these compounds in brochures and on the Internet, while belittling Premarin and Prempro as synthetic products derived from a not-so-natural source: the urine of pregnant mares.
Two powerful forces have added oomph to the compounding pharmacists' message. The first was the 2002 Women's Health Initiative study, which suggested that Premarin and Prempro raise the risk of breast cancer and heart disease. Then in 2004, former Three's Company actress Suzanne Somers published a book called The Sexy Years, which elevates bio-identical hormones as cures for the so-called seven dwarfs of menopause: "Itchy, Bitchy, Sweaty, Sleepy, Bloated, Forgetful, and All-Dried-Up." Health experts were stunned by the blind trust people placed in the TV star's testimony. "They walked into their doctors' offices with the book and said: 'I want this,'" reports Susan Wysocki, president of the National Association of Nurse Practitioners in Women's Health.
Last October, Wyeth challenged the compounders. It petitioned the FDA to force the pharmacists to disclose the risks of bio-identical therapy and cough up data supporting claims that their products are superior to FDA-approved drugs. Technically, the FDA should have the authority to do this. A policy that the agency adopted in 2002 lets regulators look the other way when compounders follow the traditional model: making one drug for one patient based on a prescription. The policy states, however, that the agency can take action against compounders who behave like drug manufacturers -- making batches of pills before they receive prescriptions for them, say, or including ingredients that aren't approved by the agency. Separately, federal law allows the FDA to crack down on unsubstantiated marketing claims about safety and efficacy.
If the FDA takes a tougher stance on compounding, Wyeth stands to benefit. Annual sales of the Premarin family of drugs shriveled in the wake of the Women's Health study, falling from $2.1 billion in 2001 to $909 million last year. Wyeth is now fighting 4,500 personal injury cases related to Premarin and Prempro. The first will go to trial July 31 in Little Rock. Recent interpretations of the Women's Health study, however, muted some of the concerns about cancer and heart disease. "It is important that women talk to their doctors about the recent results," says Wyeth's Constantine.
Wyeth's credibility suffered a blow in May when the FDA complained to the company about quality lapses at a Prempro plant in Puerto Rico. A Wyeth spokesman says there were no reports of patient harm. But compounders seized on the mishap, deriding Wyeth's hormone-safety campaign as rank hypocrisy.
Are yam derivatives less risky than Wyeth's products? Many compounders say bio-identicals mimic the body's own processes more accurately than the regulated products do. But that's hard to validate because "these cocktails have never been studied," says Dr. Michelle P. Warren, director of a women's health center at Columbia University. More disturbing, many compounded estrogen mixtures contain estriol, a version of the hormone that has not been approved by the FDA.
Warren says she has seen patients who were prescribed bio-identical estrogen without progesterone, increasing their risk of developing uterine cancer. "Some patients come in on crazy doses of [compounded] progesterone cream," she adds, which may not protect the uterus as effectively as does oral progesterone. Some of Warren's patients have reported abnormal bleeding. And while experts know of no deaths caused by bio-identical hormones, several other compounded drugs have been linked to serious, sometimes fatal injuries.
Safety questions aside, some buyers of compounded drugs are getting duped. The Board of Pharmacy in Missouri recently tested 410 compounded products, some of which were collected by undercover agents posing as patients. More than 15% of the drugs were lacking in potency, and a few contained no active ingredients. Critics wonder if other compounders might similarly be passing off placebo-like products as drugs and charging patients as much as $100 a month for them.
A Mar. 31 letter to Wyeth elucidated just how hard the FDA is struggling to resolve the debate over bio-identical hormones. The agency wrote that it needs more time to review Wyeth's petition because it "raises complex issues requiring extensive review." The FDA did not say how long that review would take.