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As druggists mix customized brews, FDA raises alarm

Friday, February 27, 2004
Jane Spencer and Anna Wilde Matthews
Associated Press

When Donald Boles fell off a ladder and ruptured a disc in 2002, his doctor prescribed a spinal steroid injection to ease the pain. But six months later, after two more shots and back surgery, the pain suddenly got worse. The 45-year-old home inspector from Eagle Springs, N.C., was drinking a half-bottle of Nyquil just to get to sleep.

That's when doctors made a startling discovery. A rare fungus, normally found only in soil, was growing inside the soft tissues of Mr. Boles's lower back, eating away at his bones. Investigators from the Centers for Disease Control and Prevention traced the mold to a batch of contaminated steroid shots that had already infected five people.

The injections weren't manufactured by a major pharmaceutical company. Instead, they were mixed from raw ingredients in the lab of a neighborhood drugstore, Urgent Care Pharmacy, in Spartanburg, S.C., according to the CDC.

Mr. Boles's case illustrates the potential health risks posed by a growing industry of small-scale drug mixers who make customized prescription medications from scratch in a practice known as "pharmacy compounding." These pharmacists purchase bulk chemicals and use them to make prescription medications in their drugstore laboratories. For example, they prepare dye-free cough syrups for patients who are allergic to the coloring found in commercial products, or antihistamine gummy bears for kids who can't swallow pills. "It's a life-saving measure," says Alexander Peralta Jr., a pain specialist in Fort Worth, Texas, who regularly turns to compounding pharmacies to make customized drugs for patients who don't respond to commercial pain medications.

Compounders are operating in something of a regulatory vacuum. In 2002, the Supreme Court wiped out nearly all federal law directly addressing the practice of compounding. Today, the Food and Drug Administration says "virtually all" compounded products are technically illegal. But since it recognizes that much of what the compounders offer serves a legitimate need, the agency is selective in its enforcement. The FDA generally targets only large-scale compounders who are acting more like manufacturers than corner pharmacies.

The high-court decision left regulation of compounders largely in the hands of state pharmacy boards, which often lack the resources to patrol the growing industry. Many compounders argue that they are regulated by the states and that the FDA has limited jurisdiction over their business.

The industry is sparking probes by a range of federal agencies. The Justice Department is investigating more than 50 compounding pharmacies in Southern Florida for potential involvement in a Medicare fraud scheme, according to people familiar with the matter. The Drug Enforcement Administration is looking into compounders' distribution of large amounts of narcotic painkillers. And the FDA is investigating some compounders -- and the companies that supply chemicals to them -- for selling ingredients the FDA considers inappropriate for use in compounding.

The tainted shot Mr. Boles received was one example in a string of public-health problems -- including a handful of deaths -- linked to compounded drugs. State officials in Missouri say that last year they ordered a mail-order compounding pharmacy to recall a batch of respiratory drugs that may have been contaminated with deadly bacteria. The drugs may have reached more than 19,000 people. In 2001, three California patients died of meningitis after receiving contaminated steroid shots made by a compounder. Nevada authorities say some pharmacists have illegally sold large batches of treatments for erectile dysfunction that sent men to emergency rooms after the injections' effects lasted too long, risking permanent damage.

In Mr. Boles's case, the pharmacy was not following proper sterilization techniques, according to state investigators. One of the infected patients using the Urgent Care products later died of fungal meningitis. After a long course of antifungal treatment, Mr. Boles is back at work, but doctors don't know whether the fungus will return. Lawyers for Urgent Care, which is facing several lawsuits about the steroid injections, say they don't comment on pending cases. The pharmacy has filed for Chapter 7 liquidation bankruptcy and is no longer operating.

Incidents such as these, which regulators found out about, "might be the tip of the iceberg" when it comes to concerns with compounded drugs, because there is no mandatory reporting of problems, says David Horowitz, director of the Office of Compliance in the FDA's Center for Drug Evaluation and Research. Compounded products aren't typically tested for safety or purity before being dispensed to patients. The raw chemicals used by compounders often originate from overseas plants that in many cases aren't inspected by the FDA.

Still, the FDA tries to take a balanced approach. "It's very difficult to draw the lines in ways that prevent compounding abuses without shutting off or foreclosing the kind of compounding that benefits patients in a meaningful way," Mr. Horowitz says.

Compounding pharmacists defend the safety and effectiveness of their products. "There's no evidence to suggest that pharmacy compounding is any more unsafe than hospital practice or the use of commercially available drugs," says L.D. King, executive director of the International Academy of Compounding Pharmacists.

Compounding pharmacies require a prescription from a doctor. To generate demand for their products, many compounders advertise their ability to make custom-tailored drugs through television and direct mail, and some employ sales reps to visit doctors' offices. In rare cases, patients may not realize they are getting a compounded product if, for example, a clinic purchases a compounded drug and administers it on the premises.

While much of what compounders prepare serves legitimate medical needs, there are also pharmacists who cross the line into murkier areas. Some compounders -- with their access to the source chemicals for many drugs -- have found a lucrative market in selling medicines before they are formally approved. Others offer their own versions of Viagra and other popular drugs, raising the hackles of the big pharmaceutical companies.

The scope of the compounders' share of the $216 billion U.S. pharmaceutical market is difficult to assess. Trade groups estimate that compounding pharmacists currently fill at least 30 million prescriptions a year, or 1 percent of the three-billion-plus prescriptions dispensed in the U.S. annually.

In 1997, the Food and Drug Administration Modernization Act cleared up longstanding ambiguity over compounders with a provision that directly addressed the issue. The law established that compounding was legal, but it included strict guidelines.

A group of pharmacists challenged the new law, arguing the restrictions on advertising were a violation of their First Amendment free-speech rights. In 2002, the Supreme Court sided with the pharmacists. But the court also held that the advertising restrictions could not be severed from the rest of the provisions on compounding. As a result, the entire section of the 1997 act that specifically addressed compounding was nullified. That decision created the current regulatory gap.

Today's compounders are reviving an old practice. Until the 1950s, pharmacists whipped up nearly all prescriptions with a mortar and pestle behind the drugstore counter. Pharmacists were often called "doc" and they worked in close consultations with physicians to make personalized treatments for each patient. The earliest pharmaceutical companies, such as today's Merck & Co., supplied raw ingredients to pharmacists, instead of finished products. But as the commercial pharmaceutical industry expanded in the 1960s and '70s, pharmacists found themselves counting out pills rather than mixing powders.

In 1981, a group of Houston pharmacists set out to revive the dying practice. They formed a company, Professional Compounding Centers of America Inc., that is widely credited with helping fuel the compounding resurgence.

Twenty-three years later, the closely held company, which describes itself as a "one stop shop" for compounding pharmacies, has more than 3,000 member pharmacies and 200 employees. It doesn't disclose its financial results but says it has been experiencing double-digit growth. The company operates out of a sprawling Houston headquarters, home to gleaming laboratories, a massive chemical warehouse, and a lobby that resembles an old apothecary shop with wooden shelves lined with brown glass jars of powders. Members, who pay an initial $20,000 fee, get a compounding start-up kit that includes many of the basics needed to transform a local pharmacy into a compounding laboratory, including scales, beakers and bottles of tutti-frutti flavoring.

Most important, members get access to PCCA's chemical catalog. The phone-book-size volume contains a range of intriguing ingredients, including New Zealand green-lipped mussel extract and absinthe oil, an intoxicant favored by Oscar Wilde and Vincent Van Gogh.

The catalogue also lists a number of bulk chemicals that can be used to make drugs that aren't permitted for sale in this country by the FDA. Some chemicals listed are found in drugs that are still in clinical trials, such as 4-amino pyridine for multiple sclerosis. Other chemicals listed are the active ingredients in drugs that are available only in Europe such as domperidone, a drug known to stimulate the production of breast milk in nursing mothers. The FDA calls the practice "inappropriate."

PCCA says domperidone is safe and has been widely available in this country for years. "That drug is available in every lactation center, and the FDA is not doing anything about it," says PCCA Chief Executive and President David Sparks. The company also cites a publication from the American Academy of Pediatrics showing that there is no evidence to suggest the drug is transferred to babies through breast milk.

Members also get access to the thousands of formulas PCCA has developed to help pharmacists turn the raw materials in the catalog into drugs. Many of these formulas read like cookbook recipes. A formula for anesthetic lollipops, for example, begins: "Spray lollipop mold with PAM (cooking spray) and allow to drain excess on a paper towel. Melt the PCCA lollipop base at 90 C. Add tetracaine hydrochloride and stir until dissolved. Allow to cool at room temperature."

PCCA says it plays a vital role in the American health-care system by supporting pharmacists who help underserved patient populations get access to important and sometimes lifesaving medications. The company says it places a strong emphasis on safety in all of its training courses and that all of its active pharmaceutical ingredients come from FDA-registered facilities that comply with good manufacturing practices.

PCCA has had several conflicts with federal regulators. In 1994, the FDA seized chemicals from PCCA, claiming they were "misbranded" for reasons including improper labeling. A summary on the FDA Web site listed the value of those chemicals as $503,000, with a potential value of $2.3 million. PCCA now says the agency seized goods valued at only $73,000. A legal battle ensued and PCCA says the situation was resolved through a consent decree in 1996 "that had no finding of any violation." Although the specific goods in question were destroyed, PCCA says it was allowed by FDA to continue its operations without any changes.

A 2001 warning letter from the FDA said the company had engaged in chemical repackaging techniques that risked cross contamination of chemicals. PCCA says it has discontinued all repackaging of the products listed in the letter.

The FDA continues to investigate another issue raised in the 2001 letter, involving PCCA's sale of the active ingredient in a blood-pressure drug -- adenosine-5-monophosphate -- that was withdrawn from the market by the FDA for safety reasons. PCCA says the company is working with the FDA to resolve the concerns. PCCA says the FDA only ruled that the drug couldn't be used in injectable form. The company says it clearly labels its product as a dietary supplement.

The compounding industry has derailed several legislative efforts to restrict it, with the help of powerful allies. PCCA is located just outside House Majority Leader Tom DeLay's Texas district. PCCA Chairman Lawson Kloesel lives in the congressman's hometown. Mr. Sparks, the PCCA CEO, and Mr. Kloesel have donated more than $15,000 combined to Mr. DeLay's campaigns in the past eight years, according to the Center for Responsive Politics. Last fall, according to people familiar with the matter, Mr. DeLay was instrumental in ensuring that the final Medicare bill passed in 2003 didn't include a provision from the Senate version that would have reestablished an FDA advisory committee on compounding. Industry leaders say they met with Mr. DeLay prior to the bill's passage to voice concerns about the compounding provision.

A spokesman for Mr. DeLay said the congressman believes that compounding is already regulated by the states, and he thought a new federal role wouldn't enhance safety and "might hamper legitimate and effective practices." He said Mr. DeLay's position wasn't based on donations from or a relationship with PCCA.

In a statement, PCCA said: "U.S. corporations and individuals make donations to various political campaigns and politicians, routinely. We believe the amount of $15,000 made over eight years by two individuals is reasonable to provide to a state representative."

States from Arkansas to Wyoming are moving to tighten their rules, and federal regulators are considering new action. California now requires compounding pharmacies to go through an accreditation process or get a special license in order to mix certain complex drugs. Missouri's state board recently began requesting random samples of compounded drugs so they could test them for purity. Last October, Sens. Kit Bond, Republican of Missouri, and Pat Roberts, Republican of Kansas, held committee hearings on compounding safety.

The industry is hoping to stave off a regulatory crackdown by encouraging self-regulation. Industry leaders are assembling an accreditation program for compounders who currently must have only a standard pharmacy degree.

The regulatory gap has hampered the FDA's ability to pursue questionable compounding activity, and emboldened some pharmacists to mix experimental products from chemicals the FDA considers "inappropriate" for compounding.

One such product is polidoconal, a powerful industrial chemical commonly used in detergents. The chemical has been approved in Europe for the treatment of varicose veins. Two European companies that produce a pharmaceutical-grade version of the chemical have applied to the FDA to get versions of the drug approved in the U.S. Meanwhile, PCCA is selling the compound to pharmacists, who dilute the chemical, turn it into a solution and sell it to doctors as a vein treatment.

Compounders are required to purchase their active ingredients from chemical factories that have registered with the FDA, but PCCA may not be following that rule in every instance. A document provided by PCCA shows that the company purchased a shipment of polidoconal from Heterene Chemical Co., a Patterson, N.J., chemical company that filed for Chapter 7 bankruptcy protection last September and has ceased operations. Herb Frank, a former technical director at Heterene, says the company never registered with the FDA, and that it was an industrial chemical facility that didn't produce pharmaceutical-grade products.

PCCA says that polidoconal is "not classified as a drug substance and therefore it is not required to be sourced from an FDA-registered facility." The FDA holds that bulk chemicals intended for use in pharmacy compounding are considered drugs, and are therefore required to come from a registered facility and meet quality standards.

Made to Order

Compounders, who mix prescription medicines from raw ingredients, often provide useful products but some can be risky if not prepared carefully:

Safer compounded drugs

Riskier compounded drugs

Copyright © 2004, Associated Press