Specialized, drug-producing pharmacies like the one implicated in the nation's ongoing meningitis outbreak have been tied to a string of fatal infections and overdoses stretching back more than a decade, a USA TODAY examination of public records shows.
The cases have prompted repeated calls since at least 2001 for better oversight of "compounding" pharmacies, which are not subject to the same stringent safety rules as large-scale drug manufacturers.
Despite those calls - from public health officials, patient advocates and pharmacists themselves - compounding pharmacies continue to operate in the seams of the regulatory system. They fall somewhere between the U.S. Food and Drug Administration (FDA), the federal regulator of the pharmaceutical industry, and the state boards of pharmacy that oversee more traditional druggists.
Thousands of these pharmacies play a critical role in providing custom drug mixtures and hard-to-find compounds that might otherwise be unavailable to doctors and their patients. But a proliferation of compounding operations in recent years and the growth of some into de facto manufacturing enterprises that produce and ship thousands of doses of medication all over the country have paved the way for serious problems.
Since 2001, records show that the FDA has issued more than 40 warning letters to compounding pharmacies for sanitary violations and failure to take proper steps to prevent the sale of dangerous or ineffective drugs.
"This has been a concern for the last 20 years and it's only going to get worse," says Eric Kastango, a pharmacist whose company, Clinical IQ, provides consulting services and training programs for improving quality at compounding pharmacies.
Demand for compounded drugs is growing, Kastango says, and more traditional pharmacies are compounding drugs as a profitable side business. In some cases, "their quality systems have been outstripped by the volume of compounding," he adds. "They're focusing less on quality and more on meeting demand and the profit associated with it."
Investigators are looking at whether the company suspected in the current meningitis outbreak, Framingham, Mass., based-New England Compounding Center (NECC), violated state and federal rules by manufacturing bulk quantities of drugs without underlying prescriptions, according to Dr. Madeleine Biondolillo, director of the Mass. Bureau of Health Care Safety and Quality, which regulates pharmacies.
FDA and the state are investigating whether contamination in an injectible steroid made by NECC is linked to meningitis cases that have killed 14 people and sickened 170 in 11 states.
In a statement, NECC said Saturday that it is cooperating with investigators and has recalled all products produced at the Framingham facility, but it noted that there is no conclusive evidence that its other drugs were contaminated.
A HISTORY OF PROBLEMS
If the NECC drug is implicated in the ongoing meningitis episode, it would be the worst recorded U.S. outbreak of illness associated with medication produced by a compounding pharmacy. But it would be far from the first.
More than two dozen deaths since 2001 have been linked to contaminated or mismeasured doses of medications produced by compounding pharmacies, according to USA TODAY's review of state and federal records, academic journals, and industry reports. Scores more patients have been badly injured, sometimes resulting in permanent disability.
Among the cases:
In March, 33 patients in seven states developed fungal eye infections after surgery in which they were injected with contaminated drugs prepared by a compounding pharmacy in Florida, according to Centers for Disease Control and Prevention (CDC) reports. Three-quarters of the patients suffered vision loss, some severe; 80% required additional surgery.
In March 2011, nine patients died in six Alabama hospitals after receiving contaminated nutritional supplements prepared by a compounding pharmacy in Birmingham, according to an investigation by the state health department and the CDC. The outbreak is traced to contaminated water used in the product.
In March 2007, two patients in Washington and Oregon died after getting doses of an intravenous pain medication that was measured improperly by a compounding pharmacy in Texas, the CDC reported. A third patient in Oregon also died, "likely associated with the same compounding error," the report said.
In September 2005, three patients died and several others were sickened at a Virginia hospital after receiving drugs made at a compounding pharmacy in Maryland, according to a state pharmacy board investigation. The drugs, shipped to three states and Washington, D.C., were recalled after the FDA found contamination in remaining samples.
Calls for better oversight of compound pharmacies have been repeatedly made since 2001, when state and county health officials in Los Angeles documented what they characterized as the first known infection outbreak associated with compounded drugs. In that case, three patients died with meningitis and eight more were sickened at two California medical centers after receiving injections of a contaminated drug prepared at a compounding pharmacy.
"Enforceable national standards for pharmaceutical compounding are needed to reduce the risk of such outbreaks," investigators concluded in a report published after the outbreak. "Clinicians will need to stay vigilant for potential infections among patients who have received injections with compounded medications."
COMPOUNDING IN DEMAND
The practice of compounding has been a mainstay in pharmacies for centuries. It typically involves preparing medications to meet a prescribing doctor's requirements for dosages or combinations of ingredients that are not available from commercial manufacturers. For example, a pharmacist might add allergy medications to a topical steroid cream, or mix a drug into a liquid solution so it's easier to consume.
Faced with shortages of some popular drugs, compounding pharmacies also use raw ingredients to produce their own substitutes - typically with a doctor's request - and demand for that work has soared as some drugs have grown hard to find. More than half the nation's 56,000 pharmacies do some compounding, and about 7,500 offer what are considered advanced compounding services, according to the International Academy of Compounding Pharmacists.
As more and more pharmacies have expanded compounding operations, oversight questions have become more complex. Traditional pharmacies are regulated by state pharmacy boards, while the FDA regulates commercial drug manufacturing.
Confusion often arises over when a large compounding operation has crossed the line into manufacturing, and "some of the guidance from FDA can be confusing," says Linda Bentley, a Boston lawyer who represents pharmaceutical manufacturers for the firm Mintz Levin. FDA guidance "lists some of the situations that might cause them to take a closer look as to whether what a pharmacy is doing really is manufacturing, as opposed to traditional compounding. But there's no bright line standard."
When FDA investigators determine that a compounding pharmacy has crossed the manufacturing threshold, they often find that the operation fails to meet the tough standards set for commercial manufacturers.
More than half the FDA's 40 warning letters have been issued since 2008, including citations for producing banned compounds, distributing drugs that were adulterated or contaminated, and selling medication in improper dosages or without accurate labels.
This summer, the agency issued a warning letter to Infupharma, a Florida compounding pharmacy that was inspected in connection with a rash of infections among patients who had eye injections with a drug made at the facility. "As you were made aware during the course of the inspection, FDA laboratory analysis confirmed the presence of Streptococcus mitis/oralis, as well as other microorganisms, in samples of Avastin collected during the outbreak investigation," the letter said. "These findings demonstrate that the affected lots of Avastin prefilled syringes are adulterated within the meaning (of law) in that the products consist in whole or in part of a filthy, putrid or decomposed substance."
Infupharma declined to comment, citing litigation issues.
The CDC has suggested repeatedly that compounding pharmacies adopt stringent quality control measures, including prerelease product testing, particularly when producing "large quantities" of medication. And the nation's leading pharmacy associations have set up a voluntary certification program, under the Pharmacy Compounding Accreditation Board, for compounders whose operations meet best practices standards.
Calls for tougher regulation have grown amid the latest compounding scare. Public Citizen issued a statement this week calling for increased regulatory scrutiny of compounding pharmacies, and Rep. EdMarkey, D-Mass., said he would introduce legislation to tighten oversight.
"We want to sit down with pharmacies and regulators to put in place a scheme that recognizes that the practice of pharmacies and the industry of compounding has evolved over time," Deborah Autor, deputy FDA commissioner for regulatory operations and policy, said Thursday in a conference call with reporters.
Others argued that talk of increased regulation is premature.
In a written statement, the Association of American Physicians and Surgeons noted that the ongoing meningitis outbreak still is under investigation and that its not clear that it will be tied to the New England compounding pharmacy.
"No one knows yet," the statement said. "Calls by politicians to expand the power of the Food and Drug Administration over compounding pharmacies are nothing more than political demagoguery."