On Sept. 18, 2012, doctors at Vanderbilt University in Nashville, Tenn., diagnosed a rare case of life-threatening fungal meningitis in an otherwise healthy patient. A culture of the patient’s cerebral spinal fluid revealed the cause of the infection: a type of mold called Aspergillus. The doctors quickly suspected that the source of the mold was an injection of steroid medication administered for back pain. Thus began one of the most serious infectious disease outbreaks in modern U.S....
On Sept. 18, 2012, doctors at Vanderbilt University in Nashville, Tenn., diagnosed a rare case of life-threatening fungal meningitis in an otherwise healthy patient. A culture of the patient’s cerebral spinal fluid revealed the cause of the infection: a type of mold called Aspergillus. The doctors quickly suspected that the source of the mold was an injection of steroid medication administered for back pain. Thus began one of the most serious infectious disease outbreaks in modern U.S. history due to contamination of a drug produced by a compounding pharmacy.
Within two weeks, 13 additional patients — 12 in Tennessee and one in North Carolina — were found to have contracted fungal meningitis after receiving steroid injections for back pain. Epidemiologists from the U.S. Centers for Disease Control and Prevention (CDC) linked the source of the outbreak to contaminated vials of a steroid, methylprednisolone acetate, produced by the New England Compounding Center (NECC), a compounding pharmacy located in Framingham, Mass.
The outbreak represents an ongoing public health catastrophe: By Nov. 2, at least 404 people were affected (395 with meningitis and nine with infected joints) across 19 states, and 29 have died. What is particularly tragic for those sickened or killed by the tainted drug, as well as their loved ones, is that this situation was completely avoidable.
What is drug compounding?
Drug compounding traditionally involves a local pharmacist combining, mixing or altering ingredients to create a unique, custom medication for an individual patient whose medical needs cannot be met by a standard, commercially available brand-name or generic drug manufactured by a drug company. The preparation of such individually tailored drugs requires a prescription from a licensed health care provider.
Prior to the early 1900s, essentially all drugs in the U.S. were compounded for individual patients by pharmacists or physicians. After more than 100 patients were killed in 1937 by an antibiotic solution of sulfanilamide containing the highly toxic solvent diethylene glycol, Congress passed the Food, Drug and Cosmetic Act (FDCA) requiring drug companies to conduct tests to ensure a drug’s safety before it could be used in patients. The FDCA was amended in 1962 to require companies to show that new drugs were both safe and effective. With passage of the FDCA and the subsequent rapid expansion of the commercial drug manufacturing industry, the use of compounded drugs greatly diminished.
Though the Food and Drug Administration (FDA), the agency responsible for enforcing the FDCA, has long considered the compounding of drugs to be subject to FDA regulations, the agency has recognized both the useful health care role of drugs compounded for certain individual patients and the infeasibility of mandating that such traditional compounding activities comply with the same regulations imposed on drug companies. Therefore, it has used “enforcement discretion” to allow these companies to produce drugs without complying with FDA regulations, generally deferring regulatory oversight to state pharmacy boards.
Over the past two decades, many compounding pharmacies have expanded their reach by engaging in large-scale production of drugs, moving from the narrow role traditionally filled by such pharmacies into a realm clearly involving both drug manufacturing and the distribution of standardized formulations of drugs. In many cases, the drugs have been sold in multiple states, thus involving interstate commerce. In the case of NECC, the company held pharmacy licenses in all 50 states and produced and sold across the country thousands of different drugs.
Compounded drugs produced under less stringent safety standards
All drugs marketed in the U.S. are subject to multiple FDA regulatory requirements intended to ensure patient safety, including the following:
- FDA review and approval. Prior to marketing a drug, a drug manufacturer must obtain approval by the FDA of a new drug application. The application must provide evidence supporting the safety, efficacy and quality of the drug.
- Good manufacturing practice (GMP). Once approved, the drug must be manufactured in accordance with GMP regulations. These regulations are intended to ensure the quality andpurity of the final finished product.
- Labeling requirements. Each drug approved by the FDA must include appropriate labeling that describes the drug’s indications (the diseases and conditions for which the drug is approved), known side effects, warning about any potential serious adverse events, contraindications (circumstances in which the drug should not be used because it is too dangerous) and instructions for how to use the drug safely.
These regulatory requirements are intended to prevent exactly the type of public health disaster that is now unfolding as a result of fungal contamination in the injectable steroid medication produced by NECC. Indeed, the FDA has repeatedly asserted over the past two decades that compounding pharmacies that engage in large-scale production and distribution of standardized versions of compounded drugs, such as NECC, are subject to the above regulatory requirements. However, most such companies have disregarded these requirements, placing huge numbers of patients at great risk.
Previous noncompliance of NECC
One of the many disturbing facts about the ongoing fungal meningitis scandal is that NECC had been warned. On Dec. 4, 2006, the FDA cited the company for multiple violations of the FDCA related to the large-scale production of at least four different drugs.
The violations cited in the warning letter were based on a joint inspection of NECC by investigators from the FDA and inspectors from the Massachusetts Board of Registration in Pharmacy that took place over a four-month period between September 2004 and January 2005.
The FDA’s letter explicitly noted that the agency had directed its “enforcement resources against [compounding pharmacies] whose activities raise the kinds of concern normally associated with a drug manufacturer and whose compounding practices result in significant violations of the new drug, adulteration, or misbranding provisions of the FDCA.” The letter proceeded to cite NECC for numerous violations of the FDCA regarding the production of four different drugs, including a high-strength topical anesthetic cream and a drug intended for injection into the eye.
For all four drugs, the FDA found that NECC had violated the FDCA by not obtaining FDA approval. Furthermore, the agency declared these drugs misbranded because their labeling failed to include adequate directions for safe use and, in the case of the topical anesthetic cream, was false and misleading since it did not disclose serious adverse events, including death, that could result from use of the product.
On the same day the FDA sent its 2006 warning letter to NECC, it sent very similar warning letters to four other compounding pharmacies that were violating the requirements of the FDCA by producing and distributing standardized versions of topical anesthetic creams similar to the one produced by NECC. The agency issued a press release, “FDA Warns Five Firms to Stop Compounding Topical Anesthetic Creams,” stating that “firms that do not resolve violations in FDA warning letters risk enforcement such as injunctions against continuing violations and seizure of illegal products.”
Clearly, the FDA was attempting to send a broader warning targeting the entire compounding pharmacy community at large: Compounding pharmacies that behave like drug manufacturers must comply with all regulatory requirements related to the approval and manufacture of drugs or face enforcement action by the agency.
For whatever reason, whether inattentiveness or lack of resources, the FDA dropped the ball following its 2006 warning letter to NECC and failed to prevent the company from engaging in large-scale drug production activities that violated both the FDCA and related FDA regulations. Thus, the company was allowed to continue wide-scale manufacturing and interstate distribution of many injectable medications, including steroids.
The injectable steroid medication produced by NECC was never approved by the FDA and was not manufactured in accordance with the rigorous manufacturing standards designed to ensure that drugs are uncontaminated by bacteria or fungi before being sold and distributed. As a result, as many as 14,000 patients in 23 states were exposed to potentially contaminated steroids and will need to be monitored for several months for signs of fungal meningitis or other infections.
The contaminated steroid injections, along with all other injectable products distributed by NECC, have now been recalled. Hospitals and physicians who administered shots linked to the outbreak have been instructed to contact patients who could have received contaminated injections as early as May 21, 2012. By mid-October, most patients had been contacted.
A decade of alarm bells
While the current infectious disease outbreak linked to a compounding pharmacy may be unique in terms of scope, similar troubling outbreaks have occurred repeatedly for the last 12 years.
As reported in the August 2001 issue of Worst Pills, Best Pills News, another injectable steroid, betamethasone injection, produced and distributed by a compounding pharmacy in California, was linked to illness and death in multiple patients. The betamethasone became contaminated with Serratia bacteria and was sold to at least 60 San Francisco-area physicians, hospitals and clinics. Of the 38 patients known to have received the drug via spinal injections for back pain, 13 were hospitalized and five contracted meningitis, three of whom died.
In 2002, four patients with back pain developed a rare form of fungal meningitis after receiving spinal injections of a steroid contaminated with the fungus Exophiala that was produced by a compounding pharmacy in South Carolina. One patient died as a result of the infection. A fifth patient developed an infection of the sacroiliac joint after receiving an injection of the same tainted steroid.
More recently, in 2011, 19 patients in six hospitals in Alabama developed life-threatening blood stream infections (sepsis) after receiving intravenous nutritional solutions contaminated with the bacteria Serratia marcescens, prepared by a compounding pharmacy in Birmingham, Ala. Nine of these patients died.
And in May 2012, the CDC reported an outbreak of fungal eye infections linked to contaminated eye drugs prepared by a compounding pharmacy in Florida. Thirty-three eye surgery patients across seven states were affected.
These cases represent just a few of the examples of contaminated drugs prepared by compounding pharmacies that have led to serious outbreaks of disease. Thus, the current fungal meningitis outbreak should surprise no one.
Many deserve blame
Numerous investigations into this outbreak are ongoing, and litigation targeting the producer of the tainted drug and health care providers who used it will certainly take years to resolve. Blame for this disaster will undoubtedly rest with many parties: NECC, health care facilities and providers who chose to use a drug lacking both FDA approval and evidence of sterility, trade associations and professional groups representing compounding pharmacies that have vigorously resisted federal regulatory oversight of their members, state and federal regulators, and Congress. As discussed earlier, at the federal level, the FDA bears significant responsibility.
What You Can Do
There are some legitimate medical reasons for using compounded drugs, but they are extremely limited.
Whenever a commercially available, FDA-approved, brand-name or generic version of a drug made by a pharmaceutical company is available for a particular disease or condition, that drug should always be selected over a version of the drug produced by a compounding pharmacy. This is particularly true for drugs intended to be injected, which must be sterile.
It is likely that most, if not all, of the back-pain patients who received injections of NECC’s contaminated steroid drug were unaware that they were receiving a compounded drug that was not approved by the FDA or made in accordance with the high quality standards required for drug companies. If your doctor is going to give you an intravenous or injected medicine, you should inquire whether the drug was made by a pharmaceutical company or a compounding pharmacy. If there is uncertainty about the source of the drug, ask to see the FDA-approved drug label.
If the drug was produced by a compounding pharmacy, you should demand an explanation for why a compounded version of the drug is to be used and whether a generic or brand-name version of the same drug from a pharmaceutical company is available. If such FDA-approved versions exist but are out of stock or in short supply, ask whether the treatment can be delayed until the higher-quality, safer, FDA-approved version becomes available.
You should be very skeptical of physicians or pharmacies promoting compounded drugs. If a physician or pharmacist tells you the only treatment for your condition is a compounded drug and you don’t need emergency treatment, get a second opinion.
This article has been revised to reflect the following correction:
Correction: January 2, 2013
An earlier version of this article stated that 19 patients in Alabama developed sepsis after receiving contaminated intravenous nutritional solutions in 2009. The text has been corrected to indicate that this took place in 2011.