Health Letter, September 2013
In December 2012, Health Letter reported on the widespread outbreak of fungal meningitis that was linked to injections of contaminated steroid medication administered for back pain. The contaminated steroid had been produced by the New England Compounding Center (NECC), a company located in Framingham, Mass., that identified itself as a compounding pharmacy.
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. Many companies, like NECC, have extended their operations well beyond traditional compounding and engaged in illegal drug manufacturing — the large-scale production and distribution of standardized formulations of multiple drugs that were not approved by the Food and Drug Administration (FDA) — under the guise of pharmacy compounding.
In the wake of the preventable public health disaster caused by contaminated drugs produced by NECC, Public Citizen has been highly critical of the FDA for failing to use the agency’s existing legal authority to take aggressive enforcement action against companies like NECC — action that could have averted this disaster. This article provides an update on the scope of the fungal meningitis outbreak, the impact on affected patients and actions taken by the FDA against NECC.
The scope and course of the fungal infection outbreak
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. The infection was caused by a type of mold called Aspergillus fumigatus, which the doctors quickly suspected was linked to a contaminated 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 company identified as a compounding pharmacy.
Within a month of the diagnosis of the initial case, the fungal meningitis outbreak involved 137 cases in 10 states, including 12 deaths. By late September 2012, 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 NECC. The CDC discovered that a total of approximately 17,500 vials from three contaminated lots of this drug had been shipped by NECC to 75 medical facilities in 23 states, where they were used to treat more than 13,400 patients with back or peripheral joint pain.
As of Aug. 5, 2013, 749 patients across 20 states had developed fungal infections after exposure to NECC’s contaminated steroid drugs. Sixty-three of these patients have died, although the CDC noted that death may not have been attributed to fungal infection in all cases. Michigan and Tennessee had the highest number of cases, 264 and 153, respectively. Fortunately, since the early spring, the number of newly diagnosed fungal infections linked to the NECC-produced steroids has dramatically decreased, with only four new cases diagnosed between June 3 and Aug. 5.
As the disease outbreak evolved, it became clear that the types of infections linked to treatment with the contaminated steroids were not limited to meningitis. Other types of fungal infections that have occurred include localized infections (abscesses or pockets of infection) in the spine or soft tissues surrounding the spine (paraspinal tissues) and infections in peripheral joints (for example, the knee or shoulder joint). These more localized infections have occurred right at the sites of injections of the contaminated steroids. Some patients have experienced more than one type of fungal infection, such as meningitis and a spinal or paraspinal infection. The table below shows the number of patients who have experienced each type of infection. Seven patients suffered strokes presumed to have been caused by fungal infections following back injections with a contaminated steroid.
One intriguing observation is that the type of fungus found in the first patient, Aspergillus fumigatus, has not been detected in any subsequent patients during the outbreak. Instead, a different type of mold called Exserohilum rostratum has been the predominant type of fungus causing the infections, detected in 153 patients. This type of mold typically causes disease in plants but rarely in humans. In fact, the CDC reported that fungal meningitis due to Exserohilum had never before been seen. (Exserohilum is a type of black mold commonly found in the environment, on plant debris, in soil and in water.)
Twelve other types of mold have been detected in a small number of cases (ranging from one to eight patients for each type). The fact that so many different types of mold have been isolated from patients with infections linked to the contaminated steroids is indicative of the filthy conditions under which these drugs were produced, as well as the abject failure of NECC to follow the necessary procedures for preparing and testing sterile drugs.
The most successful, safest treatment for these rarely or never-before-seen fungal infections is long and difficult and has evolved since the outbreak began, when the exact type of fungus causing the infections in many patients was unknown. Patients diagnosed early in the outbreak were initially treated with high doses of a combination of two antifungal antibiotics, amphotericin B (given intravenously) and voriconazole (given intravenously or orally), both of which have serious toxic side effects, particularly at high doses. Later in the outbreak, as physicians gained more experience treating these infections, most patients were treated with voriconazole alone. Amphotericin B was reserved for the sickest patients or those who could not tolerate the unpleasant side effects of voriconazole. Common adverse reactions seen with voriconazole include visual hallucinations, vision disturbances, confusion, concentration problems, nausea, liver damage, rash, fatigue and hair loss.
The ideal duration of treatment for these unusual infections has not been established. Three months appears to be sufficient for patients who only have meningitis and at three months of therapy have no evidence of fungal infection on spinal tap tests (tests done on the fluid that surrounds the spinal cord and brain, which is obtained by inserting a needle between two vertebral bones in the lower back). For patients who have localized abscesses in the spine or paraspinal tissues, treatment appears to be needed for six months or longer, and surgery is often needed to remove pockets of infected tissue.
|Type of Fungal Infection||Number of Patients|
|Meningitis + paraspinal/spinal infection||151|
|Paraspinal/spinal infection only||323|
|Peripheral joint infection only||33|
|Paraspinal/spinal infection + peripheral joint infection||2|
|Stroke, without meningitis being diagnosed||7|
The FDA inspection
Between Oct. 1 and Oct. 26, 2012, the FDA conducted an extensive inspection of the NECC facilities and records. Notably, the NECC facility in which the contaminated steroid drugs were made was located adjacent to a garbage and recycling facility. The preliminary findings of the FDA inspection, which were released to the public on Oct. 26, 2012, demonstrated a facility used to make sterile drugs on a large scale that generally had filthy conditions and failed to implement even the most basic standard procedures needed to safely produce such drugs.
Among the specific findings cited in the FDA’s inspection report were the following:
- Approximately 100 vials of the same injectable steroids that caused the fungal infection outbreak contained greenish-black foreign material and a white filamentous material inside, indicative of gross contamination.
- NECC was unable to demonstrate during the inspection that the steam autoclave procedure that was used to sterilize injectable drug products made from nonsterile ingredients was capable of sterilizing those products.
- Multiple problems were identified regarding NECC’s ability to maintain its clean room, an enclosed space designed to maintain a controlled environment with low levels of airborne dust and surface contamination, which could lead to contamination of drugs being produced in this setting.
- NECC’s own environmental monitoring revealed bacteria and mold in multiple locations, including on surfaces in its clean rooms, between January and September 2012. However, the FDA investigators observed that no documented corrective actions were taken to address these findings.
Given the FDA’s inspection findings, the widespread outbreak of fungal meningitis and other infections caused by the NECC steroid drugs in retrospect comes as no surprise.
As we noted in the December 2012 issue of Health Letter, one of the more disturbing aspects of this story is the fact that several years before the outbreak, NECC had been warned by the FDA. On Dec. 4, 2006, the FDA cited the company for multiple violations of federal drug laws and other FDA regulations related to the large-scale production of at least four different drugs. These violations were identified during an FDA inspection of NECC conducted between September 2004 and January 2005. Among the violations was the failure of NECC to obtain FDA approval for new drugs. Had the FDA shown due diligence and conducted a follow-up inspection before, rather than after, the fungal meningitis outbreak began, the problems related to the NECC’s production of sterile drugs likely would have been detected sooner, and the agency could have taken action to help prevent the current tragedy.
For many affected patients and their families, the fungal disease outbreak has caused great suffering and permanently altered, if not ended, their lives.
In the wake of the fungal disease outbreak, numerous lawsuits have been filed against NECC and its owners in federal and state courts around the country. However, because of the number of deaths and injuries and the fact that NECC has filed for bankruptcy and has limited assets, lawyers representing patients injured or killed by the contaminated steroids doubt that they will be able to recover just compensation from NECC, its owners or any liability insurers of the company. Other lawsuits have been brought against clinics and medical centers that bought and administered the contaminated steroid drugs to patients. These lawsuits undoubtedly will take years to be resolved.
In addition to the extensive civil litigation, the FDA’s investigation into NECC is ongoing, and federal criminal charges potentially could be filed against the company and its owners in the future. Some states also may undertake criminal probes into the outbreak. For example, in March, Bill Schuette, the attorney general from Michigan — the state with the most cases of fungal infections tied to the outbreak — called for a criminal investigation by a state grand jury into the conduct of NECC related to the production and distribution of the contaminated drugs. In discussing the outbreak, Schuette said that “hundreds of Michigan citizens and their families have endured terrible pain and deaths of loved ones suffering from illnesses caused by these tainted steroid injections. This investigation is necessary to uncover the truth as to how this unspeakable tragedy happened and to restore public faith in our healthcare system.”
In the aftermath of the outbreak, Public Citizen urged the FDA to conduct inspections and to take aggressive enforcement action against other companies that, like NECC, appear to be engaged in illegal drug manufacturing under the guise of pharmacy compounding. The FDA began to take such action, inspecting more than 50 drug compounding facilities between December 2012 and June 2013. In nearly all cases, the FDA’s reports of these inspections revealed significant problems related to the production of sterile drugs.
The U.S. Congress also has been debating several legislative proposals purportedly intended to prevent another similar disaster from occurring. Public Citizen has strongly opposed many of these proposals because they would weaken U.S. drug safety by exempting companies like NECC from the critically important legal requirements intended to ensure the safety and quality of all manufactured drugs that have been in place for more than half a century.
In future issues of Health Letter, we will discuss the implications and outcomes of these ongoing regulatory and legislative responses to the NECC-caused tragedy.