New England Compounding Center meningitis outbreak
Fungus (stained black) in infected brain tissue
|Date||September 21, 2012(on-going)|
|Location||United States (23 States)|
|Cause||Fungal contamination of steroid medication|
|Litigation||400+ lawsuits filed against NECC|
In October 2012, an outbreak of fungal meningitis was reported in the United States. The U.S. Centers for Disease Control and Prevention (CDC) traced the outbreak to fungal contamination in three lots of medication used for epidural steroid injections. The medication was packaged and marketed by the New England Compounding Center (NECC), a compounding pharmacy in Framingham, Massachusetts. Doses from these three lots had been distributed to 75 medical facilities in 23 states, and doses had been administered to approximately 14,000 patients after May 21 and before September 24, 2012. Patients began reporting symptoms in late August, but, because of the unusual nature of the infection, clinicians did not begin to realize that the cases had a common cause until late September. Infections other than meningitis were also associated with this outbreak, which spanned 19 states. As of March 10, 2013, 48 people had died and 720 were being treated for persistent fungal infections. In November 2012, it was reported that some patients recovering from meningitis were experiencing secondary infections at the injection site. Although no cases of infection were reported to be associated with any other lots of medication, all lots of all medications distributed by NECC were recalled in separate actions by NECC and regulators. Subsequent analysis identified some contamination in other lots.
On October 9, 2012, members of the United States Congress asked federal health officials for briefings on the outbreak as a first step toward possible legislative action to strengthen federal drug safety regulations. On November 14, 2012, members of a congressional committee investigating the outbreak accused the Food and Drug Administration (FDA) of failing to prevent the crisis by moving too slowly against the Massachusetts pharmacy. In the same hearing, the co-owner of NECC chose to plead the Fifth, refusing to answer all questions. By mid-December over 400 lawsuits had been filed against NECC.
In October 2012, Massachusetts shut down two more compounding pharmacies over sterility concerns after they conducted a surprise inspection. In December, unexpected inspections of three more Massachusetts pharmacies found problems as well.
- 1 Source of infectious agents
- 2 Infectious agents
- 3 Clinical features
- 4 Treatment
- 5 Cases
- 6 Compounding pharmacies
- 7 Prescribing of steroids for back and joint pain
- 8 Investigation
- 9 Long-term consequences
- 10 References
- 11 External links
Source of infectious agents
The U.S. Centers for Disease Control and Prevention (CDC) traced the outbreak to contaminated medication used for epidural steroid injections. The U.S. Food and Drug Administration (FDA) examined foreign materials from unopened vials under microscope and found fungal matter. The fungus was found in the cerebrospinal fluid of several patients, which confirmed that the fungus caused the meningitis. The medication was packaged and marketed by the New England Compounding Center (NECC) of Framingham, Massachusetts.
According to the CDC, between May 21 and September 24, 2012, patients in 23 U.S. states received injections from three implicated lots of a steroid, preservative-free methylprednisolone acetate, for back pain, and some of these patients developed symptoms consistent with fungal meningitis. This form of meningitis can be caused by epidurally administered medications but is not contagious by person-to-person contact. On October 9, authorities estimated as many as 14,000 patients may have been exposed to the contaminated drug, but are not necessarily infected.
The NECC said that immediately after it was notified about the infections, it initiated a voluntary recall September 26. Next, on October 4 the Massachusetts Department of Public Health issued a recall of all NECC medications, advising hospitals and clinics to remove and segregate all lots from their stock inventory. NECC also announced on that day they were suspending all of their operations and voluntarily surrendered their licenses to the Massachusetts Department of Health and Human Services, while continuing to cooperate with the ongoing investigations by the CDC and the FDA.
On October 15, the FDA issued a warning that two more drugs may have been contaminated. Both come from NECC. One is a steroid called triamcinolone acetonide and another is a product used during heart surgery. If injected epidurally, this second steroid may cause fungal mengitis, while the heart drug may cause a different fungal infection.
Although no cases of infection are reported to be associated with any other lots of medication, all lots of all medications distributed by NECC were recalled in separtate actions by NECC and regulators. Subsequent analysis identified some contamination in other lots.
As of November 15, the CDC reported that 85 patients had laboratory-confirmed fungal infections. A black mold called Exserohilum rostratum was found in 84 of these cases and Aspergillus fumigatus was found in one case. Other fungi were found in 8 cases, but are not known to be significant. According to specialists in fungal diseases, cases of meningitis caused by aspergillus are rare, but cases caused by black mold are even more so, making the discovery of the outbreak and the recommended treatment almost entirely untrodden medical ground.
Aspergillus is a common mold that humans and animals are continually breathing but that rarely causes problems. However, in patients with suppressed immune systems, or if introduced directly into the spinal column, the fungus can be deadly. Despite the availability of antifungal agents, aspergillosis in the central nervous system carries a poor prognosis. Though this case sparked the nationwide investigation, as of November 4, the CDC said Aspergillus fumigatus had been identified in only one patient. Almost all cases in the current outbreak involve a different fungus, Exserohilum rostratum, another common mold that rarely causes problems.
On October 12 the Centers for Disease Control and Prevention (CDC) reported that as of that date the median age of the patients was 68 years (range: 23–91 years); 48 (69%) were female. At presentation, 57 (81%) had headache, 24 (34%) had fever, 21 (30%) had nausea, and seven (10%) had photophobia (intolerance to bright light). Atypical neurologic symptoms were observed in a minority of patients; subtle gait disturbances were seen in three (4%), and a history of falls was described in eight (11%). Meningeal signs, including nuchal rigidity (the inability to flex the neck forward), Kernig's sign, or Brudzinski's sign, were uncommon, occurring in 10 (14%) patients. Stroke, either as a presenting sign, or as a complication of infection, occurred in 12 (17%).
Fungal infections associated with non-epidural injections were also reported. They were related to injections in a peripheral joint space, such as a knee, shoulder or ankle. People injected in peripheral joints were at risk for joint infections but were not believed to be at risk for meningitis.
On November 4, it was reported that some people that had been treated for meningitis and released returned to the hospital with abscesses at the injection site. Abscesses are different from meningitis which affects the brain and spinal cord but are a localized infection which affects the tissues. However, if left untreated they may lead to meningitis. The deputy chief of the mycotic diseases branch of the Centers for Disease Control and Prevention said, "We don't have a good handle on how many people are coming back. We are just learning about this and trying to assess how best to manage these patients. They're very complicated." The chief medical officer of St. Joseph Mercy Hospital in Ann Arbor, Michigan, one of the states hardest hit by the outbreak, said, "This is a significant shift in the presentation of this fungal infection, and quite concerning. An epidural abscess is very serious. It's not something we expected."  As of December 7, spinal abscesses had been reported in 23 patients who received injections in Tennessee, and 37 patients in Michigan.
The CDC reported that doctors were also reporting that some people that had been injected with the contaminated drugs had arachnoiditis, a nerve inflammation that can cause intense pain, bladder problems and numbness.
For the 61 people with symptom onset date available, the earliest date was August 18. For the 48 patients with both injection date and symptom onset date available for analysis, the median time from last steroid injection to onset of symptoms was 15 days (range: 1–42). A total of 25 of the 48 patients received a single steroid injection; the median time from injection to onset of symptoms for those patients was 16 days (range: 4–42). People that received injections were most vulnerable to stroke and infection within the first 42 days of injection, but it can take up to three months for symptoms to appear.
Once the infection and its source were identified, due to the rarity of fungal meningitis few clinicians were accustomed to dealing with it. The CDC convened an expert advisory panel to develop recommended treatment guidelines. Many affected patients were elderly and had other existing health problems, further making the choice of treatment difficult. On October 23, 2012, the CDC issued an Official Health Advisory Issuance of Guidance on Management of Asymptomatic Patients Who Received Epidural or Paraspinal Injections with Contaminated Steroid Products. The CDC recommended that health care providers monitor patients who received contaminated injections but advised against prophylactic treatment with antifungal drugs for patients who did not show signs of infection. They indicated that the greatest risk of developing an infection was within the first six weeks after injection. People diagnosed with meningitis could expect to take antifungal drugs for a minimum of three months, and possibly as long as a year.
The Centers for Disease Control and Prevention (CDC) reported that as of January 14, 2013, 678 people in nineteen states had contracted a fungal disease, of which 44 people died. As of March 10, 2013, 48 people had died and 720 were being treated for persistent fungal infections. The product was also sent to four states where no cases had been reported, and no complaints or cases have been found in Massachusetts, the only State where NECC has a license. Tennessee was the first state to have a reported case on September 21. These cases are associated with three lots of methylprednisolone acetate, portions of which were shipped by NECC to 73 health care facilities in 23 states.
|State [note 1]||Total
notes for table
- Case counts by state are based on the state where the procedure was performed, not the state of residence.
- Some deaths of infected patients may not be directly attributable to the infection.
- facilities in Nevada received shipments, but no doses were administered and all were returned to NECC
The NECC is classified as a compounding pharmacy. Such pharmacies are authorized to combine, mix or alter ingredients to create specific formulations of drugs to meet the specific needs of individual patients, and only in response to individual prescriptions. Since 1938, the U.S. Food and Drug Administration has had sole authority to regulate drug manufacturing, which is subject to strict FDA regulations, but oversight of compounding is shared by state and federal agencies. Compounding pharmacies must register with the FDA, but are not registered as drug manufacturers, and the agency does not approve their prescriptions before marketing, nor automatically receive adverse events reports. State law generally controls record keeping, certifications, and licensing for compounding pharmacies. In 2003, an official from the Food and Drug Administration told the Senate Health, Education, Labor and Pensions Committee that in 2001 the agency had done a "limited" survey of drugs from 12 compounding pharmacies, including hormones, antibiotics, steroids and drugs to treat glaucoma, asthma and erectile dysfunction, and ten of the 29 drugs failed one or more quality tests. However, grassroots mobilization of compounding pharmacists and actions of congressional lobbyists prevented an attempt to establish an FDA oversight committee on pharmacy compounding.
Responding to the recent NECC meningitis outbreak, health officials and lawmakers have said that compounding pharmacies can "fall into a regulatory black hole." Sen. Richard Blumenthal (D-CT), who is on the committee that oversees the FDA, said that compounding pharmacies have "relative immunity from standards of safety and effectiveness." The state, not the FDA, had oversight over NECC, though shipping out of state and manufacturing large batches of pharmaceuticals would have made them a manufacturer, and under FDA control. The compounding pharmacy industry has created safety standards, and in 2004, United States Pharmacopeia, an industry-backed nonprofit, established guidelines, but the industry is required to follow the guidelines in only 17 states. Few compounding pharmacies follow standards for manufacturers, because of the cost. Legislation in 1997 would have given the FDA authority to regulate all compounding pharmacies, but that legislation was partially overturned by a 2002 Supreme Court decision.
A recent editorial in The New England Journal of Medicine (NEJM) suggested that while NECC appeared to be in clear violation of existing FDA policy it is possible that the 2002 Supreme Court decision may have weakened federal-state cooperation. The NEJM notes:
- First, traditional compounding was limited to a pharmacist or a physician serving a specific patient. Section 503A also permitted compounding of drugs "in limited quantities before the receipt of a valid prescription order . . . based on a history of . . . receiving valid prescription orders." According to the preliminary report from the Commonwealth of Massachusetts, NECC far exceeded these limits in preparing and shipping vials of methylprednisolone acetate. Once disconnected from individual patients, compounding increasingly resembles drug manufacturing.
- Second, compounding is not needed if a drug is commercially available from an FDA-regulated facility. Section 503A prohibited compounding "regularly or in inordinate amounts" any drugs that were "essentially copies of a commercially available drug product." FDA-approved methylprednisolone acetate is sold by Pfizer and two generics companies, but since NECC's version did not contain preservatives, it could sidestep this regulatory process — with tragic results.
- Third, Congress recognized that states could effectively regulate traditional compounding pharmacies, but national-scale businesses required federal coordination. Section 503A provided a test for distinguishing between the two: it limited interstate shipments to no more than 5% of the compounder's business, unless the home state had entered into a "memorandum of understanding" with the FDA, bolstering state and federal cooperation. NECC shipped substantial quantities of drugs to many states. If Section 503A had not been struck down, both the FDA and Massachusetts would have been more directly involved in regulating NECC for more than a decade.
Prescribing of steroids for back and joint pain
Some doctors believe that the use of steroid injections for back and joint pain has not been demonstrated by scientific evidence, and challenge their use in these cases at all. According to The New England Journal of Medicine, "... it's important to note that many patients received these sterile injections for back and joint pain, a procedure that lacks high-quality evidence of efficacy. These problems cannot be laid entirely at the feet of compounders when clinicians persist in clinical practices despite weak evidence of efficacy." Doctors in professional societies are not in agreement about treatment guidelines. The use of steroid injections to treat back pain increased 121 percent from 1997 to 2006, the number of pain clinics and pain specialists has increased, and spinal injections can cost $600 to $2,500. Although steroid injections for back pain clearly works in some cases, health researchers are "nearly unanimous" that it is "vastly overused."
A 2009 Cochrane review of injection therapy for subacute and chronic low back pain indicated that there is no strong evidence for or against the use of any type of injection therapy. A four-year study released in 2013 suggested that epidural steroid injections may actually lead to worse outcomes whether or not the patient later underwent surgery, and there was no evidence that receiving steroid injections helped patients to avoid surgery. Also, in patients who had previously been treated with epidural steroids, there was evidence that surgery was more complicated than in patients who had not.
In October 2012, an investigation of the New England Compounding Center revealed that the company had been in violation of its state license because it had been functioning as a drug manufacturer, producing drugs for broad use, rather than filling individual prescriptions as prescribed by individual doctors within the state. It was suggested that some doctors and clinics have turned away from major drug manufacturers and turned to compounding pharmacies as manufacturers because they often charge much lower prices than the major manufacturers. Reuters news service reviewed over a dozen emails to the NECC and found that they solicited bulk orders from physicians and failed to require proof of individual patient prescriptions as required under state regulations. In October, Massachusetts officials launched a criminal investigation of the NECC and the Massachusetts Board of Registration in Pharmacy voted to permanently revoke their license to operate in Massachusetts as well as the licenses of the company's three principal pharmacists to fill prescriptions in Massachusetts.
The preliminary investigation found unsanitary conditions, including fungus in steroid solutions. Massachusetts officials said that the NECC had shipped orders of the contaminated drug without waiting for final results of sterility testing. Records suggested that NECC had failed to sterilize products for "even the minimum amount of time necessary to ensure sterility." Mats used to trap dust and dirt outside the rooms were dirty, sterile hoods were not properly cleaned, and a boiler was leaking next to a clean room, according to officials.
U.S. and Massachusetts state health regulators were aware in 2002 that steroid treatments from NECC could cause adverse patient reactions. NECC had started to receive complaints in 1999, less than a year after it had been established. Many violations involved filling bulk medication orders without individual prescriptions. In 2004, state health officials charged the pharmacy with failure to comply with accepted standards when mixing methylprednisolone acetate, the same steroid that was the source of the 2012 meningitis outbreak. In 2006, the pharmacy agreed to inspections and improvement measures and an outside investigator was brought in to ensure compliance.
Problems at other compounding pharmacies
The FDA reports several previous incidents related to tainted drugs packaged at compounding pharmacies. Fungal contamination in relation to sterile drug recalls represents the second most common form of microbiological contamination. In August 2011, the FDA reported that repackaged injections of Avastin (bevacizumab) caused serious eye infections in the Miami, Florida area. A pharmacy had repackaged the Avastin from single-use vials into multiple single-use syringes, distributing them to multiple eye clinics, and infecting at least 12 patients. Some patients lost the remaining vision in the eye being treated.
From November 2011 to April 2012, 33 eye-surgery patients in seven states suffered a rare fungal eye infection tied to injectable drug products made by a compounding pharmacy in Ocala, Florida. Most of those patients suffered partial to severe vision loss.
In October 2012, Massachusetts shut down another compounding pharmacy over sterility concerns after they conducted a surprise inspection. Inspectors went to the Waltham, Massachusetts location of the Rhode Island-based Infusion Resource company and found, "significant issues with the environment in which drugs were being mixed". The manager of the company was a former employee at Ameridose, which is owned by the same people who ran New England Compounding Center.
On November 13, it was reported that manufacturing problems were found at Ameridose, a Massachusetts company that makes injectable drugs. Ameridose and NECC were founded by brothers-in-law Barry Cadden and Greg Conigliaro. According to an FDA spokesperson, an inspection revealed that the firm "fails to test finished product for potency, failed to investigate complaints for ineffective products, failed to investigate violations of their own environmental sampling plan and fails to adequately maintain equipment and facilities used to manufacture sterile drug products". The FDA report also revealed that the company had received 33 complaints claiming "lack of effect" and "ineffectiveness" about its drugs. The same problem was found at the plant in 2008, and the FDA spokesperson said that the FDA is checking to find what, if any, action was taken in 2008. According to the report, when doctors contacted the firm to say that there had been problems with its drugs, the complaints were not classified as adverse events. That included "incidents when women given Ameridose's oxytocin, a drug used to bring on labor, reported fetal distress, severe post-birth post birth bleeding and shortness of breath. A blood thinner, heparin, had a complaint that the patient had a life-threatening adverse event [and when] the firm's pain medication fentanyl, given to cancer patients and as an anesthetic, was used, two patients were reported to have gone into respiratory distress."
The New York Times interviewed eight former employees of NECC and Ameridose. Some defended the company, but six said that a corporate culture encouraged shortcuts, even when it compromised safety. At Ameridose, a pharmacist complained to management that quality control workers, who were not trained pharmacists, did work they shouldn't have done. She said there were "near misses" of wrong doses that were caught before they were shipped. A quality control technician tried to stop an assembly line and was eventually fired. An industry newsletter said that Ameridose was shipping drugs without waiting the 14 days it took for the sterility test results to come back. Compounding pharmacies are only allowed to ship drugs for specific patients; a former NECC salesman said that NECC sold large quantities without the patients' names, and would put the names in the file as the drug was used, a practice that was accepted by some hospitals but not others.
On December 7, Massachusetts regulators had taken action against three more compounding pharmacies following unannounced inspections. The Whittier Pharmacist, in Haverhill, was ordered to cease sterile compounding after unspecified violations were found and OncoMed Pharmaceutical Services was ordered to close its Waltham facility after problems with the storage of chemotherapy drugs were found. Pallimed Solutions, based in Woburn, was told to halt production of sildenafil citrate, which is sold as Viagra, after inspectors found that it had been prepared with improper components.
Two compounding pharmacies issued drug recalls in March 2013. Med Prep Consulting Inc. and Clinical Specialties Compounding Pharmacy both issued recalls after Med Prep found particles floating in five doses of a compounded solution, and Clinical Specialties heard about five eye infections in patients who'd received compounded eye injections.
House Energy and Commerce Committee hearings
On November 12, the Oversight and Investigations Subcommittee of the House Energy and Commerce Committee released a detailed report of NECC's regulatory history. The congressional report shows that in 2003 the FDA considered the company a pharmacy, significant because following the meningitis outbreak public health officials have charged that NECC was operating more as a manufacturer than a pharmacy. Manufacturers are regulated by the FDA and are subject to stricter quality standards than pharmacies. The report also shows that after investigations in 2003 the FDA officials asked that the compounding pharmacy be "prohibited from manufacturing" until it improved its operations, but Massachusetts regulators ultimately reached an agreement with the pharmacy to settle concerns about the quality of its prescription drugs.
According to documents summarized by the committee, within less than a year of the pharmacy's opening in 1998 they were cited by the state pharmacy board for providing doctors with blank prescription pads with NECC's information, which are illegal in Massachusetts—the pharmacy's owner and director, Barry Cadden, received an informal reprimand. Cadden continued to receive other complaints involving unprofessional conduct in coming years and in several instances Cadden refused to cooperate with investigators and challenged the agency's authority over his business. In 2002 the FDA investigated reports that five patients had become dizzy and short of breath after receiving a steroid used to treat joint pain and arthritis that's different from the one linked to the current meningitis outbreak. Initially Cadden cooperated with the investigation, but during a second day of inspections, Cadden told officials that he was no longer willing to provide any additional records, and the FDA did not pursue the investigation. Also in 2002, the FDA received reports that two patients at a Rochester, N.Y., hospital came down with symptoms of bacterial meningitis after receiving injections of methylprednisolone acetate, the same injectable linked to the current outbreak. When officials from the FDA and Massachusetts Board of Pharmacy questioned Cadden, he said vials of the steroid returned by the hospital had tested negative for bacterial contamination. But when FDA scientists tested samples of the drug collected in New York they found bacterial contamination in four out of 14 vials sampled.
Speaking to the committee in a statement, the interim commissioner of the Massachusetts Department of Public Health said, "It is clear that NECC knowingly disregarded sterility tests, prepared medicine in unsanitary conditions, and violated their pharmacy license. Poor judgment, missed opportunities, and a lack of appropriate oversight allowed NECC to continue on this troubling path." He announced that "the board staff who are responsible" had been either fired or replaced.
On November 14, the committee questioned the FDA Commissioner Margaret Hamburg, asking her why regulators at the FDA and the Massachusetts board of pharmacy did not take action against the pharmacy years earlier. Hamburg replied that the agency was obligated to defer to Massachusetts authorities, who have more direct oversight over pharmacies and stated, "In light of growing evidence of threats to the public health, the administration urges Congress to strengthen standards for non-traditional compounding." Joyce Lovelace, the widow of 78-year-old Eddie C. Lovelace, who was the first confirmed victim of the outbreak, also spoke at the hearing. Following Lovelace, the committee attempted to question Barry Cadden, the owner and director of the NECC, however Cadden refused to testify, invoking his Fifth Amendment right to not answer questions in order to avoid self-incrimination.
During the second day of hearings, senators said that regulators had not only failed to move aggressively against NECC, but a sister company. Ameridose LLC, a large-scale drug compounder that supplies drugs to thousands of hospitals nationwide, as well. Although the FDA had repeatedly found reports of adverse events, faulty products, and medication errors in the last decade, no warning letter had ever been issued. It was revealed that in 2002, five patients became ill and two more were hospitalized with meningitis-like symptoms after they were injected with the same steroid implicated in the current outbreak, and yet the state took no action until 2006. Although the FDA has limited authority over compounders such as New England Compounding, Ameridose is licensed by the FDA as a manufacturer and is clearly subject to its regulatory powers.
Alleged victims of the fungal meningitis outbreak linked to NECC's epidural steroid injections may be entitled to compensation for medical expenses, lost wages, pain and suffering, and more. In October, plaintiffs in federally-filed fungal meningitis lawsuits petitioned the U.S. Judicial Panel for Multidistrict Litigation (JPML) for establishment of a consolidated litigation in Minnesota federal court. NECC has requested that the litigation be transferred to federal court in Massachusetts. In December, U.S. District Judge Dennis Saylor ruled that meningitis lawsuits pending in Massachusetts federal court would be consolidated and allowed to move forward. By mid-December over 400 lawsuits had been filed against NECC.
U.S. Representative Fred Upton introduced the Drug Quality and Security Act (H.R. 3204; 113th Congress) in response to this meningitis outbreak. Rep. Upton's district had 3 deaths and there were 19 total in Michigan. The bill passed the United States House of Representatives on September 28, 2013 by a voice vote. The United States Senate began working on the bill November 12, 2013. The bill that would modify the Federal Food, Drug, and Cosmetic Act to grant the Food and Drug Administration more authority to regulate and monitor the manufacturing of compounding drugs.
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