The U.S. House Committee on Energy and Commerce held a hearing on Nov. 14 to discuss whether the fungal meningitis outbreak could have been prevented. The hearing examined the facts surrounding the recent outbreak of fungal meningitis and other infections linked to contaminated injectable products made and distributed by the New England Compounding Center (NECC) in Framingham, Mass. This hearing also examined the history of complaints associated with NECC and its affiliated entities as well as related inspections and actions taken by the U.S. Food and Drug Administration (FDA) and the Massachusetts Department of Public Health (MDPH).
The hearing explored the following issues:
- State and federal inspectors documented a number of deficiencies and violations at NECC since as early as 2002, many of which are similar to those at issue in the ongoing meningitis investigation. Were the FDA’s and the Massachusetts Board of Pharmacy’s enforcement actions appropriate?
- Why didn’t FDA pursue any enforcement actions against the NECC despite having emphasized in 2003 the potential for serious public health consequences if the company’s compounding practices, in particular those relating to sterile products, were not improved?
- Prior to this outbreak, the Massachusetts Board of Pharmacy had investigated at least 12 separate complaints relating to NECC and its management. While many of these complaints covered NECC’s sales and marketing tactics, several were associated with serious adverse events and uncovered deficiencies with NECC’s compounding operations. How was NECC able to maintain its pharmacy license despite repeated violations?
- What did state and federal authorities do to confirm that sufficient corrective measures were taken after these inspections? How did they communicate with each other to ensure such responses were adequate to protect the public health?
In a Nov. 12 memorandum to members of the Subcommittee on Oversight and Investigations, the Subcommittee on Oversight and Investigations staff outlined a history of the fungal meningitis outbreak:
As of Nov. 9, 2012, the Centers for Disease Control and Prevention (CDC) has confirmed that 32 people have died and 438 people have been sickened across 19 states after receiving contaminated injectable products made and distributed by NECC. The first case of meningitis connected to this outbreak was confirmed on Sept. 18, 2012, in Tennessee. On Sept. 21, 2012, CDC was notified by the Tennessee Department of Health (TDH) of a patient with the onset of meningitis approximately 19 days after receiving an epidural steroid injection at an ambulatory surgical center in Nashville. By Sept. 24, 2012, TDH officials contacted MDPH informing them that it was investigating an outbreak of fungalmeningitis in six patients at the same Nashville facility, with onsets between July 30 and Sept. 18, 2012. All six patients had received the same injectable steroid, preservative-free methylprednisolone acetate (80 mg/ml), compounded and distributed by NECC.
On Sept. 25, 2012, CDC informed FDA of the situation and that three lots of methylprednisolone acetate were suspected. Methylprednisolone acetate is a type of injectable steroid suspension often used to treat pain and swelling. MDPH convened a multi-agency teleconference with CDC, FDA, and Tennessee officials. Barry Cadden and Gregory Conigliaro, principal owners of NECC, joined the call as well. Cadden and Conigliaro immediately provided documentation of all facilities that had received shipments from the three suspect lots of methylprednisolone acetate. On Sept. 26, 2012, NECC instituted avoluntary recall of the suspect lots. In total, 17,676 doses had been shipped to customers in 23 states. More than 14,000 patients had already received a potentially contaminated injection. Based on surveillance efforts, CDC soon identified a patient in North Carolina displaying symptoms of meningitis after receiving an injection from one of the suspect lots.
From Sept. 26, 2012, through Oct. 5, 2012, investigators from FDA’s New England District Office (FDA NWE-DO) and MDPH inspected the NECC facility. During their inspection, state and federal investigators observed visible black particulate matter in sealed vials of purportedly sterile methylprednisolone acetate that had been returned to NECC. MDPH noted that NECC’s records showed inconsistencies in sterilization processes. The Massachusetts Board of Pharmacy voted to obtain a voluntary surrender of NECC’s license, which NECC Majority Memorandum for the Nov. 14, 2012, Oversight and Investigations Subcommittee Hearing agreed to on Oct. 3. NECC also agreed to a voluntary recall of all products intended for injection into the area around the spinal cord or brain. On Oct. 4, FDA and MDPH confirmed that fungal contamination had been identified in a vial from one of the suspect lots. FDA and CDC recommended that all healthcare professionals cease use and remove any material produced by NECC from their facilities.
On Oct. 6, NECC announced a voluntary recall of all NECC products currently in circulation. On Oct. 8, Cadden and Glenn Chin voluntarily ceased practice as pharmacists pending completion of the investigation.3 In addition to the evidence of contamination, investigators also found evidence that the NECC had not been compounding drugs for patient-specific prescriptions. Instead, the NECC accepted patient lists generated by a clinical facility and provided to NECC for the purpose of obtaining its products. On Oct. 16, agents from FDA’s Office of Criminal Investigations, along with local authorities, raided the NECC Framingham, Mass. facility.
The MDPH and FDA also inspected two other companies owned by Barry Cadden, Ameridose, LLC (Ameridose) and Alaunus Pharmaceutical, LLC (Alaunus) on Oct. 10, 2012, and Oct. 14, 2012, respectively. NECC, Ameridose, and Alaunus share common ownership and corporate structures. Cadden is a co-owner of Ameridose, a pharmacy and wholesaler based in Westborough, Mass., and Alaunus, a wholesaler located next to NECC in Framingham. Cadden, his wife, Lisa Conigliaro-Cadden, her brother, Gregory Conigliaro, and his wife, Carla Conigliaro, serve as directors of all three companies.
Based on their shared ownership, MDPH requested that Ameridose and Alaunus cease all pharmacy operations and the manufacturing and distribution of any products. According to MDPH, Cadden agreed to immediately resign as manager, director and from any other management position at NECC, Ameridose and Alaunus.
The FDA’s investigation of the fungal meningitis outbreak has expanded beyond NECC’s methylprednisolone acetate product. For example, FDA confirmed the report of a patient with meningitis-like symptoms potentially caused by epidural injection of a different NECC product, triamcinolone acetonide. In addition, one transplant patient developed a fungal infection after having been administered NECC-produced cardioplegic solution during surgery. Based on these reports, FDA announced that the sterility of any injectable drugs, including ophthalmic drugs that are injectable or used in conjunction with eye surgery, and cardioplegic solutions produced by NECC are of significant concern. FDA recommended that patients who received these products on or after May 21, 2012, be alerted to the potential risk of infection. FDA subsequently released definitive laboratory confirmation of the presence of fungal contaminants in sealed vials of methylprednisolone acetate in two of the three suspected lots from NECC. As of Nov. 3, 2012, testing of the third lot, as well as other NECC products, was ongoing.
On Oct. 22, 2012, MBP authorized MDPH staff to request voluntary permanent surrender of the licenses of Barry Cadden, Glenn Chin, and Lisa Conigliaro-Cadden, as well as NECC. According to MDPH, in response to an inquiry from Committee staff on Nov. 4, this process is ongoing.
FDA reported on Oct. 31, 2012, that Ameridose was voluntarily recalling all of its unexpired products in circulation. While the investigation remained open at the time of the announcement, FDA stated that its preliminary findings raised sterility concerns. The agency further clarified that the recall was not based on reports of patients with infections associated with any Ameridose product.
On Nov. 1, 2012, FDA and CDC released laboratory results that confirmed contaminants in two other NECC products: preservative-free betamethasone repository injection and cardioplegia solution. Bacteria were present in three separate lots of betamethasone and in a single lot of cardioplegia solution. CDC continues to investigate reports of potential infections in patients receiving NECC products. As of Nov. 1, CDC had not received reports of laboratory-confirmed cases of infection due to bacteria present in betamethasone or cardioplegia solution from NECC.
On Oct. 23, 2012, MDPH issued a Board of Registration in Pharmacy Report setting forth its preliminary findings relating to the ongoing investigation into the outbreak. In addition, on Oct. 26, 2012, FDA released its inspectional observations as well as a corresponding Form FDA 483 (483) to NECC. As previously discussed, investigators from FDA NWE-DO and MDPH first visited the NECC facility in connection with this outbreak on Sept. 26, 2012. According to MDPH, upon arriving at NECC, investigators found NECC employees cleaning sterile compounding areas. They also detected signs of bleach decontamination. Despite NECC’s apparent attempt to present the facility as compliant, State investigators still identified “serious deficiencies and significant violations of pharmacy law and regulations that clearly placed the public’s health and safety at risk.”
During the facility inspections, MDPH documented numerous deficiencies and violations. MDPH noted that this report constitutes early findings that may be subject to revision as the investigation unfolds. FDA issues a Form 483 at the end of an inspection when the investigators believe that the observed conditions or practices, in their judgment, may indicate violations of the Food, Drug, and Cosmetic Act or any related regulations. FDA has stated that its goal in issuing a 483 is to have the company act quickly to correct potential violations. The FDA considers the 483 along with an Establishment Inspection Report (EIR), prepared by FDA investigators, and any other information, including any responses received from the company. The agency then considers whether further action is appropriate.
It was discovered that:
- NECC distributed large batches of compounded sterile products directly to facilities for apparent general use rather than requiring a prescription for an individual patient.
- NECC distributed two of the recalled lots of methylprednisolone acetate prior to receiving results of sterility testing.
- Final sterilization of product did not follow proper standards pursuant to United States Pharmacopeia Standard 797 (USP 797) and NECC’s own Standard Operating Procedures.
- NECC failed to test its autoclaves to ensure proper function.
- Visible black particulate matter was seen in several recalled sealed vials of methylprednisolone acetate.
- “Tacky” mats located outside the clean room were visibly soiled with assorted debris, violating USP 797.
- A leaking boiler adjacent to the clean room had created a pool of water, an environment susceptible to contaminant growth.
FDA investigators documented similar observations in the 483, as well as additional problems with NECC’s ability to maintain its clean room and ensure the sterility of its products, as further supported by sample testing results. FDA’s observations included the following:
- Eighty-three vials out of a bin containing 321 vials of methylprednisolone acetate from one of the suspect lots contained what appeared to be greenish black foreign matter. Seventeen vials from the same bin were observed to contain what appeared to be white filamentous material. Fifty of these vials were sent to an FDA laboratory for testing and all 50 tested positive for microbial contamination.
- NECC provided no documentation or evidence to support that the autoclave used to sterilize suspensions formulated using non-sterile active pharmaceutical ingredients and raw materials was effective.
- NECC is abutted to the rear by a recycling facility producing airborne particulates. NECC rooftop HVAC units were estimated to be located approximately 100 feet from the recycling facility.
- NECC’s air conditioning was turned off at night, including in the clean rooms, despite the importance of maintaining a consistent temperature and level of humidity.
- NECC’s own environmental monitoring program yielded violative levels of bacteria and mold in clean rooms used for the production of sterile drug products, between January 2012 and September 2012. Despite the company’s action limits having been exceeded, there was no investigation conducted by the company, no identification of the isolates, no product impact assessments conducted, and no documented corrective actions taken to remove the microbial contamination from the facility.
Further, according to Steven Lynn, director of FDA’s Office of Manufacturing and Product Quality, on an Oct. 26, 2012 media call describing FDA’s observations and test results, there was overgrowth of bacteria or fungi in at least one sample testing dish. When asked to clarify what he meant, Lynn stated, “Think of a plant just growing out of control.”
While investigating the meningitis outbreak over the last six weeks, FDA and MDPH investigators have observed many serious deficiencies and significant violations of law and good compounding practices. These violations, however, were not a first for NECC. Documents produced to the Committee by the FDA and the Massachusetts Board show that NECC has a long history of very similar, if not identical, underlying misconduct. Some of the violations observed by regulators as early as 2002 include the company’s failure to maintain adequate safeguards for sterile injectable products – the very issue at the center of the current meningitis outbreak. In fact, since the company’s formation, FDA conducted three prior series of inspections of NECC, each based on a separate set of allegations or events, issuing two Form 483s in 2002 and 2003 and one Warning Letter in 2006. The Massachusetts Board of Pharmacy has an even more extensive history with NECC. Prior to this outbreak, the Board had investigated at least 12 separate complaints concerning NECC or Cadden, issued at least four advisory letters and/or informal reprimands, and entered into a consent agreement with the company in 2006.
To read further from the Majority Memorandum for the Nov. 14, 2012, Oversight and Investigations Subcommittee Hearing, CLICK HERE.
To watch the testimony and access other documents, CLICK HERE.