Grey Areas and Red Flags in the NECC Outbreak
“Patients deserve to be safe wherever they receive their medical care. This tragic outbreak highlights the need to ensure that all products, materials, and procedures used in healthcare are safe.”
-J. Todd Weber, MD, Incident Manager of the Multistate Fungal Meningitis Outbreak and Chief of the Prevention and Response Branch of the Division of Healthcare Quality Promotion, US Centers for Disease Control and Prevention
The New England Compounding Centre meningitis outbreak was a disaster decades in the making. There were many red flags raised over the years leading up to it where swift and decisive intervention may have changed the course of events, but almost a year later, 61 people have died and we are left to wonder; how did we get here?
In 2002, two patients were admitted to hospital with meningitis-like symptoms after having received an injection of betamethasone and methylprednisolone produced by the New England Compounding Centre, a company which produced various formulations of drugs including steroids for injection. The NECC was investigated and they were judged to have resolved their sterility and safety issues. After this and a series of other investigations the NECC were placed on probation and required to hire an outside evaluator, they hired a company called PSI to perform this role. The executives of the outside evaluator themselves had been convicted of federal crimes and defrauding the FDA. The board accepted PSIs statement that the NECC were now in compliance and without performing an inspection to corroborate this, they ruled the NECC compliant.
In March 2012, Colorado’s Board of pharmacy issued a cease and desist letter to the NECC for the illegal distribution of bulk medicines without patient specific prescriptions. In July 2012 Colorado contacted the Massachusetts board to inform them that NECC had not followed the cease and desist order, yet no action was taken. It was during this time in May-August that the NECC was preparing the tainted batches of prednisolone which would cause the outbreak.
Patients experiencing back or neck pain can sometimes be given spinal epidural injections to ease the pain. Although, Cochrane collaborations have so far failed to prove the efficacy of this treatment, one patient was suffering from neck pain and received a steroid injection on the 31st August 2012.
The soil fungus Exserhilium rostratum is normally harmless, but injected into the spine, it travelled through the cerebrospinal fluid and up to the brain-stem where it began to grow and invade the vessels. Tissue in the brain stem became inflamed and necrotic, blocking nearby blood vessels and damaging the meninges. Peculiarly, the fungus has little immunogenicity and was allowed to grow unchecked by the body.
One week after the injection on 7th September, the patient checked into a hospital presenting with a headache and other meningitis-like symptoms. As the illness progressed over the next days, the patient developed dizziness, double vision and start slurring her words. The clinicians worked hard to diagnose the patient and with the bacterial cultures coming back negative, treated her for viral meningitis. On day 4, the patient developed problems swallowing and was intubated. On day 9, the patient’s reflexes were found to be absent and on day 10 she was pronounced dead. On the same day, Exserohilum was discovered in her cerebrospinal fluid, days too late to be of help. The CDC later advised that “voriconazole might be effective in treating infections caused by brown-black molds”. One of the cases was reported as Aspergillus fumigatus, but the rest of the diagnosed conditions have been Exserohilum.
Following the reports of the cases, the NECC was quickly determined to be the source and a recall was ordered, over 17,000 tainted doses were recalled, but 14,000 people had already been treated.
On 1st October 2012, the FDA and the Department of Public Health conducted a site inspection and discovered the full extent of the violations at the NECC. The vials of steroids contained visible black particulate matter. They found that the company did not wait for the results of sterility testing before shipping drugs and that the sterility methods might have been lacking as autoclaves were not regularly checked. Dr. Madeleine Biondolillo, director of the Bureau of Health Care Safety and Quality at the Massachusetts Public Health Department reported that the NECC failed to sterilize the products for “even the minimum amount of time necessary to ensure sterility.” The medications on site were not labelled for each specific patient, a requirement for compounders. Damningly, it was also reported that “a leaking boiler was located next to the clean room, which created an environment in which contaminations could have occurred.” One of the many alarming findings was the discovery of a facility on site for administering intravenous injections despite not having a license to practise as a clinic.
This raises the important question, what was the function of the NECC? They claimed to function as a compounding centre, however compounding centres create formulations of drugs to meet the needs of specific patients, the NECC was creating bulk amounts of its compounds. The NECCs record of sending bulk orders of medicines to doctors and hospitals would also suggest they were not functioning as a compounder, but as a manufacturer. These large scale compounding centres are regulated by the FDA, but also by individual states, because the NECC was shipping a large amount of products across state lines it should have fallen under the jurisdiction of the FDA. Due to several laws being successfully lobbied against or struck down by the Supreme Court, compounding centres are not regulated effectively and fall into a “regulatory black hole” as Congressman Edward J. Markey (D-Mass.) described it.
Lack of communication within and between the NECC, the Massachusetts Department of Public Health, the FDA and other parties contributed to the situation where hundreds of people became sick and dozens died. In the wake of this disaster, the Massachusetts Executive Office of Health and Human Services launched a Special Commission On The Oversight Of Compounding Pharmacies which drew up many recommendations including that “The Massachusetts Department of Public Health and associated boards should seek to establish a formal communication mechanism with the United States Food and Drug Administration, including but not limited to the development of memoranda of understanding guiding sharing of information and joint or several investigations of entities licensed by Massachusetts.”
Congressman Markey introduced the The Verifying Authority and Legality in Drug (VALID) Compounding Act which according to his website will:
- Preserve state regulatory authority for traditional small compounding pharmacy activities;
- Ensure that compounding pharmacies that are operating as drug manufacturers are regulated by the FDA as drug manufacturers;
- Allow compounding pharmacies with a legitimate reason to compound drugs before the receipt of a valid prescription to request a waiver to enable them to do so;
- Allow the FDA to waive the requirement to compound drugs solely for individual patients with valid prescriptions in the event of a drug shortage or to protect public health;
- Allow the FDA to waive the requirement to compound drugs only if they are not copies of commercially-available drugs if doing so is necessary to protect public health or well- being; and
- Increases transparency to the public by mandating that compounded drugs be labeled to ensure that recipients know that the drugs have not been tested for safety or effectiveness, publishing a “Do Not Compound” list of unsafe or ineffective drugs, and reporting of bad reactions to compounded drugs or any drug that poses a safety risk.
To date there have been 749 cases in 20 States and there have been 61 deaths although this number may not be static. The incubation time of the fungus can be very long and recent reports have shown that once some patients come off the months of anti-fungal treatment, there is a threat of relapse.
This was an unnecessary disaster; it could and should have been avoided. Now with new regulations to fill in the legislative cracks and encourage states to work better with federal authorities we may be moving to a future where we can better ensure the safety of medicinal products.
Some have feared that because NECC’s operations were so badly mismanaged (investigations not carried out, previous outbreaks ignored, those who spoke out let go) that industry may take a ‘that would never happen to us’ attitude. The conditions which led to the outbreak may pass into the realms of the unbelievable, but there is still much to be learned for the wider industry when it comes to pathogen safety.