Over the past week or so, there have been numerous reports about a fungal meningitis outbreak that was traced to medicines associated with three lots of preservative-free methylprednisolone acetate produced by the New England Compounding Center. The drug is an injectable steroid that is used for pain relief. The potentially contaminated injections were given starting May 21, 2012. Symptoms of the fungal meningitis include: fever, new or worsening headache, neck stiffness, sensitivity to light, new weakness or numbness, increasing pain, redness or swelling of the injection site. So far, 7 people in the US have died.
Because the drug is delivered via an epidural injection directly into the epidural space, any contamination can lead to a meningitis infection. In this case the steroid produced by the New England Compounding Center was contaminated with a fungus which caused the fungal meningitis. It’s important to note that unlike other types of meningitis, such as bacterial meningitis, it is not contagious. Fungal meningitis also does not have a vaccine, because it is quite rare. (Viral meningitis is less severe, and usually resolves itself without treatment.)
So, how did this happen, how did a drug like this get into the hands of physicians and into hospitals? These questions are the most troubling.
The New England Compounding Center (website has been replaced by a news release) is a compounding pharmacy, which are pharmacies that mix approved drugs into new forms with additional, supposedly inert ingredients, to meet the needs of patients. They often do this to remove substances that may be allergic to some patients, to change flavors, to make drugs transdermal, or a whole host of other reasons. Many oncology drugs are compounded by pharmacies for chemotherapy, for example. Technically, the compounding center should mix the compound upon receipt of prescription, but this is requirement is often ignored.
The problem is that the FDA lacks regulatory control over compounding pharmacies according to the original Federal Acts that established the agency. A court case, Medical Center Pharmacy v. Mukasey, gave the FDA some narrow areas of control over these compounding pharmacies:
- Compounding in anticipation of receiving prescriptions,
- Compounding drugs removed from the market for safety reasons,
- Compounding from bulk ingredients not approved by FDA,
- Receiving, storing, or using drugs not made in an FDA-registered facility,
- Receiving, storing, or using drugs’ components not determined to meet compendia requirements,
- Using commercial-sale manufacturing or testing equipment,
- Compounding for third parties for resale,
- Compounding drugs that are essentially the same as commercially available products,
- Failing to operate in conformance with applicable state law.
Despite this ability to control the compounding industry, with the lack of funds and the large number of compounding pharmacies, the FDA probably does not control the industry as closely as it should have. Real pharmaceutical companies have close control in every step of research, manufacturing, quality control, packaging, shelf life, and shipping, and the FDA monitors those steps. There would be no way a fungal contaminant would have been missed in quality control of a pharmaceutical company in the United States, Canada, Europe, Japan, Korea, China, or any country where the FDA demands control before a drug is shipped to this country.
But the story is worse than that. The drug, methylprednisolone acetate, may not be all that useful in preventing pain. The Cochrane Collaboration reviewed the evidence regarding epidural injections of steroids and concluded that “there is no strong evidence for or against the use of any type of injection therapy for individuals with subacute or chronic low-back pain.” But many patients have requested the procedure in lieu of surgery, and it remains a fairly common procedure.
But the demand for the drug in a form that can be injected epidurally remained high, and compounding pharmacies found a lucrative market opportunity with little regulatory oversight.
According to an article in the New York Times, the the FDA states that the brand name product, Depo-Medrol by Pfizer, is not in short supply, but it is considered to be too expensive. Thus, some medical practices have switched to compounding pharmacies for alternative supplies.
The New York Times described PainCare, a New Hampshire-based pain management medical practice, that used New England Compounding to supply the injectable steroid now under suspicion. According to the New York Times, the medical practice’s two main locations alone do more than 100 injections a week. Dr. Michael J. O’Connell, the CEO of PainCare, states that the compounding pharmacies’ version of the injectable steroid did not contain an alcohol preservative that is used by Pfizer and other manufactures, which he thought could damage nerves. There is no indication (pdf) that such a low level of alcohol in the injectable would cause nerve damage, and, given the the problems of fungal contamination, the minimal (if any) risk far outweighs the consequences of contamination. A search of PubMed provided no clues as to whether alcohol preservatives were considered dangerous for epidural injections, and since the FDA approved it in many epidural drugs, there seems to be no issue.
Which leads to the probable reason why PainCare and other healthcare providers choose to use an unregulated compounding pharmacy as opposed to a real manufacturer, according to the New York Times article:
In addition, Medicare and many private insurers reimburse a fixed amount for the injections, about $300, giving doctors a financial incentive to prefer the less costly compounded versions, he said. “If you are using a more expensive product, there would be less left over,” Dr. O’Connell said. PainCare paid New England Compounding $25 for a vial containing five 80-milligram doses, he said. A similar vial of the Depo-Medrol by Pfizer, with the alcohol preservative, costs about $40 to $46, according to the Web site of Clint Pharmaceuticals, a distributor.
I am not surprised that the drug is cheaper from compounders, because apparently, as I mentioned previously, they don’t have to meet the strict standards that the FDA sets for real pharmaceutical companies. But New England Compounding acted like a big pharmaceutical company claiming it was “licensed” to sell its products in all 50 states (technically, it needed a Pharmacy License in all states before it could ship there). It had sales reps who called on large customers to negotiate pricing and to manage issues that might arise. The New York Times reported that a physician, who was quoted anonymously, met with a sales rep from the company, “We were impressed. It seemed like big time.” The representative “assured me that all standards are being met.”
The New York Times report also discussed just how complicated the FDA’s role is in regulating the compounding industry, and how dangerous it can be for patients:
Jeff Gibbs, a lawyer in Washington who has represented compounders and drug companies, said it was unusual for a compounding pharmacy to produce large quantities of a drug that is commercially available. Policies of the FDA were more concerned about compounders’ making drugs that are already approved and on the market, and not so much about compounders’ producing large volumes of medicine, he said.
But Sheldon T. Bradshaw, a lawyer in Washington who was chief counsel for the FDA from 2005 to 2007, said large-scale compounders often behave like manufacturers, complete with sales teams that market their products to doctors. And they do not have to abide by the F.D.A.’s regulations, which require that problems with products be reported to the agency. In effect, he said, the companies are circumventing the regulatory process.
He contended that the FDA could invoke the Food, Drug and Cosmetic Act of 1938, which makes it a criminal act “to introduce into interstate commerce an unapproved drug.” That is what New England Compounding’s products would most likely be considered because the company was doing more than traditional compounding, yet had not obtained a new drug approval, something that large drug makers spend millions of dollars and years to get. He said the agency has often sent letters to producers telling them to stop, and they usually comply, knowing there might be criminal charges if they do not.
“Some of these companies are just setting up big manufacturing shops in the guise of traditional compounding and making drugs that are, for the most part, commercially available,” Mr. Bradshaw said. “Instead of making fake Rolexes, they are making fake drugs.”
As a patient, you have little control over this process. Well, if you’re going to request a procedure that has little evidence of working, then that is your choice, but once that happens, you assume that your physician or hospital is purchasing safe products. The system is supposed to work, but compounding pharmacies are an obscure part of the system that few observe. Most admittedly are small and probably are highly ethical. Some save patients a ton of money, and that’s a good thing. But if you’re going to be injected epidurally, you probably want to have the best and safest drug out there. That would be my standard.
I hope the FDA takes control over regulating compounding pharmacies immediately, even if it drives up the costs slightly. Self-regulation of that industry proves it’s not working.