Although six people have died from a fungal meningitis outbreak in Tennessee, the state has not yet revoked the license of the Massachusetts pharmacy believed to be responsible, and Tennessee Gov. Bill Haslam says the state will not rush to implement new rules.
Regulators in California, meanwhile, are already discussing how to tighten standards in the wake of the crisis, even though the state currently has some of the nation's strictest rules for drug compounding operations and has reported no illnesses or deaths from the contaminated steroids.
The two states' contrasting approaches illustrate one reason that the New England Compounding Center in Framingham, Mass., found itself largely free of safety regulations as it shipped 17,676 vials of potentially contaminated steroid to 23 states.
While federal oversight might have blocked the same outcome from a major drug manufacturer, regulatory authority isn't as clear for compounding pharmacies, which fall under a patchwork of state and federal regulations.
"There is a hole in which these companies operate," said Linda Bentley, a Boston attorney whose specialty is drug regulatory law.
Varying state regulations, lack of U.S. Food and Drug Administration oversight and unclear inspection standards opened the door for problems with compounding pharmacies, Bentley said.
"There's a point where what they are doing is not the traditional idea of compounding but manufacturing. The FDA's authority is not entirely clear," she said.
"It is a clear formula for disaster, and now we have one."
Haslam said he will speak to Tennessee Health Commissioner Dr. John Dreyzehner about revoking New England Compounding Center's state license -- a step that several other states have already taken.
However, he said, "right now, our focus is on making certain we address the health issues.
"I think we'll come back to talk about the whys and what happened later," Haslam said. "Our Department of Health has done a really good job of responding. ... I think there will be plenty of time later to try to come to some answers about do we have the right procedures in place."
In 2001, when three California residents died from treatment with a compounded drug, that state moved to tighten its rules. The California Board of Pharmacy wants even more stringent regulations in the wake of the nationwide fungal meningitis outbreak, said Virginia Herold, executive officer of the California Board of Pharmacy.
A decade ago, a San Francisco Bay-area physician was unable to get a commercially available drug, betamethasone, and turned to a local drug compounder. Of 12 patients injected, three died from bacterial meningitis. After that catastrophe, California mandated that injectible drugs be prepared in sterile rooms with specific physical requirements. Compounding pharmacies, which require separate licenses, are held to the strictest requirements for sterile drugs.
Among the proposals under consideration now in the wake of this fungal meningitis outbreak, Herold said, is requiring that a national accrediting agency inspect companies like New England Compounding Center to be sure they're in compliance with California standards.
Large drug manufacturers are subject to strict licensing and inspection requirements. In addition, they are required to conduct tests on all drugs showng their effectiveness and safety.
A review of regulations over compounding pharmacies across the country shows wide variations in requirements and limits placed on their operations. Some states limit the number of doses that can be processed in advance of an actual prescription, while others, like Massachusetts, require a prescription in hand for every dose.
Like Tennessee, Massachusetts does not have a separate license category for compounding pharmacies.
Tennessee's compounding pharmacies operate under the same regulations as pharmacies that distribute only mass-produced drugs, state health department spokeswoman Shelley Walker said.
There are FDA-approved versions of the contaminated drug, methylprednisolone acetate, said Dr. Michael Carome, deputy director of the Health Research Group at Washington D.C.-based Public Citizen. New England Compounding Center was skirting federal regulation by manufacturing it, he said.
"The FDA could have acted under the authority it does have. What this company was doing was manufacturing a cheaper version of the drug," Carome said. "The providers could have bought an FDA-approved drug, but that would have cost more."
Saint Thomas Hospital, which administered contaminated doses in its outpatient neurosurgery center, hasn't responded to questions about why New England Compounding Center provided the drug.
Carone said a gray area resulted from a U.S. Supreme Court ruling that struck down an entire section of a new drug statute passed by Congress in 1997. That law would have given the FDA clear authority to take enforcement actions on compounding pharmacies nationwide, particularly in emergency situations.
A 2008 federally funded study of an outbreak of bacteria known as pseudomonas fluorescens cited the void of regulations for compounding pharmacies. The bacteria struck cancer patients in six states between 2004 and 2006, with 80 infected from pre-filled syringes provided by an unnamed compounding firm.
The study, published in the Journal of Clinical Infectious Diseases, also noted that the syringes "were not prepared in response to a prescription from a licensed practitioner," nor had the company "obtained the required premarket notification approval from the FDA."
"Regulators at the FDA have reported concern that the practice of performing manufacturing under the guise of compounding is a growing problem because firms try to capitalize on the regulatory exemptions afforded to compounded products to produce less expensive products."
It said contaminated products had been linked to multiple outbreaks nationwide.
Dr. Laxmaiah Manchikanti, the American Society of Interventional Pain Physicians' CEO and medical director of a Paducah, Ky., pain center, said he's been trying to tell the federal government about compounding pharmacies' problems for years. He has published several articles and studies questioning the effectiveness of epidural steroid injections.
He said he refuses to use compounded medications at his practice.
"They should tighten the regulations of these pharmacies, but it would be hard for the FDA to regulate them as they should be," Manchikanti said. "Really, the only way we can do that is to just not use them."
Compounding in TN
Tennessee's compounding pharmacists are quick to clarify the difference between their small-scale operations and the New England Compounding Center.
Many Americans don't know about compounding pharmacies, and their blends aren't FDA-approved, said Cindy Smith, pharmacist in charge at Medical Center Compounding Pharmacy in Cleveland, Tenn.
Her pharmacy's most common compound is bioidentical hormone replacement therapy, or specialized hormones. Doctors frequently use compounded hormones because of the side effects associated with commercially available synthetic hormones. She said her pharmacy compounds on an individual basis and requires a prescription for any compounded medication.
It's one of only three in Tennessee, and 162 nationwide, that is accredited by the Pharmacy Compounding Accreditation Board. The International Academy of Compounding Pharmacists estimates 7,500 U.S. pharmacies specialize in advanced-level compounding, of which about 3,000 provide sterile compounding.
New England Compounding Center is not on the Pharmacy Compounding Accreditation Board's online list of accredited pharmacies.
The accreditation requires greater documentation of compounding practices and proof that the created compounds are valid medicines.
"I can almost envision that, as a result of this tragedy, some of the things that we have been doing voluntarily (to get and keep accreditation) will become required," Smith said.
For example, the accreditation agency requires monthly testing of a percentage of the medicines pharmacies compound for bacteria, fungi and other endotoxins. Non-accredited pharmacies typically aren't required to do that unless they engage in batch compounding, or make medications intended for use by more than 25 people.
At least two Tennessee legislators who are pharmacists are calling on the state health department and Tennessee Board of Pharmacy to investigate the state's regulations on compounding pharmacies to see how the meningitis disaster could have been averted.
They could enact emergency policies free of legislative action, said Rep. David Shepard, D-Dickson, who serves on the House Health & Human Resources Committee.
Sen. Randy McNally, R-Oak Ridge, chairman of the Senate Finance Committee, said contamination of the steroid could have happened in any step of the process at New England Compounding Center, but the fungus is easily detected in a batch check.
He questioned whether a pharmacy should have been able to produce such large amounts under a compounder's license.
"When you have a manufacturer that manufactures that large a volume and is sending it out, you probably should have some kind of check by the FDA or CDC," he said.
Heidi Hall wrote this report with contributions from Walter F. Roche Jr., Duane Marsteller and Chas Sisk.