"The facts that we've uncovered so far in this investigation reveal frightening failures on multiple levels," said Colorado Representative Diana DeGette during a November 14 hearing of the House Energy and Commerce Committee's subcommittee on oversight and investigations.
The outbreak's official toll on that date was 490 patients with central nervous system infections, 34 of them fatal, plus a dozen patients with joint infections.
Old problems. The subcommittee released an investigative report that cited a decade's worth of records from FDA and the Massachusetts Department of Public Health (MDPH) about NECC.
Problems cited by MDPH during the current outbreak include visible contamination in vials of methylprednisolone acetate and evidence that NECC had distributed material from two now-recalled lots of the product before receiving sterility test results.
According to MDPH, which started its investigation of the current outbreak in late September, NECC did not test its autoclaves to ensure that they were working properly or run the devices for the minimum time necessary to ensure sterilization. MDPH also found particulate contamination in powder-containment hoods used during the manipulation of powdered substances, as well as excessive dirt and debris on contaminant-trapping mats near the entrance to cleanrooms.
The records show a long history of quality and sterility problems at NECC.
During a 2002 inspection stemming from reports of adverse events in patients treated with betamethasone, FDA and MDPH inspectors stated that NECC had apparently left a bulk batch of the supposedly sterile drug solution covered with foil in a hood for several days while awaiting sterility test results.
Other findings during inspections of NECC over the years include the failure to test final product lots for potency or sterility, the disregarding of unfavorable initial sterility and endotoxin test results, the failure to select adequate sample sizes for sterility tests, and repeated instances of compounding drugs for which NECC lacked a patient's prescription.
The Massachusetts Board of Registration in Pharmacy twice voted unanimously in 2004 to approve a consent agreement that reprimanded NECC, placed the company on probation for three years, and forced the owner, Barry Cadden, to undergo training in sterile compounding. But that agreement was never executed.
Instead—for reasons that MDPH claimed it has so far not been able to discover—a weakened, nondisciplinary agreement was signed in 2006.
Before the current outbreak, FDA's most decisive action against NECC was the issuance of a warning letter in 2006, two years after an inspection revealed a variety of problems at the company.
New problems. Legislators in November seemed particularly incensed about communication failures that occurred after April 2011, when the Colorado State Board of Pharmacy issued a cease-and-desist order to NECC for supplying compounded prescription drugs to a Colorado pharmacy without first obtaining patient-specific prescriptions.
According to MDPH documents, FDA was aware of the problem in May 2011, but the agency did not alert the Massachusetts pharmacy board.
Massachusetts pharmacy board administrators were informed of the cease-and-desist order more than a year later in a direct communication from the Colorado pharmacy board stating that NECC was violating the order. According to MDPH, the state-employed administrators apparently did not inform board members about the problem or order an investigation.
Two months later, Tennessee reported the first case of meningitis in the current outbreak.
"We are left to wonder what would have happened if FDA had investigated or at least informed the Massachusetts board . . . of this complaint. It is possible that this outbreak very well might have been prevented," said subcommittee Chairman Cliff Stearns of Florida.
FDA Commissioner Margaret Hamburg acknowledged at the hearing that the agency had been slow to act against NECC.
But, she contended, FDA had "no reason to believe that any of the specific actions in question, more timely issuance of the 2006 warning letter or inspectional follow-up, would have prevented this recent tragedy."
During the House hearing and a November 15 hearing before the Senate Health, Education, Labor and Pensions Committee, Hamburg characterized FDA's authority over pharmacy compounding as "limited, unclear, and contested."
"Stronger, clearer authority would enable more effective regulation of the drug compounding industry, especially when it has been evolving so significantly," Hamburg said.
Federal legislation passed in 1997 exempts pharmacy-compounded drugs from many of the requirements for manufactured products, including premarketing approval from FDA and observance of Good Manufacturing Practices. The law requires that compounding be performed by a licensed pharmacist or physician for a specific patient who requires the drug and has a prescription for it.
Although FDA has the authority to restrict the compounding of certain types of drugs, the agency must first undertake a rule-making procedure that includes input from the public and response to public comments.
The 1997 law has been challenged in courts, which have issued conflicting decisions in different U.S. jurisdictions.
Hamburg urged Congress to pass legislation to clearly define pharmacy compounding and drug manufacturing and expand and clarify FDA's role in overseeing compounding pharmacies. She called for a tiered approach, with state pharmacy boards given primary responsibility for oversight of traditional compounding and FDA regulating operations like NECC whose work is akin to manufacturing.
"Under the framework, certain products carrying the highest risks should not be compounded. They could only be produced by entities willing to meet the standards currently required of drug manufacturers," Hamburg said.
Kasey K. Thompson, ASHP's vice president of policy, planning, and communications, agreed with Hamburg's assessment of the regulatory landscape for compounding pharmacies.
"I do believe it's a regulatory gray area that must be [clarified] by Congress," Thompson said during the Senate hearing. He urged the passage of legislation "that would give the FDA authority that it needs to regulate these entities that fall between the Pfizers and the Mercks and the large-scale manufacturers . . . and these entities that are compounding medications in large amounts."
Massachusetts has taken recent steps to improve its oversight of pharmacy compounding. Lauren Smith, the recently named interim commissioner of MDPH, told legislators that the pharmacy board administrators who failed to investigate the Colorado incident "have been removed from their jobs."
Draft emergency regulations issued on November 1 by the Massachusetts pharmacy board require state-licensed sterile compounding pharmacies to report production volume and distribution data to the pharmacy board. All state-licensed pharmacies must report to the pharmacy board when they are the subject of a federal or out-of-state investigation.
Smith also said the state is now, for the first time, conducting unannounced inspections of Massachusetts pharmacies that engage in sterile compounding.
Senator Pat Roberts of Kansas noted that the committee has tried over the years to draft legislation related to pharmacy compounding but has met with "pushback" from the industry.
David Miller, chief executive officer of the International Academy of Compounding Pharmacists, said he believes that FDA already has sufficient authority to regulate compounding pharmacies that operate as illegal drug manufacturers.
But he assured Roberts that he is committed to working with Congress to protect the public from rogue compounding pharmacies.
Credibility. William Gouveia, adjunct clinical professor of pharmacy at the Northeastern University School of Pharmacy in Boston, said NECC's actions have damaged the credibility of the entire pharmacy profession and proved tragic for patients.
"This has been the most enormous failure in health care that I can think of," he said.
Gouveia served as a member of the Massachusetts pharmacy board during 2004–10. He said he recalled NECC's name from his time on the board but could not recollect any details of the company's interactions with the board.
Gouveia said the pharmacy profession needs to adopt a single high standard for sterile compounding that is applicable in all settings and then ensure that the standard is followed.
"What we need is to take the high road and do what we need to do to protect patient safety," he said. "I don't think anyone can let this go."
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