Compounding Crisis Spotlights Regulatory Confusion

A national fungal meningitis outbreak linked to contaminated vials of steroid injectables from a Massachusetts compounding operation has reignited the debate over the safety of compounded drugs and the need for stiffer FDA regulation of these activities. Last week, the Centers for Disease Control and Prevention (CDC) reported 7 deaths and 91 ill, with the numbers rising daily. Thousands of individuals have been exposed to some 17,000 vials of methylprednisolone acetate produced by the New England Compounding Center (NECC) and shipped to 23 states in recent months.

Such a large volume of drug compounding and marketing to such a broad geographic area runs counter to FDA policy, especially for a drug that is available from regulated manufacturers. Compounded sterile injectables have been associated with serious adverse events, and NECC has been cited by FDA and state regulators for a range of violations in recent years. In April 2012, FDA and the CDC warned against use of a contaminated product used in eye surgery from Franck’s Pharmacy in Florida. FDA inspectors found fungus in several NECC lots last week; the firm instituted a broad recall and shut down operations.

Pharmaceutical manufacturers have pressed for stricter control of compounding pharmacies, which now number over 7000 according to the International Academy of  Compounding Pharmacists.  About 3000 produce sterile products, and a growing number are large enough to compete with drug companies that have to meet extensive standards to ensure quality products. Compounding pharmacies traditionally provide a valuable service in preparing special doses or formulations not available commercially and needed by individual patients, particularly children and the elderly. But only 162 compounders have applied for voluntary industry accreditation. Efforts by FDA to stiffen the rules over compounding have been stymied by Congress and rejected by the courts.

The current meningitis outbreak reflects a rise in treatment of back pain with spinal injections of steroids, as an alternative to surgery. Sales have risen for the NECC injectible treatment apparently due to supply shortages of generic versions of methylprednisolone related to manufacturing problems at generic producers of sterile injectibles; a brand product from Pfizer (Depo-Medrol) is expensive.  Commercial versions of this product are not approved for injection into spinal joints, but evidently have been used off-label for such treatment.

Compounding pharmacies fall into a gray area between FDA enforcement of drug manufacturing and state regulation of pharmacists. FDA has long tried to impose standards on large-scale compounders that move beyond local operations and compete unfairly with pharmaceutical manufacturers. An agency report in 2007 cites 200 adverse events involving 71 compounded products since 1990. Legislation approved in 1997 authorized FDA to clarify its policies governing pharmacy compounding. But the resulting regulations were invalidated by the courts on the grounds of unfairly restricting commercial speech. After that ruling was upheld by the Supreme Court in 2002, FDA issued a compliance guide spelling out its enforcement policy, focusing on large compounders that produce unsafe products from unapproved ingredients, but the agency’s enforcement powers have been limited. And in some cases FDA has supported compounders over manufacturers, as when KV Pharmaceuticals jacked up the price on the premature birth preventive, Makena, in anticipation of FDA action against compounders. The lethal consequences of this latest compounding disaster may generate legislative changes, as seen in recent comments by Sen. Richard Blumenthal (D-Conn) about the need to strengthen FDA oversight of compounding pharmacies.