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Pancreatic Insufficiency Products to Require FDA Approval by 2008

Kate Traynor

The Food and Drug Administration (FDA) published a notice (PDF) in the April 28 Federal Register that gives manufacturers of currently marketed exocrine pancreatic insufficiency drug products until April 28, 2008, to obtain marketing approval for the products as new drugs.

"These drugs must get approval by FDA within four years in order to remain on the market," said Joyce Korvick, deputy director of the agency's division of gastrointestinal and coagulation drug products, during a teleconference held Tuesday. "This gives time for the manufacturers to upgrade their manufacturing practices and to provide clinical trials data to show that their drugs are safe and effective at the labeled dosage."

Patients with pancreatic insufficiency require specifically tailored dosages of pancreatic enzymes and are at risk for complications if treated with a preparation containing different amounts of active enzymes than the product on which the maintenance dosage was based.

Korvick described this week's action as "an extension" of a 1995 Federal Register notice that forbade the sale of pancreatic insufficiency products as nonprescription drugs. In that notice, FDA stated the agency's intent to require new drug applications (NDAs) for the products but did not set an NDA approval deadline.

Korvick noted that FDA considers pancreatic enzyme products, or PEPs, medically necessary for patients whose ability to digest food is impaired because of cystic fibrosis or pancreatitis. Because of this medical necessity, FDA will allow the 38 currently marketed PEP formulations to be sold up until the NDA deadline.

"We did not want to remove these drugs from the market while this improvement or updating in manufacturing practices is going on," Korvick said. She emphasized that putting PEPs through the NDA process will ensure "consistent strength and potency and quality to these products."

The NDA requirement does not apply to herbal supplement products that contain pancreatic enzymes but are not labeled for the treatment of pancreatic insufficiency.

Les Hendeles, Pharm.D., professor of pharmacy and pediatrics at the University of Florida in Gainesville, has been trying for years to get FDA to increase its scrutiny of PEPs.

"I was elated when I heard the news" about the regulation, he said.

Hendeles said that for cystic fibrosis patients, FDA's decision will solve problems resulting from the inaccurate labeling of PEPs.

He explained that for an NDA to be approved, "the label and the contents of the capsule have to match. Right now, they don't. Some of the brand-name products are overfilled with 150 percent of the labeled amount. Some of the generics have less than the labeled amount."

FDA's action means that treatment issues associated with generic substitution among PEPs will also be resolved, Hendeles said. He recalled that generic versions of PEPs hit the market around 2000, and that some patients were unknowingly switched from their usual product to a generic.

"Some chain pharmacies designated the generic product as their preferred formulary item," Hendeles said. "When a patient would come in, a pharmacist would substitute it, just like any other generic."

FDA has asked pharmacists to "be aware that these products have different formulations." Because FDA has no data on the equivalence of different pancreatic enzyme products, the agency does not recommend substitution of PEPs.

Technically, there are no generic PEPs on the market, because none are AB-rated equivalents of Organon's Cotazym, an immediate-release pancrelipase product that was approved by FDA in 1996 but is not currently marketed. Cotazym is the only PEP ever approved through the NDA process.

Hendeles explained that patients with cystic fibrosis cannot use immediate-release products like Cotazym because the enzymes are degraded by stomach acid.

"Nobody uses immediate-release formulations for cystic fibrosis, because you have to take too high a dose," he explained.

In a draft guidance document (PDF) issued Tuesday, FDA stated that PEP manufacturers should submit data on their products' "bioactivity and/or bioavailability" in aspirates from the stomach and the small intestine.

Hendeles said that his hospital uses three different brands of pancrelipase products to treat patients with cystic fibrosis. He noted that despite the risks of switching patients from their usual product, some people will be forced by third-party payers to use a different PEP than that prescribed.

"That would be OK, as long as the physician knows that's going on and can clinically monitor" the patient and adjust the dosage as needed, Hendeles said.