In April 2004, the Food and Drug Administration (FDA) issued a new rule requiring makers of pancreatic enzyme products (PEPs) to get their drugs approved by April 28, 2010. Unapproved pancreatic enzyme products had been available for many years, but after that cut-off date, makers of pancreatic enzyme products were required to stop manufacturing and distributing unapproved products. This new regulatory requirement is designed to confirm and assure the safety, effectiveness, and consistency of PEPs, but an unintended consequence has been a steep increase in the average cost of medication per prescription.
For individuals with exocrine pancreatic insufficiency, a condition most frequently encountered in patients with cystic fibrosis or chronic pancreatitis, medication with pancreatic enzyme products (PEPs) is a lifelong regime, typically requiring three to four daily doses. Without pancreatic enzyme replacement products, malnutrition and osteoporosis are common.
A European study (Littlewood et al, 2006) found that approximately 95 percent of cystic fibrosis (CF) patients are pancreatic insufficient due to an inadequacy of their own pancreatic enzyme secretions, and will need to take pancreatic enzyme (Littlewood et al, 2006 therapy (PERT)) in order to prevent the symptoms of fat malabsorption. These which include frequent pale, oily and offensive stools, abdominal pain, poor growth, and deficiencies of fat soluble vitamins and essential fatty acids.
According to the Cystic Fibrosis Foundation, pancreatic enzyme products (PEPs) contain the active ingredient pancrelipase, a mixture of the digestive enzymes amylase, lipase, and protease. These digestive enzymes are used to improve food digestion in patients whose bodies do not produce enough pancreatic enzymes. In addition to cystic fibrosis, PEPs have been used to treat patients with various other pancreatic disorders, including Shwachman-Diamond syndrome, chronic pancreatitis, pancreatic tumors, or removal of all or a part of the pancreas. As patients get older and their food intake increases they need to take higher doses of pancreatic enzymes. Although PEPs have been used for several decades, they had been marketed in the U.S. as unapproved products.
Slow PEP Approval Process Hurts CF Patients, Say Critics
However, critics contend that the approval process for PEPs has been slow. Prior to the regulatory change, some 30 PEPs had been available on the market. Currently, only six are approved, and the average cost per prescription of PEP therapy has more than doubled. And while cystic fibrosis patients often carry insurance coverage for prescription medication, some do not, and that is more frequently the case for patients with other disorders for which PEPs are indicated such as chronic pancreatitis.
A report by Monica J. Smith in the April 2014 edition of Gastroenterology & Endoscopy News cites Dr. Timothy B. Gardner, MD, Director, Pancreatic Disorders and Assistant Professor of Medicine at the Geisel School of Medicine, Dartmouth–Hitchcock Medical Center, in Lebanon, New Hampshire, who presented research on PEPs at the 2013 American College of Gastroenterology Annual Scientific Meeting.
Dr. Gardner notes that until about seven years ago, there were around 30 different prescription-based formulations for pancreatic enzyme therapy available because prior to the FDA’s establishment in 1938, these enzyme products were already in place; “grandfathered in” as it were, and previously not required to undergo FDA New Drug Application (NDA) approval.
Ms. Smith reports that in order to determine the effect of the FDA’s new approval requirement on the cost of and access to PEPs, Dr. Gardner and his colleague Stuart L. Gordon consulted the IMS Health Product Report Database, which tracks total prescriptions and total sales of individual drugs. “Our primary outcome was the cost of prescriptions one year before and one year after the FDA NDA requirement was put into place,” Dr. Gardner told her. “We found … the total sales for nongeneric pancreatic enzyme replacement products were $281 million before this was put in place. In 2012, [the year] for which the most recent data is available, it was up to $632 million.” Dr. Gardner emphasizes that total number of prescriptions did not change but the amount spent in sales certainly did. “If we look at the cost per prescription before and after the NDA requirement,” he observes, “the cost for each individual prescription in 2008 was $247. By 2012, the cost had increased to $577,” leading him to conclude that requiring FDA/NDA… [W]e have concluded that the NDA requirement for these products resulted in universal prescription price increases and in more nongeneric prescriptions for these products. Also, at this point, three years after this requirement, there has been no postmarketing safety data published, which was the original goal of this requirement.”
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The FDA says its concern about unapproved PEPs is that they contain variable doses of the therapeutic enzymes (lipase, amylase, and protease), which were causing patients to notice changes in their ability to digest food due to under-dosing, or adverse events due to overdosing. The agency notes that an important characteristic of the drug approval process is that companies must demonstrate they are able to manufacture their products with sufficient consistency and quality to ensure patients do not experience problems due to dose variation. The goal of this rule is to make sure pancreatic enzymes prescribed have the appropriate amount and dosage of active ingredients to assist with food digestion effectively since consistencies in enzyme formulation can cause problems with digestion. By conducting clinical trials in people with cystic fibrosis and other pancreatic diseases, the safety and effectiveness of the enzymes is confirmed, and for FDA approval the manufacturing process of pancreatic enzymes is standardized, thus ensuring consistency of the medicine from batch to batch. In addition, by having more precise information on these enzymes and how effective they are, doctors are better able to prescribe the right amount of enzymes.
In her Gastroenterology & Endoscopy News report, Ms. Smith also cites Dr. Christopher E. Forsmark, MD, a professor of medicine and chief of the Division of Gastroenterology, Hepatology and Nutrition, University of Florida College of Medicine at Gainesville, noting that previous analyses of pancreatic enzyme products revealed that the content was often incorrect, but tended to be more than the packaging suggested. The new enzymes have the same level of porcine enzyme content, but undergo a better manufacturing process.
The CF Foundation also supported the FDA’s decision because it would make enzymes better and help improve nutrition and digestion for people with CF, and has pledged to continue offering its expertise to the FDA to ensure the best health for everyone with CF.
The CF Foundation considers FDA approval for pancreatic enzymes a step forward in improving quality of care for people with CF, having received reports of health problems in people with CF when an enzyme product was used that did not work as it should. Therefore they maintain that by regulatory requirement that enzymes to be consistent in their formulation and work properly helps assure that people with CF are getting the right amount of enzymes for their digestive and nutritional needs.
The FDA’s PEP Approval Process Timeline
Indeed, manufacturers had plenty of notice. The FDA announced In July 1991 that all PEPs would need to be approved, and that any company wishing to newly market or continue to market a PEP would have to submit a New Drug Application (NDA) in order to assure the safety, effectiveness, and product quality of their PEPs. Some companies began the application process soon after that announcement, and in 2004, FDA notified PEP manufacturers of its intent to permit marketing of unapproved products while the companies worked on their applications. However, approval was required for all marketed PEPs by April 28, 2008. In 2006, FDA issued a guidance describing requirements manufacturers would be obliged to meet to ensure that a PEP product was effective, safe and of sufficient quality for FDA approval. In 2007, because of certain difficulties encountered in manufacturing these products, FDA extended the deadline for approval to April 28, 2010.
However, despite the FDA’s offer of technical assistance to all manufacturers of PEPs, and the extension of the approval deadline, most previously available products did not receive FDA approval for marketing prior to the April 28, 2010 deadline after the agency discovered quality problems with the unapproved PEPs. The FDA notes that it has worked intensively with the manufacturers of these products towards approval.
The CF Foundation also offered its expertise about CF and pancreatic enzyme products to the FDA, and shared its concerns about variations and inconsistencies in the previously available pancreatic enzymes. The Foundation also identified experts who could provide the FDA with more information about the importance of reliable and effective pancreatic enzymes for people with CF. The CF Foundation can also help people with CF work with their insurance companies to get enzymes covered; for more information visit http://www.cfservicespharmacy.com or call (800) 541-4959.
In 2008, before the NDA requirement kicked in, some 16 to 30 enzymatic therapies are cited as being available on the U.S. market. However currently, six products — Creon, Zenpep, Pancreaze, Ultresa, Viokace, and Pertzye — are the only FDA-approved PEPs marketed in the United States. The newest of these are Ultresa (pancrelipase) and Viokace (pancrelipase), marketed by Bridgewater, N.J.-based Aptalis Pharma U.S. Inc., which were approved by the U.S. Food and Drug Administration March, 1, 2012, and Pertzye (pancrelipase) marketed by Digestive Care, Inc. (DCI) — approved May 18, 2012.
A PEP Primer For Cystic Fibrosis
Ultresa is a delayed-release capsule used to treat both children and adults with CF or other conditions rendering them unable digest food normally because their pancreas does not make enough pancreatic enzymes.
Viokace, in combination with a proton pump inhibitor, is used to treat adults who cannot digest food normally. Adults with chronic pancreatitis, a continuing, chronic inflammatory process of the pancreas, or those who have had some or all of their pancreases removed (pancreatectomy) may not digest food normally because they lack needed enzymes or because their enzymes are not released into the bowel (intestine). Viokace’s safety and efficacy in children has not been established.
Pertzye is a pancreatic enzyme product containing bicarbonate-buffered enteric-coated microspheres and is protected by several U.S. and international patents. The Pertzye formulation was previously marketed by DCI for over a decade under the trade name Pancrecarb MS-16.
“The approvals of Ultresa and Viokace, along with the other approved pancreatic enzyme products, allow health care providers to prescribe the product that is most appropriate for the estimated 200,000 patients in the United States who have pancreatic insufficiency,” commented Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research in a March 2012 release.
Ultresa, Viokace, and Pertzye were the fourth, fifth, and sixth pancreatic enzyme products approved by FDA. The first three FDA-approved pancreatic enzyme products were Creon (2009), Zenpep (2009) and Pancreaze (2010). Approved pancreatic enzyme products meet FDA standards for safety, efficacy and product quality.
Creon, Zenpep, Pancreaze, Ultresa, and Pertzye are enteric coated to help prevent the drug from breaking down in the stomach, and delay the release of the drug until it reaches the lower gastrointestinal tract. Viokace is the only non-enteric coated pancrelipase product, and must be taken in combination with a PPI to help prevent the drug from breaking down in the stomach, and delay the release of the drug until it reaches the lower gastrointestinal tract. Viokace, in combination with a proton pump inhibitor (PPI), is indicated in adults for the treatment of exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatectomy.
For more information on Pancreatic Enzyme Replacement
for people with cystic fibrosis, click here.
U.S. Food and Drug Administration
Cystic Fibrosis Foundation
Cystic Fibrosis Medicine
Gastroenterology & Endoscopy News
Geisel School of Medicine, Dartmouth–Hitchcock Medical Center
University of Florida College of Medicine, Gainesville