Will FDA Apply a Presumption in Favor of NCE Status for Pancreatic Enzyme Products?

By Kurt R. Karst & Frank J. Sasinowski –      

FDA’s recent decision to approve the Pancreatic Enzyme Product (“PEP”) CREON (pancrelipase) to help patients with cystic fibrosis and others with Exocrine Pancreatic Insufficiency (“EPI”) digest and absorb nutrients from foods has apparently left the Agency in a quandary about whether or not to grant five years of New Chemical Entity (“NCE”) exclusivity for the drug product.  Although FDA approved CREON in early May 2009, the most recent Orange Book Cumulative Supplement does not yet show any period of exclusivity applicable to the drug product.  (FDA has already granted exclusivity with respect to more recent approvals.)

PEPs have a long and interesting regulatory history.  PEPs have been available in the U.S. since before the enactment of the 1938 FDC Act.  In 1995, FDA concluded as part of its Over-the-Counter (“OTC”) Drug Review for PEPs that OTC PEPs are not generally recognized as safe and effective.  In December 1996, FDA approved one PEP – Organon Inc.’s COTAZYM (pancrelipase [amylase; lipase; protease]) Capsules (NDA No. 20-580) – for the treatment of EPI.  That drug product, which has since been discontinued from marketing, was apparently not granted any period of market exclusivity. 

In April 2004, FDA announced in a Federal Register notice that all PEPs are new drugs and described the conditions for continued marketing of these drug products.  In particular, FDA announced that manufacturers who wish to continue to market PEP drug products must submit NDAs.  In April 2008, FDA published a guidance document to assist manufacturers in preparing and submitting NDAs and stating that the Agency would exercise enforcement discretion for firms who submitted INDs by April 28, 2008 and NDAs by April 28, 2009.  CREON is the first PEP approved under the process described in FDA’s guidance document.

Importantly, FDA states in the PEP notice and guidance document that, for purposes of seeking FDA approval for a generic version of an approved PEP, two PEPs cannot be the same:

For a [PEP] to be submitted as an ANDA, the proposed drug product would have to be shown to contain the same active ingredient(s) as an approved reference listed drug.  Because of the complexity of [PEPs], it is unlikely that currently available physiochemical and biological analytical tools would be able to demonstrate that the active ingredients in [PEPs] from two different manufacturers are the same. [(emphasis added)]

With regard to patient needs, FDA’s PEP notice states:

To meet the needs of patients requiring pancreatic enzyme replacement therapy, [PEPs] in varying dosage forms, enzyme content, and activity are currently being marketed. . . . [T]here is a need for a range of products to remain available for patient use.  The dosage requirements of patients vary, and the appropriate daily dose of pancreatic enzyme supplements must be individualized and adjusted when clinically indicated.  Furthermore, physicians have identified and stabilized their patients on currently available products with different ratios of lipase, protease, and amylase that meet the patients’ needs.  Thus, to meet the dosing requirements and to maintain compliance with treatment, pancreatic supplements are needed with varied concentrations of lipase, protease, and amylase.  Accordingly, FDA will permit currently marketed [PEPs] to be marketed without approved applications until April 28, 2008, to give manufacturers time to conduct the required studies and to prepare and submit applications, and to allow time for [FDA] review of and action on these applications.  [(emphasis added)]

As we previously reported, although FDA initially determined that one PEP was an orphan drug eligible for seven years of orphan drug exclusivity, that designation was revoked after the Agency determined that the U.S. prevalence of EPI was greater than the statutory 200,000 person prevalence established under the Orphan Drug Act when orphan drug designation was requested.  FDA has since stated that “[p]eople of all ages with EPI due to cystic fibrosis, chronic pancreatitis, and other conditions take these products.  The estimated number of patients in the United States with EPI is over 200,000.”

Although FDA stated in the preamble to the Agency’s proposed 1989 regulations implementing the Hatch-Waxman Amendments that “FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis,” the usual situation in which a drug product is eligible for five-year exclusivity is when it contains only known previously unapproved (that is “new”) active moieties.  FDA has, however, found a drug to be an NCE – post-NDA approval – despite the presence of its active moiety in a previously approved drug.  For example, in July 1993, FDA granted five-year exclusivity to CONDYLOX (podofilox) Topical Solution (NDA No. 19-795), a refined, single-ingredient version of a product already approved in an NDA as a mixture, after the Agency determined that the record of previous NDA approvals did not demonstrate that podofilox was an active ingredient in the mixtures FDA approved.  Specifically, FDA stated in response to a citizen petition (FDA Docket No. 1992P-0051) that although “several previously approved NDA’s contained podophyllum or podophyllum resin . . . these previously approved NDA’s did not characterize podofilox as an active ingredient.  Consequently, your request for five-year exclusivity for podofilox is granted . . . .”  Thus, in rendering its decision that CONDYLOX was entitled to five-year NCE exclusivity, FDA relied on the fact that previously approved NDAs containing podofilox failed to characterize podofilox as an active ingredient. 

More recently, FDA presumed NCE status and granted NCE exclusivity for a drug about which the Agency has insufficient information to know whether or not it contains a previously approved active moiety.  FDA stated this “presumption in favor of NCE status” policy in the context of the Agency’s approval of various non-recombinant hyaluronidase drug products.  In the case of hyaluronidase, uncertainty arose from the fact that such drug products are complex proteins that are not fully characterized.  FDA stated in an October 2005 citizen petition response (FDA Docket No. 2005P-0134)  concerning hyaluronidase exclusivity that:

Generally, if the Agency has insufficient information to know whether a product contains a previously approved active moiety, the applicant would be required to submit an NDA containing substantial clinical safety and efficacy data.  These data requirements could reasonably be expected to be comparable to those that would be needed for approval of an NCE.  Under the presumption, if it is not known whether a product contains a previously approved active moiety, the product also would be treated as an NCE for marketing exclusivity purposes, and, accordingly, granted 5-year exclusivity.  [(emphasis added)]

Importantly, with respect to pancrelipase, FDA stated in the Agency’s exclusivity determination contained in the summary basis of approval package for one hyaluronidase drug product – HYDASE (hyaluronidase) Injection (see pages 15-21) – that “[i]n at least two instances, however, the Agency did not grant NCE status in a circumstance where it might have been presumed . . .  (menotropin/urofollitropin and pancrelipase)” (emphasis added).  It seems reasonable to conclude that FDA’s delayed exclusivity determination for CREON is the result of debate within the Agency over the further application of FDA’s presumption in favor of NCE status, and how FDA can meet the stated “need for a range of products to remain available for patient use” if the Agency ultimately decides to grant three-year new clinical investigation exclusivity instead of five-year NCE exclusivity.  It is unclear whether FDA will soon make a decision, but we will be closely watching this case.