[Federal Register Volume 72, Number 207 (Friday, October 26, 2007)]
[Notices]
[Pages 60860-60862]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-21082]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2003N-0205]


Exocrine Pancreatic Insufficiency Drug Products; Extension to 
Obtain Marketing Approval

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that it 
intends to continue to exercise enforcement discretion to ensure the 
continued availability of exocrine pancreatic insufficiency drug 
products after April 28, 2008. FDA intends to exercise its enforcement 
discretion with respect to unapproved pancreatic enzyme drug products 
until April 28, 2010, if the manufacturers have investigational new 
drug applications (INDs) on active status on or before April 28, 2008, 
and have submitted new drug applications (NDAs) on or before April 28, 
2009. FDA is granting this extension to ensure the availability of 
exocrine pancreatic insufficiency drug products during the additional 
time needed by manufacturers to obtain marketing approval.

DATES: The period during which FDA intends to exercise its enforcement 
discretion against unapproved pancreatic insufficiency drug products is 
extended to April 28, 2010, if the manufacturer has an active IND on or 
before April 28, 2008, and has submitted an NDA on or before April 28, 
2009.

FOR FURTHER INFORMATION CONTACT: Mary Catchings, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION: In the Federal Register of April 28, 2004 
(69 FR 23410) (the 2004 notice), FDA announced that all exocrine 
pancreatic insufficiency drug products are new drugs and announced the 
conditions for continued marketing of the drug products. The 2004 
notice covered pancreatic enzyme preparations containing the 
ingredients pancreatin and pancrelipase. Both ingredients are extracted 
mainly from hog pancreas and contain principally the enzymes amylase, 
protease, and lipase. Pancreatic extract drug products are indicated as 
replacement therapy to treat conditions associated with exocrine 
pancreatic insufficiency, including cystic fibrosis, chronic 
pancreatitis, pancreatic tumors, or pancreatectomy.
    Pancreatic extract drug products have been marketed in the United 
States for many years. Marketing of some versions of these products 
predates the 1938 passage of the Federal Food, Drug, and Cosmetic Act 
(the act). Over the years, other pancreatic extract drug products have 
entered the market. Various dosage forms of pancreatic enzyme drug 
products are currently marketed as prescription drug products: Uncoated 
tablets, powders, capsules, enteric-coated tablets, and encapsulated 
enteric-coated microspheres.
    Some pancreatic extract drug products were marketed over-the-
counter (OTC). As part of the OTC drug review, FDA evaluated the safety 
and effectiveness of drug products used to treat exocrine pancreatic 
insufficiency. FDA's review of data and information on pancreatic 
extract drug products found significant variations in bioavailability 
among the various dosage forms and among products from different 
manufacturers of the same dosage form. Available data have shown that 
the formulation, dosage, and manufacturing process of pancreatic enzyme 
drug products have a critical effect on the safe and effective use of 
these drugs. FDA concluded that preclearance of each product to 
standardize enzyme bioactivity would be necessary. FDA also determined 
that continuous physician monitoring of patients is a collateral 
measure necessary to the safe and effective use of pancreatic enzyme 
drug products, requiring that these products be available by 
prescription only and that the products be approved through the new 
drug approval process to standardize enzyme activity (56 FR 32282, July 
15, 1991; 60 FR 20162, April 24, 1995).
    The 2004 notice reiterated FDA's determination that all pancreatic 
extract drug products are new drugs under section 201(p) of the act (21 
U.S.C. 321(p)), requiring approved NDAs under section 505 of the act 
(21 U.S.C. 355) and 21 CFR part 314. The document stated that FDA 
expects to receive only NDAs, including applications submitted under 
section 505(b)(2) of the act, for these products. To assist 
manufacturers of pancreatic extract drug products in preparing and 
submitting documentation to meet NDA requirements for the drug 
products, FDA announced the availability of a draft guidance for 
industry entitled ``Exocrine Pancreatic Insufficiency Drug Products--
Submitting NDAs'' in the Federal Register of April 28, 2004 (69

[[Page 60861]]

FR 23414). In response, FDA received a number of comments which the 
agency considered in finalizing the guidance. In the Federal Register 
of April 14, 2006 (71 FR 19524), FDA announced the availability of the 
final guidance (available on the Internet at http://www.fda.gov/cder/guidance/index.htm).
    FDA stated in the 2004 notice that pancreatic extract drug products 
are used to treat exocrine pancreatic insufficiency, a condition in 
which symptoms are due to deficient secretion of pancreatic enzymes 
(i.e., lipase, protease, amylase) essential for normal digestion and 
absorption, and no alternative drug is relied upon by the medical 
community to treat the lack of lipase, protease, and amylase caused by 
exocrine pancreatic insufficiency. The severity of the conditions 
varies from patient to patient as does the dosage requirement of 
pancreatic enzyme replacement therapy needed to relieve the symptoms of 
pancreatic insufficiency.
    Pancreatic enzyme therapy is a daily requirement for patients with 
exocrine pancreatic insufficiency and is needed for survival for many 
of these patients (e.g., cystic fibrosis patients). The appropriate 
daily dose of pancreatic enzymes must be individualized and adjusted 
when clinically indicated. To meet the needs of patients requiring 
pancreatic enzyme replacement therapy, drug products with varying 
dosage forms, enzyme content, and activity need to remain available for 
patient use. Only one product, Cotazym, sponsored by Organon, Inc., is 
the subject of an approved NDA and that product is not currently being 
marketed.
    The 2004 notice advised that FDA intended to exercise its 
enforcement discretion until April 28, 2008, as to unapproved 
pancreatic enzyme drug products that were marketed on or before April 
28, 2004. FDA determined that pancreatic enzyme drug products are 
medically necessary and, accordingly, FDA intended to exercise its 
enforcement discretion so that pancreatic extract drug products would 
remain available during the period necessary for manufacturers to 
conduct the required studies, prepare applications, and have the 
applications approved.
    This provision for the exercise of enforcement discretion applied 
only to pancreatic enzyme products marketed on or before the 
publication of the April 28, 2004, Federal Register document. The 
document stated that after April 28, 2008, any pancreatic enzyme drug 
product that is introduced or delivered for introduction into 
interstate commerce without an approved application will be subject to 
regulatory action, unless there has been a finding by FDA under a 
citizen petition submitted for that product that the product is not 
subject to the new drug requirements of the act. The deadline for 
filing a citizen petition was June 28, 2004. No one submitted a citizen 
petition in response to the 2004 notice.
    In response to the 2004 notice, a number of manufacturers of 
pancreatic extract drug products have indicated that they need an 
extension of time to obtain approved applications. The manufacturers 
contend that additional time is needed because of numerous problems 
encountered during the drug development process, predominantly 
manufacturing issues, and difficulty conducting all of the required 
studies needed for NDA filing and approval.
    The agency has carefully considered the requests and concludes that 
additional time is justified to ensure the continued availability of 
pancreatic extract drug products after April 28, 2008. As these 
pancreatic extract drugs are naturally-derived products of porcine 
origin, manufacturers must conform with currently accepted standards 
for protein therapeutic products. The justification for this extension 
is based upon chemistry, manufacturing, and control issues that 
previously have not been well-understood and have been found to be 
particularly challenging for these enzyme preparations derived from 
porcine pancreas. These issues include the following:
     Control and evaluation of variability of pancreatic source 
materials used in drug substance manufacture;
     Measurement of viral loads, viral inactivation, and 
resultant risk assessment and mitigation strategies as described in 
International Conference on Harmonisation guidance Q5A;
     Development and implementation of validated purity and 
identity drug substance and product release and stability testing 
methodologies for the very complex protein mixtures derived from 
porcine pancreas;
     Required modification and validation of the traditional 
lipase potency assay methodology based upon recent scientific studies; 
and
     Maintenance and confirmation of drug product stability 
without the use of overages to increase the dating period.
    By this notice, FDA is extending the period during which it intends 
to exercise its enforcement discretion as to certain unapproved 
pancreatic enzyme products until April 28, 2010.
    This extension of the period during which FDA intends to exercise 
its enforcement discretion applies to any manufacturer of pancreatic 
extract drug products marketed on or before publication of the 2004 
notice, if the manufacturer has an active IND for its pancreatic 
extract product on or before April 28, 2008, has submitted an NDA on or 
before April 28, 2009, and is pursuing approval of its application with 
due diligence as determined by FDA. In determining the due diligence of 
an applicant, FDA will examine the facts and circumstances of the 
applicant's actions during the drug development and review period to 
determine whether the applicant exhibited the degree of attention, 
continuous directed effort, and timeliness as may reasonably be 
expected from, and are ordinarily exercised by, an applicant during 
this period. FDA will take into consideration whether the applicant is 
conducting its clinical trials in a manner and at a rate sufficient for 
NDA submission on or before April 28, 2009, the adequacy and 
completeness of any required or necessary documents submitted by the 
applicant to FDA, the speed and thoroughness with which the applicant 
responds to any FDA requests for information or notifications of 
deficiencies, and any other relevant evidence of whether the applicant 
is making a genuine effort to meet the deadlines set out in this notice 
and obtain FDA approval for its products.
    FDA believes that establishing certain milestones will ensure that 
manufacturers are actively pursuing an NDA approval. Under those 
circumstances, extending the period of enforcement discretion as 
described in this notice will provide sufficient time for manufacturers 
to obtain approval of NDAs. Therefore, the agency does not anticipate 
that any further extensions will be needed. The agency, however, does 
not intend to exercise its enforcement discretion as described in this 
notice if the following conditions exist: (1) A person manufacturing or 
shipping an unapproved product covered by this notice is violating 
other provisions of the act or (2) there is significant new information 
related to a safety risk associated with a specific product covered by 
this notice.
    FDA intends to take regulatory action, including but not limited to 
initiating seizure, injunction, or other judicial or administrative 
proceedings, against manufacturers that are marketing unapproved 
pancreatic insufficiency drug products and are not actively pursuing 
approval. Actively pursuing approval means that the manufacturer has an 
active IND on or before April 28, 2008, and has submitted an NDA on or

[[Page 60862]]

before April 28, 2009.\1\ The agency may choose not to issue a warning 
letter or any further warning prior to taking a regulatory action 
against a firm that is marketing an unapproved exocrine pancreatic 
insufficiency drug product and not actively pursuing approval.
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    \1\ If FDA decides to take enforcement action against a firm's 
unapproved exocrine pancreatic insufficiency drug product, the 
agency may at the same time take action relating to any and all of 
the firm's other violations. For example, if a firm continues to 
market an unapproved exocrine pancreatic insufficiency drug product 
but fails to actively pursue approval, to preserve limited agency 
resources, FDA may take enforcement action relating to any and all 
of the firm's other unapproved drugs that require applications (see, 
e.g., United States v. Sage Pharmaceuticals, 210 F. 3d 475, 479-480 
(5th Cir. 2000) (permitting the agency to combine all violations of 
the act in one proceeding, rather than taking action against 
multiple violations of the act in ``piecemeal fashion'')).
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    This notice is issued under sections 502 and 505 of the act (21 
U.S.C. 352) and under authority delegated to the Assistant Commissioner 
for Policy.

    Dated: October 22, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-21082 Filed 10-25-07; 8:45 am]
BILLING CODE 4160-01-S