[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]
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