Exocrine Pancreatic Insufficiency Drug Products; Extension to Obtain Marketing Approval, 60860-60862 [E7-21082]
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Federal Register / Vol. 72, No. 207 / Friday, October 26, 2007 / Notices
Section Head, Health Services Research
and Rural Health Policy, University of
Nebraska; Lee Partridge, Senior Health
Policy Advisor, National Partnership for
Women and Families; Rebecca Snead,
Executive Vice President/Chief
Executive Officer, National Alliance of
State Pharmacy Associations; William
A. Steel, President, The National
Grange; Marvin Tuttle, Jr., CAE,
Executive Director and Chief Executive
Officer, Financial Planning Association;
Catherine Valenti, Chairperson and
Chief Executive Officer, Caring Voice
Coalition; and Grant Wedner, Vice
President, Partnerships and Corporate
Development, Daily Strength, Inc.
The agenda for the December 4, 2007
meeting will include the following:
• Recap of the previous (September
20, 2007) meeting.
• Medicare Enrollment, Outreach,
Education, and Partnering Activities
Update.
• Public Comment.
• Listening Session with CMS
Leadership.
• Next Steps.
Individuals or organizations that wish
to make a 5-minute oral presentation on
an agenda topic should submit a written
copy of the oral presentation to Lynne
Johnson at the address listed in the
ADDRESSES section of this notice by the
date listed in the DATES section of this
notice. The number of oral presentations
may be limited by the time available.
Individuals not wishing to make a
presentation may submit written
comments to Ms. Johnson at the address
listed in the ADDRESSES section of this
notice by the date listed in the DATES
section of this notice.
Individuals requiring sign language
interpretation or other special
accommodations should contact Ms.
Johnson at the address listed in the
ADDRESSES section of this notice by the
date listed in the DATES section of this
notice.
rmajette on PROD1PC64 with NOTICES
Authority: Sec. 222 of the Public Health
Service Act (42 U.S.C. 217a) and sec. 10(a)
of Pub. L. 92–463 (5 U.S.C. App. 2, sec. 10(a)
and 41 CFR 102–3).
(Catalog of Federal Domestic Assistance
Program No. 93.733, Medicare—Hospital
Insurance Program; and Program No. 93.774,
Medicare—Supplementary Medical
Insurance Program)
Dated: October 19, 2007.
Kerry Weems,
Acting Administrator, Centers for Medicare
& Medicaid Services.
[FR Doc. E7–21080 Filed 10–25–07; 8:45 am]
BILLING CODE 4120–01–P
VerDate Aug<31>2005
15:23 Oct 25, 2007
Jkt 214001
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.
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.
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,
SUPPLEMENTARY INFORMATION:
PO 00000
Frm 00065
Fmt 4703
Sfmt 4703
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, entericcoated tablets, and encapsulated entericcoated microspheres.
Some pancreatic extract drug
products were marketed over-thecounter (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
E:\FR\FM\26OCN1.SGM
26OCN1
rmajette on PROD1PC64 with NOTICES
Federal Register / Vol. 72, No. 207 / Friday, October 26, 2007 / Notices
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 https://
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
VerDate Aug<31>2005
15:23 Oct 25, 2007
Jkt 214001
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 wellunderstood 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
PO 00000
Frm 00066
Fmt 4703
Sfmt 4703
60861
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
E:\FR\FM\26OCN1.SGM
26OCN1
60862
Federal Register / Vol. 72, No. 207 / Friday, October 26, 2007 / Notices
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.
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
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. 2007D–0364]
Draft Guidance for Industry and Food
and Drug Administration Staff; ImpactResistant Lenses: Questions and
Answers; Availability
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
SUPPLEMENTARY INFORMATION:
Notice.
The Food and Drug
Administration (FDA) is announcing the
availability of the draft guidance
entitled ‘‘Impact-Resistant Lenses:
Questions and Answers.’’ This draft
guidance document answers
manufacturer, importer, and consumer
questions on impact-resistant lenses,
including questions on test procedures,
lens testing apparatus, record
maintenance, and exemptions to testing.
DATES: Although you can comment on
any guidance at any time (see 21 CFR
10.115(g)(5)), to ensure that the agency
considers your comment on this draft
guidance before it begins work on the
final version of the guidance, submit
written or electronic comments on the
draft guidance by January 24, 2008.
ADDRESSES: Submit written requests for
single copies of the guidance document
rmajette on PROD1PC64 with NOTICES
SUMMARY:
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’’)).
VerDate Aug<31>2005
15:23 Oct 25, 2007
entitled‘‘Impact-Resistant Lenses:
Questions and Answers’’ to the Division
of Small Manufacturers, International,
and Consumer Assistance (HFZ–220),
Center for Devices and Radiological
Health, Food and Drug Administration,
1350 Piccard Dr., Rockville, MD 20850.
Send one self-addressed adhesive label
to assist that office in processing your
request, or fax your request to 240–276–
3151. See the SUPPLEMENTARY
INFORMATION section for information on
electronic access to the guidance.
Submit written comments concerning
this draft guidance to the Division of
Dockets Management (HFA–305), Food
and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852.
Submit electronic comments to either
https://www.fda.gov/dockets/ecomments
or https://www.regulations.gov. Identify
comments with the docket number
found in brackets in the heading of this
document.
FOR FURTHER INFORMATION CONTACT: John
Stigi, Center for Devices and
Radiological Health (HFZ–220), Food
and Drug Administration, 1350 Piccard
Dr., Rockville, MD 20850, 240–276–
3150.
Jkt 214001
I. Background
Eyeglasses and sunglasses are medical
devices and are subject to device
regulations, including § 801.410 (21 CFR
801.410). This draft guidance document
revises the original guidance document
entitled ‘‘Impact-Resistant Lenses:
Questions and Answers’’ (FDA 87–
4002), issued September 1987. This
draft guidance document also contains
detailed and updated discussions of the
following: (1) Lens blanks; (2) semifinished, finished, and plano lenses; and
(3) import entry inspections.
To reduce the number of eye injuries,
eyeglasses and sunglasses must be fitted
with impact-resistant lenses capable of
withstanding the impact test described
under § 801.410(d)(2). This draft
guidance answers questions for
manufacturers, importers, and testing
laboratories on such topics as test
procedures, lens testing apparatus,
record maintenance, and exemptions to
testing.
approach may be used if such approach
satisfies the requirements of the
applicable statute and regulations.
III. Electronic Access
Persons interested in obtaining a copy
of the draft guidance may do so by using
the Internet. To receive ‘‘ImpactResistant Lenses: Questions and
Answers,’’ you may either send an email request to dsmica@fda.hhs.gov to
receive an electronic copy of the
document or send a fax request to 240–
276–3151 to receive a hard copy. Please
use the document number (23) to
identify the guidance you are
requesting.
CDRH maintains an entry on the
Internet for easy access to information
including text, graphics, and files that
may be downloaded to a personal
computer with Internet access. Updated
on a regular basis, the CDRH home page
includes device safety alerts, Federal
Register reprints, information on
premarket submissions (including lists
of approved applications and
manufacturers’ addresses), small
manufacturer’s assistance, information
on video conferencing and electronic
submissions, Mammography Matters,
and other device-oriented information.
The CDRH Web site may be accessed at
https://www.fda.gov/cdrh. A search
capability for all CDRH guidance
documents is available at https://
www.fda.gov/cdrh/guidance.html.
Guidance documents are also available
on the Division of Dockets Management
Internet site at https://www.fda.gov/
ohrms/dockets.
II. Significance of Guidance
IV. Paperwork Reduction Act of 1995
This draft guidance refers to
previously approved collections of
information found in FDA regulations.
These collections of information are
subject to review by the Office of
Management and Budget (OMB) under
the Paperwork Reduction Act of 1995
(44 U.S.C. 3501–3520). The collections
of information in 21 CFR 801.109 have
been approved under OMB Control No.
0910–0485; the collections of
information in 21 CFR 807.87 have been
approved under OMB Control No. 0910–
0120; and the collections of information
in 21 CFR part 820 have been approved
under OMB Control No. 0910–0073.
This draft guidance is being issued
consistent with FDA’s good guidance
practices regulation (21 CFR 10.115).
The draft guidance, when finalized, will
represent the agency’s current thinking
on impact-resistant lenses. It does not
create or confer any rights for or on any
person and does not operate to bind
FDA or the public. An alternative
V. Comments
Interested persons may submit to the
Division of Dockets Management (see
ADDRESSES), written or electronic
comments regarding this document.
Submit a single copy of electronic
comments or two paper copies of any
mailed comments, except that
individuals may submit one paper copy.
PO 00000
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]]>Agencies
[Federal Register Volume 72, Number 207 (Friday, October 26, 2007)]
[Notices]
[Pages 60860-60862]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E7-21082]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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 https://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
