[Federal Register Volume 73, Number 185 (Tuesday, September 23, 2008)]
[Notices]
[Pages 54829-54831]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-22305]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2008-N-0482]
Ophthalmic Balanced Salt Solutions for Ocular Surgical
Procedures; Enforcement Action Dates
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing its
intention to take enforcement action against unapproved ophthalmic
balanced salt solutions for irrigation of the eye during surgery and
persons\1\ who manufacture or cause the manufacture of such products or
their shipment in interstate commerce. Unapproved ophthalmic balanced
salt solutions have been associated with adverse events, some of them
leading to permanent loss of visual acuity, because of contamination of
the product or other product defects. Ophthalmic balanced salt
solutions are new drugs that require approved applications because they
are not generally recognized as safe and effective. Two firms have
approved applications to market these products. Manufacturers who wish
to market ophthalmic balanced salt solutions must obtain FDA approval
of a new drug application (NDA) or an abbreviated new drug application
(ANDA).
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\1\ A ``person'' includes individuals, partnerships,
corporations, or associations (21 U.S.C. 321(e)).
DATES: This notice is effective September 23, 2008. For information
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about enforcement dates, see SUPPLEMENTARY INFORMATION, section III.B.
ADDRESSES: All communications in response to this notice should be
identified with Docket No. FDA-2008-N-0482 and directed to the
appropriate office listed as follows:
Regarding applications under section 505(b) of Federal Food, Drug,
and Cosmetic Act (the act) (21 U.S.C. 355(b)): Division of Anti-
Infective and Ophthalmology Products, Office of New Drugs, Center for
Drug Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire
[[Page 54830]]
Ave., Bldg. 22, Silver Spring, MD 20993-0002.
Regarding applications under section 505(j) of the act: Office of
Generic Drugs, Center for Drug Evaluation and Research (HFD-600), Food
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.
All other communications: Jennifer Devine, Center for Drug
Evaluation and Research (HFD-310), Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 51, rm. 5240, Silver Spring, MD 20993-0002.
FOR FURTHER INFORMATION CONTACT: Jennifer Devine, Office of Compliance,
Division of New Drugs and Labeling Compliance, Center for Drug
Evaluation and Research (HFD-310), Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 51, rm. 5240, Silver Spring, MD 20993-0002,
301-796-3347, e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
Ophthalmic balanced salt solutions are sterile, isotonic irrigating
solutions used during surgical procedures on the eye. Prior to the
1960s, saline was the ophthalmic irrigating solution most commonly used
to replace small amounts of intraocular fluid and wet the external eye.
Balanced salt solutions for use during ocular surgery were developed in
the 1960s to provide a temporary replacement for the aqueous humor,
physiologically supporting the cornea until sufficient fluid is
replaced by the ciliary body. These products enable the conduct of
complex intraocular surgery techniques that require the replacement of
large amounts of aqueous and vitreous humor. Some of the products
marketed today are designed for use in surgical procedures of limited
duration, while others are appropriate for use in procedures of any
expected duration.
Two firms--Alcon Laboratories and Akorn, Inc. (Adorn),--have
approved applications for ophthalmic balanced salt solutions. Alcon's
approved products are marketed under the names BSS (NDA 20-742),
intended for surgeries of under 60 minutes, and BSS-plus (NDA 18-469),
intended for surgery of any expected duration. Akorn's approved
products include Balanced Salt Solution (ANDA 75-503) and Endosol Extra
(NDA 20-079). BSS, BSS-plus, and Endosol Extra have been designated as
reference listed drugs, meaning that FDA can accept ANDAs referencing
these products and filed under section 505(j) of the Federal, Food,
Drug, and Cosmetic Act (act). In addition, the agency is aware that
other firms market unapproved ophthalmic balanced salt solutions.
II. Safety Issues Associated With Ophthalmic Balanced Salt Solutions.
Serious safety concerns associated with ophthalmic balanced salt
solutions are mentioned in adverse drug events reported to the agency
and in the literature. Through January 31, 2008,\2\ FDA had received
over 300 spontaneous reports of serious adverse events associated with
all ophthalmic balanced salt solution products. Adverse events
associated with these products that have been reported to FDA include
toxic anterior segment syndrome (TASS) (a noninfectious inflammation of
the anterior segment of the eye), bacterial endophthalmitis, corneal
edema, and corneal opacity (clouding). In some cases, these adverse
events have resulted in permanent loss of visual acuity. Because the
adverse event reports sometimes include limited information on the
product used, it is often difficult to establish whether an adverse
event was caused by a particular product. In some instances, adverse
events may be the result of improperly manufactured products. Product
defects affecting the safety and performance of ophthalmic balanced
salt solutions include contaminants (such as bacteria, endotoxins,
fungi, or particulates) and variations in pH and osmolality.\3\ In
2006, for example, contamination with endotoxins of unapproved products
made by one manufacturer was associated with several hundred reports of
adverse events (both serious and nonserious), including TASS. Given the
safety concerns described previously, FDA's review of the individual
applications and application supplements for ophthalmic balanced salt
solutions, including their manufacturing methods and controls, is
essential to ensuring the safety, efficacy, and quality of these
products.
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\2\ Data in the current system date back to 1969, when FDA first
implemented an adverse event reporting system.
\3\ McDermott, M.L., H.F. Edelhauser, H.M. Hack, and R.H.S.
Langston, ``Ophthalmic Irrigants: A Current Review and Update,''
Ophthalmic Surgery, 19(10):724 733, 1988; Briggs, R.B. and D.L.
McCartney, ``Balanced Salt Solution Infusion Alert,'' Archives of
Ophthalmology, 106:718, 1988.
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III. Legal Status
A. Ophthalmic Balanced Salt Solutions Are New Drugs Requiring Approved
Applications
As described previously, ophthalmic balanced salt solution products
used for irrigation of the eye during surgery are not generally
recognized as safe and effective under section 201(p) of the act (21
U.S.C. 321(p)). Therefore, ophthalmic balanced salt solution products
are regarded as new drugs as defined in section 201(p) of the act and
are subject to the requirements of section 505 of the act. As set forth
in this notice, approval of an NDA or an ANDA under section 505 of the
act is required as a condition for manufacturing or marketing all
ophthalmic balanced salt solutions. After the dates identified in this
notice, FDA intends to take enforcement action against unapproved
ophthalmic balanced salt solutions and persons who cause the
manufacture or interstate shipment of such products. Any person who
submits an application for an ophthalmic balanced salt solution but has
not received approval must comply with this notice.
B. Notice of Enforcement Action
Although not required to do so by the Administrative Procedure Act,
the act, or any rules issued under its authority, or for any other
legal reason, FDA is providing this notice to persons who are marketing
unapproved ophthalmic balanced salt solution products that the agency
intends to take enforcement action against such products and those who
manufacture them or cause them to be manufactured or shipped in
interstate commerce.
Manufacturing or shipping unapproved ophthalmic balanced salt
solution products can result in enforcement action, including seizure,
injunction, or other judicial or administrative proceeding. Consistent
with policies described in the agency's guidance entitled ``Marketed
Unapproved Drugs--Compliance Policy Guide'' (the Marketed Unapproved
Drugs CPG), the agency does not expect to issue a warning letter or any
other further warning to firms marketing unapproved ophthalmic balanced
salt solution products prior to taking enforcement action. The agency
also reminds firms that, as stated in the Marketed Unapproved Drugs
CPG, any unapproved drug marketed without a required approved drug
application is subject to agency enforcement action at any time. The
issuance of this notice does not in any way obligate the agency to
issue similar notices or any notice in the future regarding marketed
unapproved drugs.\4\
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\4\ The agency's general approach for dealing with these
products in an orderly manner is spelled out in the Marketed
Unapproved Drugs CPG. That CPG, however, provides notice that any
product that is being marketed illegally, and the persons
responsible for causing the illegal marketing of the product, are
subject to FDA enforcement action at any time.
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[[Page 54831]]
As described in the Marketed Unapproved Drugs CPG, the agency may,
at its discretion, identify a period of time during which the agency
does not intend to initiate an enforcement action against a currently
marketed unapproved drug solely on the ground that it lacks an approved
application under section 505 of the act. With respect to unapproved
ophthalmic balanced salt solution products, the agency intends to
exercise its enforcement discretion for only a limited period of time
because ophthalmic balanced salt solution products are drugs with
potential safety risks and approved ophthalmic balanced salt solutions
for use in surgical procedures of both shorter and longer durations
have been available since 1997. Therefore, the agency intends to
implement this notice as follows.
For the effective date of this notice, see the DATES section of
this document. FDA intends to take enforcement action to enforce
section 505(a) of the act against any unapproved ophthalmic balanced
salt solution product that is not listed with the agency in full
compliance with section 510 of the act (21 U.S.C. 360) before September
22, 2008, and is manufactured, shipped, or otherwise introduced or
delivered for introduction into interstate commerce by any person on or
after September 23, 2008. FDA also intends to take enforcement action
to enforce section 505(a) of the act against any unapproved ophthalmic
balanced salt solution that is listed with FDA in full compliance with
section 510 of the act but is not being commercially used or sold\5\ in
the United States on September 22, 2008 and that is manufactured,
shipped, or otherwise introduced or delivered for introduction into
interstate commerce by any person on or after September 23, 2008.
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\5\ For the purposes of this notice, the term ``commercially
used or sold'' means that the product has been used in a business or
activity involving retail or wholesale marketing and/or sale.
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However, for unapproved ophthalmic balanced salt solution products
that are commercially used or sold in the United States, have a
National Drug Code (NDC) number listed with FDA, and are in full
compliance with section 510 of the act before September 22, 2008
(``currently marketed and listed''), the agency intends to exercise its
enforcement discretion as follows. FDA intends to initiate enforcement
action against any currently marketed and listed unapproved ophthalmic
balanced salt solution product that is manufactured on or after
November 24, 2008 or that is shipped on or after January 21, 2009.\6\
Further, FDA intends to take enforcement action against any person who
manufactures or ships such products after these dates. Any person who
has submitted or submits an application for an ophthalmic balanced salt
solution product but has not received approval must comply with this
notice.
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\6\ If FDA finds it necessary to take enforcement action against
a product covered by this notice, the agency may take action
relating to all of the defendant's other violations of the act at
the same time. For example, if a firm continues to manufacture or
market a product covered by this notice after the applicable
enforcement date has passed, to preserve limited agency resources,
FDA may take enforcement action relating to all of the firm's
unapproved drugs that require applications at the same time (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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The agency, however, does not intend to exercise its enforcement
discretion as outlined previously if the following apply: (1) A
manufacturer or distributor of an unapproved ophthalmic balanced salt
solution product covered by this notice is violating other provisions
of the act, including but not limited to, violations related to FDA's
current good manufacturing practices, adverse drug event reporting,
labeling or misbranding requirements or (2) it appears that a firm, in
response to this notice, increases its manufacture or interstate
shipment of ophthalmic balanced salt solution products above its usual
volume during these periods.
Nothing in this notice, including FDA's intent to exercise its
enforcement discretion, alters any person's liability or obligations in
any other enforcement action, or precludes the agency from initiating
or proceeding with enforcement action in connection with any other
alleged violation of the act, whether or not related to an unapproved
drug product covered by this notice. Similarly, a person who is or
becomes enjoined from marketing unapproved drugs may not resume
marketing of unapproved ophthalmic balanced salt solution products
based on FDA's exercise of enforcement discretion that is set forth in
this notice.
Drug manufacturers and distributors should be aware that the agency
is exercising its enforcement discretion as described previously only
in regard to ophthalmic balanced salt solution products that are
marketed under an NDC number listed with the agency in full compliance
with section 510 of the act before September 22, 2008. As previously
stated, unapproved ophthalmic balanced salt solution products that are
currently marketed but not listed with the agency on the date of this
notice must, as of the effective date of this notice, have approved
applications prior to their shipment in interstate commerce. Moreover,
any person or firm that has submitted or submits an application but has
yet to receive approval for such products is still responsible for full
compliance with this notice.
C. Discontinued Products
Some firms may have previously discontinued the manufacturing or
distribution of products covered by this notice without removing them
from the listing of their products under section 510(j) of the act.
Other firms may discontinue manufacturing or marketing listed products
in response to this notice. Firms that wish to notify the agency of
product discontinuation should send a letter, signed by the firm's
chief executive officer, fully identifying the discontinued product(s),
including NDC number(s), and stating that the product(s) has (have)
been discontinued. The letter should be sent to Jennifer Devine (see
ADDRESSES). Firms should also update the listing of their products
under section 510(j) of the act to reflect discontinuation of
unapproved ophthalmic balanced salt solution products. FDA plans to
rely on its existing records, including drug listing records, or other
available information when it targets violations for enforcement
action.
This notice is issued under the Federal Food, Drug, and Cosmetic
Act (sections 502 and 505 (21 U.S.C. 352)) and under authority
delegated to the Deputy Commissioner for Policy under section 1410.10
of the FDA Staff Manual Guide.
Dated: September 8, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-22305 Filed 9-22-08; 8:45 am]
BILLING CODE 4160-01-S