[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