[Federal Register Volume 76, Number 149 (Wednesday, August 3, 2011)]
[Notices]
[Pages 46820-46822]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-19566]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-N-0513]


Proposal To Refuse To Approve a Supplemental New Drug Application 
for Bromday (Bromfenac Ophthalmic Solution), 0.09%; Opportunity for a 
Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA), the Director of

[[Page 46821]]

the Center for Drug Evaluation and Research (the Center Director), is 
proposing to refuse to approve a supplemental new drug application 
submitted by ISTA Pharmaceuticals, Inc. (ISTA), for a new 2.4 
milliliter (mL) fill size for Bromday (bromfenac ophthalmic solution), 
0.09%. This notice summarizes the grounds for the proposal of the 
Center for Drug Evaluation and Research (CDER) and offers ISTA an 
opportunity to request a hearing on the matter.

DATES: Submit written requests for a hearing by September 2, 2011; 
submit data in support of the hearing request by October 3, 2011.

ADDRESSES: Submit electronic or written requests for a hearing; any 
data, information, and analyses justifying the hearing; and any other 
comments. Submit electronic requests and supporting documents to http://www.regulations.gov, or submit written requests and supporting 
documents to the Division of Dockets Management (HFA-305), Food and 
Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. 
Identify both electronic and written requests and the supporting 
documents with the docket number in brackets in the heading of this 
document.

FOR FURTHER INFORMATION CONTACT: Patrick Raulerson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6368, Silver Spring, MD 20993-0002, 301-
796-3601.

SUPPLEMENTARY INFORMATION:

I. Background

    On March 24, 2005, FDA approved ISTA's new drug application (NDA) 
21-664 to market Xibrom (bromfenac sodium ophthalmic solution), 0.09%. 
On October 16, 2010, FDA approved Bromday (bromfenac ophthalmic 
solution), 0.09%, through a supplement to NDA 21-664. Xibrom and 
Bromday are topical ophthalmic solutions supplied as sterile, aqueous 
eye drops and approved for the treatment of postoperative inflammation 
and reduction of ocular pain in patients who have undergone cataract 
extraction. Xibrom is applied to the affected eye twice daily for 2 
weeks beginning 24 hours after surgery, whereas Bromday is applied to 
the affected eye once daily beginning 1 day before surgery and 
continuing on the day of surgery and for 14 days thereafter. Xibrom 
currently is approved in 2.5 mL and 5 mL fill sizes, but, as discussed 
below, the Center is considering steps to address the safety concerns 
relating to the larger fill size. Bromday is approved in a 1.7 mL fill 
size.
    ISTA submitted supplement 15 to the Xibrom/Bromday NDA on October 
18, 2010, seeking approval to market Bromday in a 2.4 mL fill size. 
ISTA has stated--in its cover letter accompanying supplement 15 and in 
its request for an opportunity for a hearing--that patients often have 
cataract removal surgeries in both eyes, and that the 1.7 mL fill size 
does not contain a sufficient volume of product to treat two eyes for a 
full course of treatment. The Division of Anti-Infective and 
Ophthalmology Products (DAIOP) \1\ within CDER issued a complete 
response letter on February 18, 2011, determining that it could not 
approve supplement 15 in its present form, stating: (1) That the data 
submitted do not justify the need for increasing the fill volume and 
creating a new trade size; (2) that current fill volume appears to 
contain sufficient drug product for a full course of treatment; and (3) 
that a single bottle of Bromday should not be used to treat more than 
one eye in a postoperative setting. Furthermore, the February 18, 2011, 
complete response letter states that ISTA is required to resubmit the 
application or take other actions available under Sec.  314.110 (21 CFR 
314.110) (i.e., withdraw the application or request an opportunity for 
a hearing).
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    \1\ Because of a recent reorganization in the Office of 
Antimicrobial Products, the Division of Transplant and Ophthalmology 
Products is now responsible for reviewing the supplement.
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    On May 12, 2011, ISTA submitted a request for an opportunity for a 
hearing under Sec.  314.110(b)(3) on whether there are grounds under 
section 505(d) of the Federal Food, Drug, and Cosmetic Act (the FD&C 
Act) (21 U.S.C. 355(d)) for denying approval of supplement 15. 
Officials from CDER, including the Director of the Office of 
Antimicrobial Products (OAP), Dr. Edward Cox, held a telephone 
conference with ISTA on June 22, 2011, and explained that ISTA has not 
adequately justified the need for a larger fill volume, and that CDER 
believes that use of a single bottle of Bromday to treat two eyes 
unacceptably and unnecessarily increases the risk of microbial 
infection. Accordingly, CDER officials explained that, based on the 
information before them, they intended to deny approval of supplement 
15, but that they are considering whether to present the issue of fill 
sizes for postoperative topical ophthalmic products to an advisory 
committee. ISTA was asked whether it would agree to extend the 60-day 
timeframe for FDA to respond to its request for notice of an 
opportunity for a hearing (Sec.  314.110(b)(3)) until after an advisory 
committee has met, but ISTA has not agreed to such an extension. CDER 
continues to consider the issue as it relates to other postoperative 
topical ophthalmic products.

II. Proposal To Refuse To Approve Supplement 15 to NDA 21-664

    Under Sec.  314.200(a) (21 CFR 314.200(a)), this notice describes 
the reasons for the Center's proposal to refuse to approve supplement 
15 to NDA 21-664 and the proposed grounds for the order.
    ISTA submitted supplement 15 to NDA 21-664, under section 505(b)(1) 
of the FD&C Act, proposing to market Bromday in a 2.4 mL fill size. 
ISTA was required to submit, among other things, ``full reports of 
investigations which have been made to show whether or not such drug is 
safe for use'' if supplied in the proposed larger fill size (section 
505(b)(1)(A) of the FD&C Act). CDER has concluded, however, that ISTA 
did not provide sufficient data, analysis, and information to determine 
that Bromday would be safe for use if supplied in the proposed larger 
fill size.
    Specifically, CDER believes that the existing fill size is adequate 
to treat a single eye. CDER further believes that the proposed larger 
fill size, for the purpose of treating two eyes with a single bottle, 
may pose a potential risk of microbial infection associated with use of 
the product, and that ISTA has not adequately justified the need for 
that larger fill size. Microbial infection is a significant concern for 
ophthalmic products with postoperative indications, because an eye 
whose surface is compromised by a surgical procedure is more prone to 
infection than an eye with an intact cornea.\2\
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    \2\ See, for example, Yanoff, M. and Duker, Ophthalmology, 
Mosby, 2009 and Arffa, R., Grayson's Diseases of the Cornea, Mosby, 
1991.
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    The contents of the Bromday bottle could become contaminated with 
harmful bacteria if the patient accidentally causes the dropper tip to 
come into contact with any nonsterile surface. Bromday contains 
benzalkonium chloride as a preservative, but this ingredient only 
reduces, and does not eliminate, the risk of microbial contamination. 
Further, although the Bromday labeling advises that patients should 
``not touch [the] dropper tip to any surface, as this may contaminate 
the contents,'' patients may accidentally touch the dropper tip to the 
surface of the eye or the skin around the eye, which may lead to 
microbial contamination of the bottle contents. Accordingly, it is not 
uncommon that

[[Page 46822]]

initially sterile topical solutions become contaminated with bacteria 
during the course of treatment.\3\ If the product were to become 
contaminated with bacteria present on or around the surface of one eye, 
and the same bottle of product is used in both eyes, the patient could 
transmit the bacteria from one eye to the other.
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    \3\ Jokl D.H. et al., ``Bacterial Contamination of Ophthalmic 
Solutions Used in an Extended Care Facility,'' British Journal of 
Ophthalmology, 91:1308-1310, 2007.
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    The clinical studies conducted by ISTA supporting approval of 
Bromday and Xibrom specifically excluded treatment of both eyes and 
excluded the concomitant use of other nonsteroidal anti-inflammatory 
drugs. There are no data in the application supporting the safe use of 
a single bottle in more than one eye. ISTA's supplement 15 contained no 
information, data, or analysis relevant to these risks. As with any 
NDA, the sponsor bears the burden of supplying necessary data and 
information to demonstrate safety, and this includes satisfying CDER 
that a specific safety concern has been adequately addressed. 
Accordingly, the supplement lacks data, information, or analysis that 
would allay CDER's concerns about the potential risks associated with 
the larger fill size. We note that although we did not consider this 
safety issue at the time of initial approval of Xibrom and certain 
other products for which this issue may be relevant, as this issue 
develops, we also intend to take appropriate steps with respect to 
other products that raise the issue.

III. Notice of Opportunity for a Hearing

    For the reasons summarized previously, notice is given to ISTA 
Pharmaceuticals, Inc., and to all other interested persons, that the 
Center Director proposes to issue an order under section 505(d) of the 
FD&C Act refusing to approve supplement 15 to NDA 21-664 on the grounds 
that ISTA did not include data, information, or analysis sufficient to 
show that Bromday would be safe for use as labeled if supplied in the 
proposed 2.4 mL fill size. Specifically, the investigations conducted 
by ISTA in support of supplement 15 do not include adequate tests by 
all methods reasonably applicable to show whether or not Bromday would 
be safe for use as labeled if supplied in the proposed 2.4 mL fill size 
(section 505(d)(1) of the FD&C Act; Sec.  314.125(b)(2) (21 CFR 
314.125(b)(2)), and ISTA did not provide sufficient information about 
the proposed 2.4 mL fill size to permit CDER to determine whether 
Bromday is safe for use under the conditions prescribed, recommended, 
or suggested by its labeling if supplied in a 2.4 mL fill size (section 
505(d)(4) of the FD&C Act; Sec.  314.125(b)(4)).
    ISTA may request a hearing before the Commissioner of Food and 
Drugs (the Commissioner) on the Center Director's proposal to refuse to 
approve supplement 15 to NDA 21-664. If ISTA decides to seek a hearing, 
it must file: (1) A written notice of participation and request for a 
hearing (see the DATES section of this document); and (2) the studies, 
data, information, and analyses relied upon to justify a hearing (see 
the DATES section of this document), as specified in Sec.  314.200. As 
stated in Sec.  314.200(g), a request for a hearing may not rest upon 
mere allegations or denials, but must present specific facts showing 
that there is a genuine and substantial issue of fact that requires a 
hearing to resolve. The failure to request a hearing within the time 
provided and in the manner required by Sec.  314.200 constitutes a 
waiver of the opportunity to request a hearing. If a hearing request is 
not properly submitted, FDA will issue a notice refusing to approve 
supplement 15 to NDA 21-664.
    The Commissioner will grant a hearing if there exists a genuine and 
substantial issue of fact or if the Commissioner concludes that a 
hearing would otherwise be in the public interest (Sec.  
314.200(g)(6)). If a hearing is granted, it will be conducted according 
to the procedures provided in 21 CFR parts 10 through 16 and 21 CFR 
314.201.
    Paper submissions under this notice of opportunity for a hearing 
must be filed in four copies. Except for data and information 
prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 
1905, submissions may be seen in the Division of Dockets Management 
between 9 a.m. and 4 p.m., Monday through Friday, and on the Internet 
at http://www.regulations.gov. This notice is issued under section 
505(c)(1)(B) of the FD&C Act, Sec. Sec.  314.110(b)(3) and 314.200, and 
under authority delegated to the Director of CDER.

    Dated: July 28, 2011.
David Dorsey,
Acting Deputy Commissioner for Policy, Planning and Budget.
[FR Doc. 2011-19566 Filed 8-2-11; 8:45 am]
BILLING CODE 4160-01-P