[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