Proposal To Refuse To Approve a Supplemental New Drug Application for Bromday (Bromfenac Ophthalmic Solution), 0.09%; Opportunity for a Hearing, 46820-46822 [2011-19566]
Download as PDF
<![CDATA[
46820
Federal Register / Vol. 76, No. 149 / Wednesday, August 3, 2011 / Notices
the information will have practical
utility; (2) the accuracy of FDA’s
estimate of the burden of the proposed
collection of information, including the
validity of the methodology and
assumptions used; (3) ways to enhance
the quality, utility, and clarity of the
information to be collected; and (4)
ways to minimize the burden of the
collection of information on
respondents, including through the use
of automated collection techniques,
when appropriate, and other forms of
information technology.
Guidance for Industry: Notification of a
Health Claim or Nutrient Content Claim
Based on an Authoritative Statement of
a Scientific Body—(OMB Control
Number 0910–0374)—Extension
Section 403(r)(2)(G) and (r)(3)(C) of
the Federal Food, Drug and Cosmetic
Act (the FD&C Act) (21 U.S.C.
343(r)(2)(G) and (r)(3)(C)), as amended
by the FDA Modernization Act of 1997,
provides that any person may market a
food product whose label bears a
nutrient content claim or a health claim
that is based on an authoritative
statement of a scientific body of the U.S.
Government or the National Academy of
Sciences (NAS). Under this section of
the FD&C Act, a person that intends to
use such a claim must submit a
notification of its intention to use the
claim 120 days before it begins
marketing the product bearing the
claim. In the Federal Register of June
11, 1998 (63 FR 32102), FDA announced
the availability of a guidance entitled
‘‘Guidance for Industry: Notification of
a Health Claim or Nutrient Content
Claim Based on an Authoritative
Statement of a Scientific Body.’’ The
guidance provides the Agency’s
interpretation of terms central to the
submission of a notification and the
Agency’s views on the information that
should be included in the notification.
The Agency believes that the guidance
will enable persons to meet the criteria
for notifications that are established in
section 403(r)(2)(G) and (r)(3)(C) of the
FD&C Act. In addition to the
information specifically required by the
FD&C Act to be in such notifications,
the guidance states that the notifications
should also contain information on
analytical methodology for the nutrient
that is the subject of a claim based on
an authoritative statement. FDA intends
to review the notifications the Agency
receives to ensure that they comply with
the criteria established by the FD&C Act.
FDA estimates the burden of this
collection of information as follows:
TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN 1
Number of
responses per
respondent
Number of
respondents
Section of the FD&C Act
Average
burden per
response
Total annual
responses
Total hours
403(r)(2)(G) (nutrient content claims) ..................................
403(r)(2)(C) (health claims) .................................................
Guidance for Notifications ....................................................
1
1
2
1
1
1
1
1
2
250
450
1
250
450
2
Total ..............................................................................
........................
........................
........................
........................
702
srobinson on DSK4SPTVN1PROD with NOTICES
1 There
are no capital costs or operating and maintenance costs associated with this collection of information.
These estimates are based on FDA’s
experience with health claims, nutrient
content claims, and other similar
notification procedures that fall under
our jurisdiction. To avoid estimating the
number of respondents as zero, the
Agency estimates that there will be one
or fewer respondents annually for
nutrient content claim and health claim
notifications. FDA estimates that it will
receive one nutrient content claim
notification and one health claim
notification per year over the next 3
years.
Section 403(r)(2)(G) and (r)(3)(C) of
the FD&C Act requires that the
notification include the exact words of
the claim, a copy of the authoritative
statement, a concise description of the
basis upon which such person relied for
determining that this is an authoritative
statement as outlined in the FD&C Act,
and a balanced representation of the
scientific literature relating to the
relationship between a nutrient and a
disease or health-related condition to
which a health claim refers or to the
nutrient level to which the nutrient
content claim refers. This balanced
representation of the scientific literature
is expected to include a bibliography of
the scientific literature on the topic of
VerDate Mar<15>2010
16:24 Aug 02, 2011
Jkt 223001
the claim and a brief, balanced account
or analysis of how this literature either
supports or fails to support the
authoritative statement.
Since the claims are based on
authoritative statements of a scientific
body of the U.S. Government or NAS,
FDA believes that the information that
is required by the FD&C Act to be
submitted with a notification will be
readily available to a respondent.
However, the respondent will have to
collect and assemble that information.
Based on communications with firms
that have submitted notifications, FDA
estimates that 1 respondent will take
250 hours to collect and assemble the
information required by the statute for
a nutrient content claim notification.
Further, FDA estimates that 1
respondent will take 450 hours to
collect and assemble the information
required by the statute for a health claim
notification.
Under the guidance, notifications
should also contain information on
analytical methodology for the nutrient
that is the subject of a claim based on
an authoritative statement. The
guidance applies to both nutrient
content claim and health claim
notifications. FDA has determined that
PO 00000
Frm 00100
Fmt 4703
Sfmt 4703
this information should be readily
available to a respondent and, thus, the
Agency estimates that it will take a
respondent 1 hour to incorporate the
information into each notification. The
Agency expects there will be 2
respondents for a total of 2 hours.
Dated: July 28, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011–19601 Filed 8–2–11; 8:45 am]
BILLING CODE 4160–01–P
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.
The Food and Drug
Administration (FDA), the Director of
SUMMARY:
E:\FR\FM\03AUN1.SGM
03AUN1
Federal Register / Vol. 76, No. 149 / Wednesday, August 3, 2011 / Notices
srobinson on DSK4SPTVN1PROD with NOTICES
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 https://
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.
VerDate Mar<15>2010
16:24 Aug 02, 2011
Jkt 223001
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 § 314.110 (21 CFR
314.110) (i.e., withdraw the application
or request an opportunity for a hearing).
On May 12, 2011, ISTA submitted a
request for an opportunity for a hearing
under § 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
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.
PO 00000
Frm 00101
Fmt 4703
Sfmt 4703
46821
(§ 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 § 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
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
2 See, for example, Yanoff, M. and Duker,
Ophthalmology, Mosby, 2009 and Arffa, R.,
Grayson’s Diseases of the Cornea, Mosby, 1991.
E:\FR\FM\03AUN1.SGM
03AUN1
46822
Federal Register / Vol. 76, No. 149 / Wednesday, August 3, 2011 / Notices
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.
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.
srobinson on DSK4SPTVN1PROD with NOTICES
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; § 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; § 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 § 314.200. As stated in
§ 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 § 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 (§ 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
https://www.regulations.gov. This notice
is issued under section 505(c)(1)(B) of
the FD&C Act, §§ 314.110(b)(3) and
314.200, and under authority delegated
to the Director of CDER.
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Dated: July 28, 2011.
David Dorsey,
Acting Deputy Commissioner for Policy,
Planning and Budget.
National Institutes of Health
[FR Doc. 2011–19566 Filed 8–2–11; 8:45 am]
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.
VerDate Mar<15>2010
16:24 Aug 02, 2011
Jkt 223001
BILLING CODE 4160–01–P
PO 00000
Frm 00102
Fmt 4703
Sfmt 4703
National Institutes of Health
Center for Scientific Review; Notice of
Closed Meeting
Pursuant to section 10(d) of the
Federal Advisory Committee Act, as
amended (5 U.S.C. App.), notice is
hereby given of the following meeting.
The meeting will be closed to the
public in accordance with the
provisions set forth in sections
552b(c)(4) and 552b(c)(6), Title 5 U.S.C.,
as amended. The grant applications and
the discussions could disclose
confidential trade secrets or commercial
property such as patentable material,
and personal information concerning
individuals associated with the grant
applications, the disclosure of which
would constitute a clearly unwarranted
invasion of personal privacy.
Name of Committee: Center for Scientific
Review Special Emphasis Panel, Member
Conflict: Physiological Chemistry and
Genomics.
Date: August 15, 2011.
Time: 1 p.m. to 2 p.m.
Agenda: To review and evaluate grant
applications.
Place: National Institutes of Health, 6701
Rockledge Drive, Bethesda, MD 20892
(Telephone Conference Call).
Contact Person: Ronald Adkins, PhD,
Scientific Review Officer, Center for
Scientific Review, National Institutes of
Health, 6701 Rockledge Drive, Room 2206,
MSC 7890, Bethesda, MD 20892, 301–495–
4511, ronald.adkins@nih.gov.
This notice is being published less than 15
days prior to the meeting due to the timing
limitations imposed by the review and
funding cycle.
(Catalogue of Federal Domestic Assistance
Program Nos. 93.306, Comparative Medicine;
93.333, Clinical Research, 93.306, 93.333,
93.337, 93.393–93.396, 93.837–93.844,
93.846–93.878, 93.892, 93.893, National
Institutes of Health, HHS)
Dated: July 28, 2011.
Jennifer S. Spaeth,
Director, Office of Federal Advisory
Committee Policy.
[FR Doc. 2011–19695 Filed 8–2–11; 8:45 am]
BILLING CODE 4140–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
National Eye Institute; Notice of Closed
Meetings
Pursuant to section 10(d) of the
Federal Advisory Committee Act, as
amended (5 U.S.C. App.), notice is
hereby given of the following meetings.
E:\FR\FM\03AUN1.SGM
03AUN1
]]>Agencies
[Federal Register Volume 76, Number 149 (Wednesday, August 3, 2011)]
[Notices]
[Pages 46820-46822]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-19566]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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 https://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).
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\2\ See, for example, Yanoff, M. and Duker, Ophthalmology,
Mosby, 2009 and Arffa, R., Grayson's Diseases of the Cornea, Mosby,
1991.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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 https://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
