81 FR 71741 - Kremers Urban Pharmaceuticals Inc.; Proposal To Withdraw Approval of an Abbreviated New Drug Application for Extended-Release Methylphenidate Tablets; Opportunity for a Hearing

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 201 (October 18, 2016)

Page Range		71741-71745
FR Document		2016-25092

The Food and Drug Administration's (FDA or Agency) Center for Drug Evaluation and Research (CDER) is proposing to withdraw approval of an abbreviated new drug application (ANDA) for methylphenidate hydrochloride (HCl) extended-release (ER) tablets and is announcing an opportunity for the holder of the ANDA to request a hearing on this proposal.

Federal Register, Volume 81 Issue 201 (Tuesday, October 18, 2016)

[Federal Register Volume 81, Number 201 (Tuesday, October 18, 2016)]
[Notices]
[Pages 71741-71745]
From the Federal Register Online [www.thefederalregister.org]
[FR Doc No: 2016-25092]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-N-3120]

Kremers Urban Pharmaceuticals Inc.; Proposal To Withdraw Approval
of an Abbreviated New Drug Application for Extended-Release
Methylphenidate Tablets; Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration's (FDA or Agency) Center for
Drug Evaluation and Research (CDER) is proposing to withdraw approval
of an abbreviated new drug application (ANDA) for methylphenidate
hydrochloride (HCl) extended-release (ER) tablets and is announcing an
opportunity for the holder of the ANDA to request a hearing on this
proposal.

DATES: Kremers Urban Pharmaceuticals Inc., may submit a request for a
hearing by November 17, 2016. Submit all data, information, and
analyses upon which the request for a hearing relies by December 19,
2016. Submit written or electronic comments by December 19, 2016.

ADDRESSES: The request for a hearing may be submitted by Kremers Urban
Pharmaceuticals Inc., by either of the following methods:

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments to submit your request
for a hearing. Your request for a hearing submitted electronically to
http://www.regulations.gov, including any attachments to the request
for hearing, will be posted to the docket unchanged.

Written/Paper Submissions

Submit written/paper submissions as follows:
Mail/Hand delivery/Courier (for written/paper request for
a hearing): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Because your request for a hearing will be made public, you are
solely responsible for ensuring that your request does not include any
confidential information that you may not wish to be publicly posted,
such as confidential business information, e.g., a manufacturing
process. The request for a hearing must include the Docket No. FDA-
2016-N-3120 for ``Kremers Urban Pharmaceuticals Inc.; Proposal to
Withdraw Approval of an Abbreviated New Drug Application for Extended-
Release Methylphenidate Tablets; Opportunity for a Hearing.'' The
request for a hearing will be placed in the docket and publicly
viewable at http://www.regulations.gov or at the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday.
Kremers Urban Pharmaceutical Inc., may submit all data and analysis
upon which the request for a hearing relies in the same manner as the
request for a hearing except as follows:
Confidential Submissions--To submit any data and analyses
with confidential information that you do not wish to be made publicly
available, submit your data and analyses only as a written/paper
submission. You should submit two copies total of all data and
analysis. One copy will include the information you claim to be
confidential with a heading or cover note that states ``THIS DOCUMENT
CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will review this copy,
including the claimed confidential information, in its consideration of
any decisions on this matter. The second copy, which will have the
claimed information redacted/blacked out, will be available for public
viewing and posted on http://www.regulations.gov or available at the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday. Submit both copies to the Division of Dockets
Management. Any information marked as ``confidential'' will not be
disclosed except in accordance with 21 CFR 10.20 and other applicable
disclosure law.
Comments Submitted by Other Interested Parties: For all comments
submitted by other interested parties you may submit comments as
follows:

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the

[[Page 71742]]

instructions for submitting comments. Comments submitted electronically
to http://www.regulations.gov, including attachments, will be posted to
the docket unchanged. Because your comment will be made public, you are
solely responsible for ensuring that your comment does not include any
confidential information that you or a third party may not wish to be
posted, such as medical information, your or anyone else's Social
Security number, or confidential business information, such as a
manufacturing process. Please note that if you include your name,
contact information, or other information that identifies you in the
body of your comments, that information will be posted on http://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

Submit written/paper submissions as follows:
Mail/Hand delivery/Courier (for written/paper
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Division of
Dockets Management, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2016-N-3120 for ``Kremers Urban Pharmaceuticals Inc.; Proposal to
Withdraw Approval of an Abbreviated New Drug Application for Extended-
Release Methylphenidate Tablets; Opportunity for a Hearing.'' Received
comments will be placed in the docket and, except for those submitted
as ``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9
a.m. and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on http://www.regulations.gov.
Submit both copies to the Division of Dockets Management. If you do not
wish your name and contact information to be made publicly available,
you can provide this information on the cover sheet and not in the body
of your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Division of Dockets Management, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Maryll W. Toufanian, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 75, Rm. 1716, Silver Spring, MD 20993-0002, 240-
402-7944.

SUPPLEMENTARY INFORMATION:

I. Background

A. Approval of ANDA Referencing CONCERTA

CONCERTA (methylphenidate HCl) ER tablet is the subject of new drug
application (NDA) 021121, held by Janssen Pharmaceuticals, Inc., and
was approved on August 1, 2000. CONCERTA is a central nervous system
stimulant intended for the treatment of attention deficit hyperactivity
disorder in children 6 years of age and older, adolescents, and adults
up to the age of 65. CONCERTA is a multiphasic modified-release product
that is formulated to release a bolus of methylphenidate, resulting in
an initial rapid rise in plasma concentration comparable to the effect
of an immediate-release (IR) methylphenidate formulation, followed by
sustained delivery later in the day, thereby allowing for once daily
dosing. The relative bioavailability of CONCERTA in adults is
comparable to IR methylphenidate administered three times daily, but
the CONCERTA formulation minimizes the fluctuations between peak and
trough concentrations associated with IR methylphenidate administered
three times daily. CONCERTA is approved for the following strengths: 18
milligrams (mg), 27 mg, 36 mg, and 54 mg. CONCERTA was approved based
on, among other things, safety studies and adequate and well-controlled
clinical efficacy studies showing that the product is safe for its
intended uses and has the effects claimed for it.
FDA's Office of Generic Drugs (OGD) approved ANDA 091695, held by
Kremers Urban Pharmaceuticals Inc. (Kremers),\1\ for a generic version
of CONCERTA pursuant to the requirements of section 505(j) of the
Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 355(j))
and FDA's implementing regulations. OGD approved ANDA 091695 on July 9,
2013, for the 18-mg and 27-mg strengths and approved the 36-mg and 54-
mg strengths on September 23, 2013.
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\1\ The ANDA applicant was originally Kudco Ireland, Ltd.;
subsequently, all rights to the ANDA were transferred to Kremers.
For ease of reference, throughout this document, the ANDA holder
will be referred to as Kremers.
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At the time of approval, FDA determined that the ANDA included data
sufficient to demonstrate the bioequivalence of the Kremers product to
CONCERTA. The bioequivalence (BE) testing and data submitted in the
ANDA conformed to recommendations provided in a draft guidance for
industry on ``Methylphenidate hydrochloride.'' The draft guidance was
issued on September 14, 2012 (77 FR 56851), and provided information
and recommendations for establishing bioequivalence to CONCERTA that
reflected FDA's understanding, at that time, of how to evaluate the
pharmacokinetic (PK) properties of CONCERTA to support a demonstration
of bioequivalence. The demonstration of bioequivalence was necessary to
the approval of Kremers' product. Unlike CONCERTA, Kremers was not
required to submit clinical studies to demonstrate the safety and
effectiveness of its product. Instead, Kremers' ANDA was approved based
on a finding that the product was bioequivalent to CONCERTA and met the
other requirements for ANDA approval in section 505(j) of the FD&C Act.

[[Page 71743]]

B. Concerns About Insufficient Therapeutic Effect

1. ANDA 091695
Kremers began marketing the 18-mg and 27-mg strengths of its
generic version of CONCERTA in August 2013 and began marketing the 36-
mg and 54-mg strengths in October 2013. OGD routinely monitors all
newly approved ANDA products for safety and efficacy concerns as they
penetrate the marketplace, including the monitoring of adverse events
reported to the Agency. Beginning in September 2013, the FDA Adverse
Event Reporting System (FAERS) received reports describing insufficient
therapeutic effect of the Kremers product, particularly reports of
insufficient effect later in the day.\2\ These reports indicated
potential therapeutic inequivalence of the Kremers product as compared
to CONCERTA. In light of the reports received, CDER began an
investigation of the Kremers product.\3\
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\2\ In addition to reports submitted to FAERS, FDA received
complaints related to therapeutic failure from multiple other
sources, including FDA's Detroit District Office and a director of
anesthesia support at a children's hospital.
\3\ FDA investigated ANDA 091695 concurrently with ANDA 202608,
which is another generic product referencing CONCERTA, held by
Mallinckrodt Pharmaceuticals. Elsewhere in this issue of the Federal
Register, FDA is proposing to withdraw approval of ANDA 202608.
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2. CDER's Investigations
a. Tracked safety issue (TSI). CDER began its investigation of the
Kremers product with a reevaluation of the data and information
submitted in the application to demonstrate bioequivalence; an
assessment of FAERS data; and a comparative analysis of the design,
composition, dissolution, and active pharmaceutical ingredient (API)
degradation of the generic product as compared to CONCERTA. The
findings of these investigations led to the initiation of a TSI. In
general, when CDER staff suspect that a potential safety issue could be
significant, a TSI is opened and an interdisciplinary team assesses the
safety issue, reevaluates the risk-benefit profile of the drug, and
determines the need for further action. CDER considers postmarketing
safety issues to be significant for tracking purposes if those issues
have the potential to lead to, among other things, withdrawal of FDA
approval of a drug application.
The initial meeting of the TSI Committee occurred in December 2013.
The TSI Committee was composed of CDER physicians, pharmacists, and
chemists, as well as other CDER scientists and experts, who carefully
reviewed all of the data and information related to the Kremers
product. Key information reviewed and discussed by the TSI Committee is
summarized as follows.
Adverse event reports. An analysis was conducted of FAERS
reports, along with additional data regarding therapeutic failure
provided by Kremers and Janssen (CONCERTA's NDA holder), to assess,
among other things, the reporting rate for therapeutic failure for the
Kremers product as compared to the reporting rate for therapeutic
failure for the authorized generic version of CONCERTA marketed by
Actavis plc.\4\ The reporting rate for therapeutic failure was found to
be 67 per 100,000 person-years of exposure for the Kremers product and
7.0 per 100,000 person-years of exposure for the authorized generic
drug product.
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\4\ Authorized generic drug is defined in section 505(t) of the
FD&C Act and in Sec. 314.3(b) (21 CFR 314.3(b)) (Authorized generic
drug means a listed drug, as defined in Sec. 314.3(b), that has
been approved under section 505(c) of the FD&C Act and is marketed,
sold, or distributed directly or indirectly to retail class of trade
with labeling, packaging (other than repackaging as the listed drug
in blister packs, unit doses, or similar packaging for use in
institutions), product code, labeler code, trade name, or trademark
that differs from that of the listed drug.). A listed drug is a new
drug product that has an effective approval under section 505(c) of
the FD&C Act for safety and effectiveness, or under section 505(j),
that has not been withdrawn or suspended under section 505(e)(1)
through (e)(5) or (j)(5) of the FD&C Act, and that has not been
withdrawn from sale for what FDA determines are reasons of safety or
effectiveness (Sec. 314.3(b)). Listed drugs are identified as drugs
with an effective approval in FDA's current edition of ``Approved
Drug Products With Therapeutic Equivalence Evaluations'' (commonly
referred to as the ``Orange Book'') (Id.). A list of currently
available authorized generic drugs is available at http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm126391.htm. (FDA has
verified the Web site addresses, as of the date this document
publishes in the Federal Register, but Web sites are subject to
change over time.)
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Product composition. The Kremers product and CONCERTA were
tested in FDA laboratories to evaluate differences in drug design,
composition, stability, and dissolution. The testing identified
concerns with API degradation and in vivo dissolution, which could
result in differences in drug release. These differences could, in
turn, result in differences in therapeutic effect of the generic
product compared to CONCERTA.
BE data. A review and reanalysis were conducted of the
data that were submitted in the ANDA to establish bioequivalence to
CONCERTA. In particular, an outlier analysis was performed on the BE
data to evaluate the difference in product absorption between the
Kremers product and CONCERTA across various PK sampling time-points.
The analysis showed that the greatest difference in product absorption
between the Kremers product and CONCERTA occurred at 8 hours post-
dosing under fasting conditions.
The TSI was concluded in June 2014. Based on the information
considered, the TSI Committee determined that the Kremers product may
deliver methylphenidate into the body at a slower rate than CONCERTA
during the time period of 7 to 12 hours post-dosing, and therefore, the
product may not be bioequivalent or therapeutically equivalent to
CONCERTA. Following the TSI Committee's investigation, CDER concluded
that the therapeutic equivalence (TE) rating for the Kremers product in
FDA's ``Approved Drug Products With Therapeutic Equivalence
Evaluations'' (commonly referred to as the ``Orange Book'') should be
changed from AB to BX to indicate that the data are insufficient to
determine that the Kremers product is therapeutically equivalent to
CONCERTA.\5\
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\5\ In the Orange Book, FDA ``classifies as therapeutically
equivalent those products that meet the following general criteria:
(1) [T]hey are approved as safe and effective; (2) they are
pharmaceutical equivalents in that they (a) contain identical
amounts of the same active drug ingredient in the same dosage form
and route of administration, and (b) meet compendial or other
applicable standards of strength, quality, purity, and identity; (3)
they are bioequivalent in that (a) they do not present a known or
potential bioequivalence problem, and they meet an acceptable in
vitro standard, or (b) if they do present such a known or potential
problem, they are shown to meet an appropriate bioequivalence
standard; (4) they are adequately labeled; (5) they are manufactured
in compliance with Current Good Manufacturing Practice regulations''
(Orange Book Preface at vii, available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM071436.pdf. (FDA has
verified the Web site addresses, as of the date this document
publishes in the Federal Register, but Web sites are subject to
change over time.)).
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On November 6, 2014 (79 FR 65978), CDER issued a revised draft
guidance for industry on ``Bioequivalence Recommendations for CONCERTA
(Methylphenidate Hydrochloride) Extended-Release Tablets'' (revised
draft BE guidance) (Ref. 1)), with recommendations for establishing
bioequivalence to CONCERTA that reflect CDER's refined understanding of
the relationship between the PK profile of CONCERTA and its therapeutic
effect. The revised draft BE guidance is available on FDA's Web site
and will be placed in Docket No. FDA-2016-N-3120.
On November 12, 2014, representatives from OGD and other CDER
offices notified Kremers by telephone of CDER's concerns regarding its
generic product. OGD explained that

[[Page 71744]]

the TE rating for the product would be changed from AB to BX
immediately. OGD requested that Kremers: (1) Voluntarily withdraw its
product from the market under Sec. 314.150(d) (21 CFR 314.150(d)) and
request that FDA withdraw approval of the ANDA or (2) confirm
bioequivalence of its product within 6 months, consistent with the
recommendations in the revised draft BE guidance issued on November 6,
2014. Kremers declined to voluntarily withdraw its product from the
market. In June 2015, Kremers submitted data from new BE studies that
were conducted in accordance with the design recommended in the revised
draft BE guidance; these data are discussed in section I.B.2.b.
b. Post-TSI investigations. After communicating CDER's concerns to
Kremers about its methylphenidate product and changing the TE rating
for the product to BX, CDER continued to evaluate data and information
related to the bioequivalence of Kremers' product to CONCERTA. CDER
reanalyzed the BE data originally submitted in Kremers' ANDA in
accordance with the recommendations provided in the November 6, 2014,
revised draft BE guidance. The reanalysis showed that the 54-mg Kremers
product on which the in vivo BE testing was conducted does not provide
the same extent of methylphenidate exposure as CONCERTA during the 7-
to 12-hour post-dosing time period under fasting conditions and 8- to
12-hour post-dosing time period under fed conditions. Specifically, the
90 percent confidence interval (CI) of the geometric mean ratio of the
test product (Kremer's) to reference product (CONCERTA) for
AUC7-12 \6\ under fasting conditions (at 73.06 percent to
85.92 percent) falls outside of the 80 percent to 125 percent BE
acceptance range (Ref. 3). The 90 percent CI of the geometric mean
ratio of the test to reference product for AUC8-12 \7\ under
fed conditions (at 76.19 percent to 83.09 percent) also falls outside
of the 80 percent to 125 percent BE acceptance range. The lower level
of methylphenidate exposure compared to CONCERTA at 7 to 12 hours
(under fasting conditions) and 8 to 12 hours (under fed conditions)
after tablet administration is consistent with the reports received
describing lack of therapeutic effect later in the day.
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\6\ The area under the plasma concentration-time curve (AUC) is
used to evaluate the extent of absorption of a drug (see section
505(j)(7)(B) of the FD&C Act). AUC7-12 captures the
extent of absorption from 7 to 12 hours post-dosing (see, e.g., the
draft guidance for industry entitled ``Bioequivalence Studies With
Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA'' (Ref.
2)).
\7\ AUC8-12 captures the extent of absorption from 8
to 12 hours post-dosing.
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In light of the close relationship between the PK profile and
therapeutic effect of methylphenidate products (Refs. 4 and 5), FDA
performed a clinical trial simulation based on the BE data submitted in
the ANDA to predict the potential clinical significance of the
difference in PK profile, i.e., methylphenidate absorption, of the
Kremers product compared to CONCERTA. The simulation suggested some
potential difference in effect between Kremers' product and CONCERTA
after 6 hours post-dosing. The greatest mean percentage reduction in
efficacy for the Kremers product was predicted to be 13.12 percent at
10 hours post-dosing, with individual changes ranging from a 37.76
percent decrease and an 18.22 percent increase in efficacy compared
with CONCERTA.
In addition to a reanalysis of data submitted in the original ANDA,
FDA also reviewed BE data submitted by Kremers in June 2015. Kremers
conducted fully replicated BE studies under fasting and fed conditions
using the 54-mg strength product, in accordance with the
recommendations in the revised draft BE guidance. FDA independently
analyzed the data submitted and found that Kremers' product failed to
meet the criteria for bioequivalence under fed conditions because it
did not provide the same extent of methylphenidate exposure as CONCERTA
during the 8- to 12-hour time period after administration.
Finally, FDA analyzed FAERS reports from February 2014 to May 2015.
The types and quality of reports received by FDA during that time
period were very similar to the FAERS reports received before the
change in TE rating. The reports continued to contain specific
complaints describing the lack of therapeutic effect during the latter
part of the day.
A memorandum describing in detail the information considered
following the TSI and explaining CDER's determination will be placed in
Docket No. FDA-2016-N-3120 (Ref. 6).

II. Conclusions and Proposed Action

An NDA (or reference listed drug) applicant must submit ``full
reports of investigations'' to show that the drug for which the
applicant is seeking approval is safe and effective. In other words,
reference listed drugs must meet the safety and substantial evidence of
effectiveness standard (see section 505(b)(1), (b)(2), (c), and (d) of
the FD&C Act). A reference listed drug applicant can meet the standard
by conducting its own clinical studies (stand-alone application) or
relying, in part, on the Agency's previous finding of safety and/or
effectiveness or literature (a 505(b)(2) application). An ANDA
applicant does not submit independent clinical studies to demonstrate
safety and effectiveness. Rather, an ANDA applicant relies on the
Agency's previous finding of safety and effectiveness for the reference
listed drug and is required to meet other requirements, such as
demonstrating bioequivalence to the reference listed drug to support
approval. In the absence of information showing bioequivalence between
the generic drug at issue and the reference listed drug, there is no
basis for concluding that the Agency's finding of safety and efficacy
(or substantial evidence of effectiveness) supporting approval of the
reference listed drug likewise supports approval of the generic drug.
Therefore, based on all available data and information, notice is
given to Kremers and to all other interested persons that the Director
of CDER proposes to issue an order, under section 505(e)(3) of the FD&C
Act and Sec. 314.150(a)(2)(iii), withdrawing approval of ANDA 091695
and all amendments and supplements to it on the grounds that, on the
basis of new information, evaluated together with the evidence
available when the application was approved, there is a lack of
substantial evidence that the drug will have the effect it is
represented to have under the conditions of use prescribed,
recommended, or suggested in its labeling.

III. Hearing Procedures

In accordance with section 505(e) of the FD&C Act, the applicant is
hereby provided an opportunity to request a hearing to show why
approval of ANDA 091695 should not be withdrawn and an opportunity to
raise, for administrative determination, all issues relating to the
legal status of the drug product covered by this application.
An applicant who decides to seek a hearing must file the following:
(1) A written notice of participation and request for hearing (see
DATES) and (2) the data, information, and analyses relied on to
demonstrate that there is a genuine and substantial issue of fact that
requires a hearing to resolve (see DATES). Any other interested person
may also submit comments on this notice. The procedures and
requirements governing this notice of opportunity for a hearing, notice
of participation and request for a hearing, the information and
analyses to justify a hearing, other comments, and a grant or denial of
a hearing are contained in Sec. 314.200 (21 CFR 314.200) and in 21 CFR
part 12.

[[Page 71745]]

The failure of an applicant to file a timely written notice of
participation and request for a hearing, as required by Sec. 314.200,
constitutes an election by that applicant not to avail itself of the
opportunity for a hearing concerning CDER's proposal to withdraw
approval of the application and constitutes a waiver of any contentions
concerning the legal status of the drug product. FDA will then withdraw
approval of the application, and the drug product may not thereafter be
lawfully introduced or delivered for introduction into interstate
commerce. Any new drug product introduced or delivered for introduction
into interstate commerce without an approved application is subject to
regulatory action at any time.
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. If a
request for a hearing is not complete or is not supported, the
Commissioner of Food and Drugs will enter summary judgment against the
person who requests the hearing, making findings and conclusions, and
denying a hearing.
All submissions under this notice of opportunity for a hearing must
be filed in two copies. Except for data and information prohibited from
public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 1905, the
submissions may be seen in the Division of Dockets Management (see
ADDRESSES) between 9 a.m. and 4 p.m., Monday through Friday, and will
be posted to the docket at http://www.regulations.gov.
This notice is issued under section 505(e) of the FD&C Act and
under the authority delegated to the Director of CDER by the
Commissioner of Food and Drugs.

IV. References

The following references are on display in the Division of Dockets
Management (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at http://www.regulations.gov. FDA has
verified the Web site addresses, as of the date this document publishes
in the Federal Register, but Web sites are subject to change over time.

1. FDA, draft guidance for industry, ``Bioequivalence
Recommendations for CONCERTA (Methylphenidate Hydrochloride)
Extended-Release Tablets,'' November 2014 (available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320007.pdf).
2. FDA, draft guidance for industry, ``Bioequivalence Studies With
Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA,''
December 2013 (available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM377465).
3. Dighe, S. V. and W. P. Adams, ``Bioequivalence: A United States
Regulatory Perspective.'' In: Welling, P. G., L. S. Tse, and S. V.
Dighe, eds., Pharmaceutical Bioequivalence. New York: Marcel Dekker,
Inc., pp. 347-380, 1991.
4. Swanson, J. M., S. B. Wigal, T. Wigal, et al., ``A Comparison of
Once-Daily Extended-Release Methylphenidate Formulations in Children
With Attention-Deficit/Hyperactivity Disorder in the Laboratory
School (The Comacs Study),'' Pediatrics, vol. 113, pp. 206-216,
2004.
5. Kimko, H., E. Gibiansky, L. Gibiansky, et al., ``Population
Pharmacodynamic Modeling of Various Extended-Release Formulations of
Methylphenidate in Children With Attention Deficit Hyperactivity
Disorder Via Meta-Analysis,'' Journal of Pharmacokinetics and
Pharmacodynamics, vol. 39(2), pp. 161-176, 2012.
6. Memorandum to Janet Woodcock, Director, Center for Drug
Evaluation and Research, in Support of Beginning Approval Withdrawal
Proceedings for ANDA 091695 (October 1, 2016, Peters).

Dated: October 12, 2016.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 2016-25092 Filed 10-17-16; 8:45 am]
BILLING CODE 4164-01-P

Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Notices 71741

judgment against the person who 6. Memorandum to Janet Woodcock, Director, • Mail/Hand delivery/Courier (for
requests the hearing, making findings Center for Drug Evaluation and Research, written/paper request for a hearing):
and conclusions, and denying a hearing. in Support of Beginning Approval Division of Dockets Management (HFA–
All submissions under this notice of Withdrawal Proceedings for ANDA
305), Food and Drug Administration,
202608 (October 1, 2016, Peters).
opportunity for a hearing must be filed 5630 Fishers Lane, Rm. 1061, Rockville,
in two copies. Except for data and Dated: October 12, 2016. MD 20852.
information prohibited from public Janet Woodcock, Because your request for a hearing
disclosure under 21 U.S.C. 331(j) or 18 Director, Center for Drug Evaluation and will be made public, you are solely
U.S.C. 1905, the submissions may be Research. responsible for ensuring that your
seen in the Division of Dockets [FR Doc. 2016–25093 Filed 10–17–16; 8:45 am] request does not include any
Management (see ADDRESSES) between 9 BILLING CODE 4164–01–P confidential information that you may
a.m. and 4 p.m., Monday through not wish to be publicly posted, such as
Friday, and will be posted to the docket confidential business information, e.g., a
at http://www.regulations.gov. DEPARTMENT OF HEALTH AND manufacturing process. The request for
This notice is issued under section HUMAN SERVICES a hearing must include the Docket No.
505(e) of the FD&C Act and under the FDA–2016–N–3120 for ‘‘Kremers Urban
authority delegated to the Director of Food and Drug Administration Pharmaceuticals Inc.; Proposal to
CDER by the Commissioner of Food and [Docket No. FDA–2016–N–3120] Withdraw Approval of an Abbreviated
Drugs. New Drug Application for Extended-
Kremers Urban Pharmaceuticals Inc.; Release Methylphenidate Tablets;
IV. References Opportunity for a Hearing.’’ The request
Proposal To Withdraw Approval of an
The following references are on Abbreviated New Drug Application for for a hearing will be placed in the
display in the Division of Dockets Extended-Release Methylphenidate docket and publicly viewable at http://
Management (see ADDRESSES) and are Tablets; Opportunity for a Hearing www.regulations.gov or at the Division
available for viewing by interested of Dockets Management between 9 a.m.
persons between 9 a.m. and 4 p.m., AGENCY: Food and Drug Administration, and 4 p.m., Monday through Friday.
Monday through Friday; they are also HHS. Kremers Urban Pharmaceutical Inc.,
available electronically at http:// ACTION: Notice. may submit all data and analysis upon
www.regulations.gov. FDA has verified which the request for a hearing relies in
SUMMARY: The Food and Drug the same manner as the request for a
the Web site addresses, as of the date
Administration’s (FDA or Agency) hearing except as follows:
this document publishes in the Federal
Center for Drug Evaluation and Research • Confidential Submissions—To
Register, but Web sites are subject to
(CDER) is proposing to withdraw submit any data and analyses with
change over time.
approval of an abbreviated new drug confidential information that you do not
1. Swanson, J.M., et al., ‘‘A Comparison of application (ANDA) for
Once-Daily Extended-Release wish to be made publicly available,
methylphenidate hydrochloride (HCl) submit your data and analyses only as
Methylphenidate Formulations in extended-release (ER) tablets and is
Children With Attention-Deficit/ a written/paper submission. You should
Hyperactivity Disorder in the Laboratory
announcing an opportunity for the submit two copies total of all data and
School (The Comacs Study),’’ Pediatrics, holder of the ANDA to request a hearing analysis. One copy will include the
vol. 113, pp. 206–216, 2004. on this proposal. information you claim to be confidential
2. FDA, draft guidance for industry, DATES: Kremers Urban Pharmaceuticals with a heading or cover note that states
‘‘Bioequivalence Recommendations for Inc., may submit a request for a hearing ‘‘THIS DOCUMENT CONTAINS
CONCERTA (Methylphenidate by November 17, 2016. Submit all data,
Hydrochloride) Extended-Release
CONFIDENTIAL INFORMATION.’’ The
information, and analyses upon which Agency will review this copy, including
Tablets,’’ November 2014 (available at
the request for a hearing relies by the claimed confidential information, in
http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatory December 19, 2016. Submit written or its consideration of any decisions on
Information/Guidances/ electronic comments by December 19, this matter. The second copy, which
UCM320007.pdf). 2016. will have the claimed information
3. FDA, draft guidance for industry, ADDRESSES: The request for a hearing redacted/blacked out, will be available
‘‘Bioequivalence Studies With may be submitted by Kremers Urban for public viewing and posted on http://
Pharmacokinetic Endpoints for Drugs www.regulations.gov or available at the
Pharmaceuticals Inc., by either of the
Submitted Under an ANDA,’’ December
2013 (available at http://www.fda.gov/ following methods: Division of Dockets Management
Drugs/GuidanceComplianceRegulatory between 9 a.m. and 4 p.m., Monday
Electronic Submissions through Friday. Submit both copies to
Information/Guidances/UCM377465).
4. Dighe, S.V. and W.P. Adams. Submit electronic comments in the the Division of Dockets Management.
‘‘Bioequivalence: A United States following way: Any information marked as
Regulatory Perspective.’’ In Welling, • Federal eRulemaking Portal: http:// ‘‘confidential’’ will not be disclosed
P.G., L.S. Tse, and S.V. Dighe, eds., www.regulations.gov. Follow the except in accordance with 21 CFR 10.20
Pharmaceutical Bioequivalence. New instructions for submitting comments to and other applicable disclosure law.
York: Marcel Dekker, Inc., pp. 347–380, submit your request for a hearing. Your Comments Submitted by Other
1991. request for a hearing submitted Interested Parties: For all comments
5. Kimko, H., et al., ‘‘Population electronically to http://
Pharmacodynamic Modeling of Various
submitted by other interested parties
Lhorne on DSK30JT082PROD with NOTICES

Extended-Release Formulations of
www.regulations.gov, including any you may submit comments as follows:
Methylphenidate in Children With attachments to the request for hearing,
will be posted to the docket unchanged. Electronic Submissions
Attention Deficit Hyperactivity Disorder
Via Meta-Analysis,’’ Journal of Submit electronic comments in the
Written/Paper Submissions following way:
Pharmacokinetics and
Pharmacodynamics, vol. 39(2), pp. 161– Submit written/paper submissions as • Federal eRulemaking Portal: http://
176, 2012. follows: www.regulations.gov. Follow the

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Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Notices
Action		Notice.
Dates		Kremers Urban Pharmaceuticals Inc., may submit a request for a hearing by November 17, 2016. Submit all data, information, and analyses upon which the request for a hearing relies by December 19, 2016. Submit written or electronic comments by December 19, 2016.
Contact		Maryll W. Toufanian, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 75, Rm. 1716, Silver Spring, MD 20993-0002, 240- 402-7944.
FR Citation		81 FR 71741

81 FR 71741 - Kremers Urban Pharmaceuticals Inc.; Proposal To Withdraw Approval of an Abbreviated New Drug Application for Extended-Release Methylphenidate Tablets; Opportunity for a Hearing

DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 81, Issue 201 (October 18, 2016)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration