Document ID: FDA-2016-N-3120-0001
Agency: fda
Document Type: Notice
Title: Kremers Urban Pharmaceuticals Inc.; Proposal To Withdraw Approval of an Abbreviated New Drug Application for Extended-Release  Methylphenidate Tablets; Opportunity for a Hearing
Posted Date: 2016-10-18T04:00Z

[Federal Register Volume 81, Number 201 (Tuesday, October 18, 2016)]
[Notices]
[Pages 71741-71745]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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