Kremers Urban Pharmaceuticals Inc.; Proposal To Withdraw Approval of an Abbreviated New Drug Application for Extended-Release Methylphenidate Tablets; Opportunity for a Hearing, 71741-71745 [2016-25092]
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Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Notices
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 https://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.
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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 https://
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. Swanson, J.M., 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.
2. FDA, draft guidance for industry,
‘‘Bioequivalence Recommendations for
CONCERTA (Methylphenidate
Hydrochloride) Extended-Release
Tablets,’’ November 2014 (available at
https://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatory
Information/Guidances/
UCM320007.pdf).
3. FDA, draft guidance for industry,
‘‘Bioequivalence Studies With
Pharmacokinetic Endpoints for Drugs
Submitted Under an ANDA,’’ December
2013 (available at https://www.fda.gov/
Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM377465).
4. 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.
5. Kimko, H., 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.
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6. Memorandum to Janet Woodcock, Director,
Center for Drug Evaluation and Research,
in Support of Beginning Approval
Withdrawal Proceedings for ANDA
202608 (October 1, 2016, Peters).
Dated: October 12, 2016.
Janet Woodcock,
Director, Center for Drug Evaluation and
Research.
[FR Doc. 2016–25093 Filed 10–17–16; 8:45 am]
BILLING CODE 4164–01–P
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.
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:
SUMMARY:
Electronic Submissions
Submit electronic comments in the
following way:
• Federal eRulemaking Portal: https://
www.regulations.gov. Follow the
instructions for submitting comments to
submit your request for a hearing. Your
request for a hearing submitted
electronically to https://
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:
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71741
• 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 ExtendedRelease Methylphenidate Tablets;
Opportunity for a Hearing.’’ The request
for a hearing will be placed in the
docket and publicly viewable at https://
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 https://
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: https://
www.regulations.gov. Follow the
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Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Notices
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instructions for submitting comments.
Comments submitted electronically to
https://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 https://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 ExtendedRelease 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 https://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
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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 https://
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: https://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 https://
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
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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.
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.
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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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 54mg 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. 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
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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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 personyears of exposure for the Kremers
product and 7.0 per 100,000 personyears of exposure for the authorized
generic drug product.
• 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
4 Authorized generic drug is defined in section
505(t) of the FD&C Act and in § 314.3(b) (21 CFR
314.3(b)) (Authorized generic drug means a listed
drug, as defined in § 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
(§ 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
https://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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71743
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
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
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 https://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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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 § 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 postdosing 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
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 AUC
8–12 captures the extent of absorption from
8 to 12 hours post-dosing.
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reports received describing lack of
therapeutic effect later in the day.
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
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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
§ 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 § 314.200 (21
CFR 314.200) and in 21 CFR part 12.
E:\FR\FM\18OCN1.SGM
18OCN1
Federal Register / Vol. 81, No. 201 / Tuesday, October 18, 2016 / Notices
The failure of an applicant to file a
timely written notice of participation
and request for a hearing, as required by
§ 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 https://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.
Lhorne on DSK30JT082PROD with NOTICES
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 https://
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
https://www.fda.gov/downloads/Drugs/
GuidanceCompliance
RegulatoryInformation/Guidances/
UCM320007.pdf).
VerDate Sep<11>2014
13:19 Oct 17, 2016
Jkt 241001
2. FDA, draft guidance for industry,
‘‘Bioequivalence Studies With
Pharmacokinetic Endpoints for Drugs
Submitted Under an ANDA,’’ December
2013 (available at https://www.fda.gov/
Drugs/GuidanceComplianceRegulatory
Information/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 MetaAnalysis,’’ 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
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Health Resources and Services
Administration
Agency Information Collection
Activities: Submission to OMB for
Review and Approval; Public Comment
Request; National Practitioner Data
Bank Attestation of Reports by
Hospitals, Medical Malpractice Payers,
Health Plans, and Certain Other Health
Care Entities
Health Resources and Services
Administration (HRSA), Department of
Health and Human Services (HHS).
ACTION: Notice.
AGENCY:
In compliance with Section
3507(a)(1)(D) of the Paperwork
Reduction Act of 1995, HRSA has
submitted an Information Collection
Request (ICR) to the Office of
Management and Budget (OMB) for
review and approval. Comments
submitted during the first public review
SUMMARY:
PO 00000
Frm 00057
Fmt 4703
Sfmt 4703
71745
of this ICR will be provided to OMB.
OMB will accept further comments from
the public during the review and
approval period.
DATES: Comments on this ICR must be
received no later than November 17,
2016.
ADDRESSES: Submit your comments,
including the ICR Title, to the desk
officer for HRSA, either by email to
OIRA_submission@omb.eop.gov or by
fax to 202–395–5806.
FOR FURTHER INFORMATION CONTACT: To
request a copy of the clearance requests
submitted to OMB for review, email the
HRSA Information Collection Clearance
Officer at paperwork@hrsa.gov or call
(301) 443–1984.
SUPPLEMENTARY INFORMATION:
Information Collection Request Title:
National Practitioner Data Bank (NPDB)
Attestation of Reports by Hospitals,
Medical Malpractice Payers, Health
Plans, and Health Centers OMB No.
0906–xxxx—NEW.
Abstract: The National Practitioner
Data Bank (NPDB) plans to collect data
from hospitals, medical malpractice
payers, health plans, and certain other
health care entities 1 that are subject to
NPDB reporting requirements to assist
these entities in understanding and
meeting their reporting requirements to
the NPDB. The NPDB currently collects
similar data (OMB No. 0915–0126) from
state licensing boards on a regular basis
and this information collection request
would expand beyond current activities
to include hospitals, medical
malpractice payers, health plans, and
certain other health care entities.
NPDB began operation on September
1, 1990. The statutory authorities
establishing and governing the NPDB
are Title IV of Public Law (Pub. L.) 99–
660, the Health Care Quality
Improvement Act of 1986, as amended,
Section 5 of the Medicare and Medicaid
Patient and Program Protection Act of
1987, Public Law 100–93, codified as
Section 1921 of the Social Security Act,
and Section 221(a) of the Health
Insurance Portability and
Accountability Act of 1996, Public Law
104–191, codified as Section 1128E of
1 Unless otherwise noted, the term ‘‘certain other
health care entities’’ refers to health centers whose
access and reporting obligations are addressed in
the NPDB statutory and regulatory requirements for
health care entities. In this document, ‘‘health
center’’ refers to organizations that receive grants
under the HRSA Health Center Program as
authorized under section 330 of the Public Health
Service Act, as amended (referred to as ‘‘grantees’’)
and FQHC Look-Alike organizations, which meet
all the Health Center Program requirements but do
not receive Health Center Program grants. It does
not refer to FQHCs that are sponsored by tribal or
Urban Indian Health Organizations, except for those
that receive Health Center Program grants.
E:\FR\FM\18OCN1.SGM
18OCN1
Agencies
[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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: https://www.regulations.gov.
Follow the instructions for submitting comments to submit your request
for a hearing. Your request for a hearing submitted electronically to
https://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 https://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 https://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: https://www.regulations.gov.
Follow the
[[Page 71742]]
instructions for submitting comments. Comments submitted electronically
to https://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 https://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 https://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 https://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: https://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 https://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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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 https://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.)
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\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 https://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.)).
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
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 https://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 https://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 https://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 https://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