Federal Register, Volume 84 Issue 208 (Monday, October 28, 2019)

[Federal Register Volume 84, Number 208 (Monday, October 28, 2019)]
[Notices]
[Pages 57736-57739]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-23461]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-3708]

InvaGen Pharmaceuticals, Inc.; Proposal To Withdraw Approval of
an Abbreviated New Drug Application for Trandolapril 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 trandolapril tablets
and is announcing an opportunity for the holder of the ANDA to request
a hearing on this proposal. The basis for the proposal is that the
holder of the ANDA has repeatedly failed to submit the required data to
support a finding of bioequivalence for this ANDA.

DATES: InvaGen Pharmaceuticals, Inc. may submit a request for a hearing
by November 27, 2019. Submit all data, information, and analyses upon
which the request for a hearing relies by December 27, 2019. Submit
electronic or written comments by December 27, 2019.

ADDRESSES: The request for a hearing may be submitted by InvaGen
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. Comments submitted electronically to https://www.regulations.gov, including any attachments to the request for a
hearing, will be posted to the docket unchanged.

Written/Paper Submissions

Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (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 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. The request for a hearing must include the
Docket No. FDA-2019-N-3708 for ``InvaGen Pharmaceuticals, Inc.;
Proposal to Withdraw Approval of an Abbreviated New Drug Application
for Trandolapril 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 Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday.
InvaGen Pharmaceuticals, Inc. may submit all data and analyses 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
analyses. 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

[[Page 57737]]

will have the claimed confidential information redacted/blacked out,
will be available for public viewing and posted on https://www.regulations.gov or available at the Dockets Management Staff
between 9 a.m. and 4 p.m., Monday through Friday. Submit both copies to
the Dockets Management Staff. 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, submit comments as follows.

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
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): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, 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-2019-N-3708 for ``InvaGen Pharmaceuticals, Inc.; Proposal to
Withdraw Approval of an Abbreviated New Drug Application for
Trandolapril Tablets; Opportunity for a Hearing.'' Received comments,
those filed in a timely manner (see ADDRESSES), will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff 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 Dockets Management Staff. 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.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
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 Dockets Management Staff, 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. 1720, Silver Spring, MD 20993-0002, 240-
402-7944.

SUPPLEMENTARY INFORMATION:

I. Background

A. Approval of ANDA 078320 for Trandolapril Tablets

FDA's Office of Generic Drugs (OGD) approved ANDA 078320, held by
InvaGen Pharmaceuticals, Inc. (InvaGen), for a generic version of
trandolapril tablets, 1 milligram (mg), 2 mg, and 4 mg, under the
requirements of section 505(j) of the Federal Food, Drug, and Cosmetic
Act (FD&C Act) (21 U.S.C. 355(j)) and FDA's implementing regulations.
OGD approved ANDA 078320 on June 12, 2007.
In seeking approval of its ANDA 078320, InvaGen relied on the
reference listed drug (RLD) product, MAVIK (trandolapril) tablets, 1
mg, 2 mg, and 4 mg, approved under new drug application (NDA) 020528
(see Sec. 314.94 (21 CFR 314.94)). As an applicant under section
505(j) of the FD&C Act, InvaGen was not required to conduct clinical
studies to demonstrate the safety and effectiveness of its drug
product. Rather, in addition to meeting the other requirements for ANDA
approval enumerated in section 505(j) of the FD&C Act and applicable
FDA regulations, InvaGen was required to demonstrate that its product
was bioequivalent to the RLD, MAVIK (see section 505(j)(2)(A)(iv) and
(j)(4)(F) of the FD&C Act; Sec. 314.94(a)(7); 21 CFR
314.127(a)(6)(i)). The information that InvaGen submitted to show that
its ANDA 078320 was bioequivalent to the RLD included bioequivalence
studies, with the bioanalytical analysis conducted by Cetero Research
at the Houston, TX site during 2005-2006.

B. Investigations Regarding Bioequivalence Studies Conducted by Cetero
Research

In May 2010 and December 2010, FDA conducted comprehensive
inspections of bioequivalence studies conducted by Cetero Research at
the Houston, TX site. The inspections were part of FDA's Bioresearch
Monitoring Program, which includes inspections to evaluate the conduct
of research, to confirm that data intended for submission to FDA are
reliable as a basis for FDA approval and regulatory decisions, and to
verify compliance with the bioavailability and bioequivalence
requirements in section 505 of the FD&C Act and 21 CFR part 320. The
findings of these inspections of bioequivalence studies conducted by
Cetero Research raised significant concerns about the validity of the
reported results of analytical studies conducted between April 1, 2005,
and June 15, 2010, in support of drug applications (see Ref. 1). The

[[Page 57738]]

inspections and a third-party audit identified significant instances of
misconduct and violations of Federal regulations, including document
falsification and sample manipulation. The pattern of misconduct was
serious enough to raise concerns about the integrity of the data that
Cetero Research generated during the 5-year time frame between 2005 and
2010. On July 26, 2011, FDA notified pharmaceutical companies that
bioanalytical studies conducted at Cetero Research between April 1,
2005, and June 15, 2010, in support of marketing applications may need
to be repeated or confirmed (see Ref. 2).
On August 9, 2011, FDA issued a letter to InvaGen regarding ANDA
078320 because this drug product application was supported by
bioequivalence studies with the bioanalytical analysis conducted by
Cetero Research at the Houston, TX site between April 1, 2005, and June
15, 2010 (see Ref. 3). As FDA noted in its August 9, 2011,
correspondence, inspection findings regarding Cetero Research's
bioequivalence studies raised significant concerns about the validity
of the reported results of the analytical studies conducted between
April 2005 and June 2010 in support of drug applications, and as such,
steps needed to be taken to demonstrate the bioequivalence of InvaGen's
drug product approved under ANDA 078320. FDA informed InvaGen that ANDA
078320 needed to be supplemented by conducting new bioequivalence
studies or re-assaying the samples from the original bioequivalence
study. FDA recommended to InvaGen that the results of the requested
bioequivalence studies, or re-assays, be submitted to ANDA 078320
within 6 months of the date of the August 9, 2011, letter. As noted in
the August 9, 2011, correspondence, if the necessary information was
not submitted within the recommended timeframe, FDA would consider
downgrading the therapeutic equivalence evaluation of approved
applications in the Agency's ``Approved Drug Products With Therapeutic
Equivalence Evaluations'' (Orange Book) from an ``AB'' to a ``BX''
rating because of new information raising a significant question as to
bioequivalence. FDA did not receive a response from InvaGen to this
August 9, 2011, correspondence.
On August 19, 2016, FDA issued another letter to InvaGen requesting
that, within 30 calendar days, InvaGen either: (1) Supplement ANDA
078320 with the requested bioequivalence data or (2) voluntarily seek
withdrawal of ANDA 078320 under Sec. 314.150 (21 CFR 314.150(d)) and
waive the opportunity for a hearing under Sec. 314.150(a) (see Ref.
4). As noted in the August 19, 2016, correspondence, if InvaGen did not
submit new bioequivalence data within 30 calendar days, if the new data
did not support a finding of bioequivalence, or if InvaGen did not
agree to voluntarily seek withdrawal of ANDA 078320 within 30 calendar
days, FDA would commence downgrading the therapeutic equivalence
evaluation of approved applications in the Orange Book from an ``AB''
to a ``BX'' rating. FDA also stated that if the aforementioned
conditions were not met, FDA would consider all other appropriate
regulatory action, including commencing steps to withdraw approval of
ANDA 078320 under section 505(e) of the FD&C Act and Sec. 314.150. In
response to the August 19, 2016, correspondence, FDA received a letter
from InvaGen dated September 16, 2016, requesting a 9-month extension
and stating that InvaGen was working to conduct new studies to submit
to the Agency (see Ref. 5).
On April 24, 2017, FDA issued a third letter to InvaGen notifying
them that FDA was denying InvaGen's request for a 9-month extension
because InvaGen had already had a lengthy period to provide the
requested data (see Ref. 6). In the April 24, 2017, correspondence, FDA
also notified InvaGen that FDA had changed the therapeutic equivalence
evaluation of ANDA 078320 in the Orange Book from an ``AB'' to a ``BX''
rating. Further, in the April 24, 2017, correspondence, FDA requested
that InvaGen voluntarily seek withdrawal for ANDA 078320 under Sec.
314.150(d) and waive the opportunity for a hearing under Sec.
314.150(a). FDA requested that InvaGen provide such a withdrawal
request or a letter stating that InvaGen would not voluntarily seek
withdrawal of the approval of ANDA 078320 no later than May 24, 2017.
As noted in the April 24, 2017, correspondence, FDA advised InvaGen
that if InvaGen did not agree to voluntarily seek withdrawal of the
approval of ANDA 078320 under Sec. 314.150(d), FDA would plan to
commence steps to withdraw approval of this ANDA under 505(e) of the
FD&C Act and Sec. 314.150. FDA did not receive a response from InvaGen
to this April 24, 2017, correspondence.
In the June 2017 Cumulative Supplement to the 37th Edition of the
Orange Book, ANDA 078320 was moved to the Discontinued Section of the
Orange Book based on notification by InvaGen to the Agency that InvaGen
was no longer marketing its drug product approved under ANDA 078320.
Because drug products that are in the Discontinued Section of the
Orange Book do not have therapeutic equivalence codes and because ANDA
078320 is currently in the Discontinued Section of the Orange Book,
ANDA 078320 is not currently assigned a therapeutic equivalence code.

II. Conclusions and Proposed Action

An NDA 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, NDAs must meet the safety and
substantial evidence of effectiveness standard (see section 505(b)(1)
and (2), (c), and (d) of the FD&C Act). An NDA 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 its
RLD and is required to meet other requirements, such as demonstrating
bioequivalence to the RLD to support approval. In the absence of
information showing bioequivalence between the generic drug at issue
and the RLD, there is no basis for concluding that the Agency's finding
of safety and efficacy supporting approval of the RLD can be used as a
basis to support approval of the generic drug. Section 505(e) of the
FD&C Act provides FDA the authority to withdraw approval of an ANDA in
these circumstances. While the InvaGen application was approved on the
basis of a bioequivalence study, new information about the facility
that conducted the bioanalytical analysis for that study leads CDER to
conclude that the results of that study are not credible.
Therefore, based on all available data and information, notice is
given to InvaGen Pharmaceuticals, Inc. and to all other interested
persons that the Director of CDER proposes to issue an order, under
section 505(e) of the FD&C Act and Sec. 314.150, withdrawing approval
of ANDA 078320 and all amendments and supplements to it on the grounds
that InvaGen has failed to submit the required bioequivalence data
necessary to demonstrate the bioequivalence of its drug product.

III. Hearing Procedures

In accordance with section 505(e) of the FD&C Act, InvaGen
Pharmaceuticals, Inc. is hereby provided an opportunity to request a
hearing to show why approval of ANDA 078320 should not be withdrawn and
an

[[Page 57739]]

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 a hearing (see
DATES and ADDRESSES) 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 (see DATES and ADDRESSES). 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.
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.
Paper 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 at the Dockets Management Staff (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 authority delegated to the Director of CDER by the Commissioner
of Food and Drugs.

IV. References

The following references are on display at the Dockets Management
Staff (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 website address, as of the date this document publishes in
the Federal Register, but websites are subject to change over time.

1. Letter from Leslie Ball, FDA, to Roger Hayes, Cetero Research,
July 26, 2011.
2. FDA, ``Notification to Pharmaceutical Companies: Acceptance of
third-party data integrity audit for Cetero studies conducted from
March 1, 2008, to August 31, 2009'' (https://wayback.archive-it.org/7993/20170113203457/http:/www.fda.gov/Drugs/DrugSafety/ucm265559.htm), accessed September 10, 2019.
3. Letter from Keith Webber, FDA, to InvaGen Pharmaceuticals, Inc.,
August 9, 2011.
4. Letter from Carol A. Holquist, FDA, to InvaGen Pharmaceuticals,
Inc., August 19, 2016.
5. Letter from Ram Mohan Kathuroju, InvaGen Pharmaceuticals, Inc.,
to FDA, September 16, 2016.
6. Letter from Carol A. Holquist, FDA, to InvaGen Pharmaceuticals,
Inc., April 24, 2017.

Dated: October 21, 2019.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 2019-23461 Filed 10-25-19; 8:45 am]
BILLING CODE 4164-01-P