[Federal Register Volume 84, Number 208 (Monday, October 28, 2019)]
[Notices]
[Pages 57739-57742]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-23490]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-3723]


Watson Laboratories, Inc.; Proposal To Withdraw Approval of an 
Abbreviated New Drug Application for Oxycodone Hydrochloride and 
Ibuprofen 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 oxycodone 
hydrochloride and ibuprofen 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: Watson Laboratories, 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 Watson 
Laboratories, 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-3723 for ``Watson Laboratories, Inc.; Proposal to 
Withdraw Approval of an Abbreviated New Drug Application for Oxycodone 
Hydrochloride and Ibuprofen 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.
    Watson Laboratories, 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,

[[Page 57740]]

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 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-3723 for ``Watson Laboratories, Inc.; Proposal to Withdraw 
Approval of an Abbreviated New Drug Application for Oxycodone 
Hydrochloride and Ibuprofen 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 078394 for Oxycodone Hydrochloride and Ibuprofen 
Tablets

    FDA's Office of Generic Drugs (OGD) approved ANDA 078394, held by 
Watson Laboratories, Inc. (Watson),\1\ for a generic version of 
oxycodone hydrochloride and ibuprofen tablets, 5 milligrams (mg)/400 
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 078394 on November 26, 2007.
---------------------------------------------------------------------------

    \1\ In correspondence dated February 23, 2017, Watson notified 
FDA that Watson is an indirect, wholly-owned subsidiary of Teva 
Pharmaceuticals USA, Inc.
---------------------------------------------------------------------------

    In seeking approval of its ANDA 078394, Watson relied on the 
reference listed drug (RLD) product, COMBUNOX (oxycodone hydrochloride 
and ibuprofen) tablets, 5 mg/400 mg, approved under new drug 
application (NDA) 021378 (see Sec.  314.94 (21 CFR 314.94)). As an 
applicant under section 505(j) of the FD&C Act, Watson 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, Watson was required to demonstrate 
that its product was bioequivalent to the RLD, COMBUNOX (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 Watson submitted to show 
that its ANDA 078394 was bioequivalent to the RLD included 
bioequivalence studies, with the bioanalytical analysis conducted by 
Cetero Research at the Houston, TX site during 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

[[Page 57741]]

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 and Act 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 
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 Watson regarding ANDA 
078394 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 Watson's 
drug product approved under ANDA 078394. FDA informed Watson that ANDA 
078394 needed to be supplemented by conducting new bioequivalence 
studies or re-assaying the samples from the original bioequivalence 
study. FDA recommended to Watson that the results of the requested 
bioequivalence studies, or re-assays, be submitted to ANDA 078394 
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 Watson to this 
August 9, 2011, correspondence.
    On August 19, 2016, FDA issued another letter to Watson requesting 
that, within 30 calendar days, Watson either: (1) Supplement ANDA 
078394 with the requested bioequivalence data or (2) voluntarily seek 
withdrawal of ANDA 078394 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 Watson did not 
submit new bioequivalence data within 30 calendar days, if the new data 
did not support a finding of bioequivalence, or if Watson did not agree 
to voluntarily seek withdrawal of ANDA 078394 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 078394 under 
section 505(e) of the FD&C Act and Sec.  314.150. FDA did not receive a 
response from Watson to this August 19, 2016, correspondence.
    On April 24, 2017, FDA issued Watson a third letter notifying them 
that FDA had changed the therapeutic equivalence evaluation of ANDA 
078394 in the Orange Book from an ``AB'' to a ``BX'' rating (see Ref. 
5). Further, in the April 24, 2017, correspondence, FDA requested that 
Watson voluntarily seek withdrawal for ANDA 078394 under Sec.  
314.150(d) and waive the opportunity for a hearing under Sec.  
314.150(a). FDA requested that Watson provide such a withdrawal request 
or a letter stating that Watson would not voluntarily seek withdrawal 
of the approval of ANDA 078394 no later than May 24, 2017. As noted in 
the April 24, 2017, correspondence, FDA advised Watson that if Watson 
did not agree to voluntarily seek withdrawal of the approval of ANDA 
078394 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 Watson to this April 24, 
2017, correspondence.
    In the June 2017 Cumulative Supplement to the 37th Edition of the 
Orange Book, ANDA 078394 was moved to the Discontinued Section of the 
Orange Book based on notification by Watson to the Agency that Watson 
was no longer marketing its drug product approved under ANDA 078394. 
Because drug products that are in the Discontinued Section of the 
Orange Book do not have therapeutic equivalence codes and because ANDA 
078394 is currently in the Discontinued Section of the Orange Book, 
ANDA 078394 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 Watson 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 Watson Laboratories, 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 
078394 and all amendments and supplements to it on the grounds that 
Watson has failed to submit the required bioequivalence data necessary 
to demonstrate the bioequivalence of its drug product.

[[Page 57742]]

III. Hearing Procedures

    In accordance with section 505(e) of the FD&C Act, Watson 
Laboratories, Inc. is hereby provided an opportunity to request a 
hearing to show why approval of ANDA 078394 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 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 Watson Laboratories, Inc., 
August 9, 2011.
    4. Letter from Carol A. Holquist, FDA, to Watson Laboratories, 
Inc., August 19, 2016.
    5. Letter from Carol A. Holquist, FDA, to Watson Laboratories, 
Inc., April 24, 2017.

    Dated: October 21, 2019.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 2019-23490 Filed 10-25-19; 8:45 am]
 BILLING CODE 4164-01-P