Document ID: FDA-2018-N-0188-0001
Agency: fda
Document Type: Notice
Title: Proposal To Refuse To Approve a New Drug Application for Oxycodone
Hydrochloride Immediate-Release Oral Capsules, 5 Milligrams, 15 Milligrams, and 30 Milligrams; Opportunity for a Hearing
Posted Date: 2018-02-13T05:00Z

[Federal Register Volume 83, Number 30 (Tuesday, February 13, 2018)]
[Notices]
[Pages 6196-6198]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-02903]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-0188]

Proposal To Refuse To Approve a New Drug Application for 
Oxycodone Hydrochloride Immediate-Release Oral Capsules, 5 Milligrams, 
15 Milligrams, and 30 Milligrams; Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Director of the Center for Drug Evaluation and Research 
(Center Director) of the Food and Drug Administration (FDA or Agency) 
is proposing to refuse to approve a new drug application (NDA) 
submitted by Pharmaceutical Manufacturing Research Services, Inc. 
(PMRS) for oxycodone hydrochloride (HCl) immediate-release (IR) oral 
capsules, 5 milligrams (mg), 15 mg, and 30 mg in its present form. This 
notice summarizes the grounds for the Center Director's proposal and 
offers PMRS an opportunity to request a hearing on the matter.

DATES: Submit either electronic or written requests for a hearing by 
March 15, 2018; submit data, information, and analyses in support of 
the hearing and any other comments by April 16, 2018.

ADDRESSES: You may submit hearing requests, documents in support of the 
hearing, and any other comments as follows. Please note that late, 
untimely filed requests and documents will not be considered. 
Electronic requests for a hearing must be submitted on or before March 
15, 2018; electronic documents in support of the hearing and any other 
comments must be submitted on or before April 16, 2018. The https://www.regulations.gov electronic filing system will accept hearing 
requests until midnight Eastern Time at the end of March 15, 2018, and 
will accept documents in support of the hearing and any other comments 
until midnight Eastern Time at the end of April 16, 2018. Documents 
received by mail/hand delivery/courier (for written/paper submissions) 
will be considered timely if they are postmarked or the delivery 
service acceptance receipt is on or before these dates.

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-2018-N-0188, for ``Proposal to Refuse to Approve a New Drug 
Application for Oxycodone Hydrochloride Immediate-Release Oral 
Capsules, 5 Milligrams, 15 Milligrams, and 30 Milligrams; 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/

[[Page 6197]]

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: Patrick Raulerson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6260, Silver Spring, MD, 20993, 301-796-
3522, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Proposal To Refuse To Approve NDA 209155

    PMRS submitted NDA 209155 for oxycodone HCl IR oral capsules in 5 
mg, 15 mg, and 30 mg strengths (oxycodone HCl IR capsules) under 
section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C 
Act) (21 U.S.C. 355(b)(2)), proposing to rely in part on the Agency's 
previous finding of safety and effectiveness for ROXICODONE (oxycodone 
HCl) IR Tablets (NDA 021011). PMRS proposed that its oxycodone HCl IR 
capsules be indicated for the management of acute pain severe enough to 
require an opioid analgesic and for which alternative treatments are 
inadequate. PMRS also attempted to show that the product had certain 
abuse-deterrent properties and sought FDA approval of labeling 
describing those properties.
    On November 16, 2017, the Division of Anesthesia, Analgesia, and 
Addiction Products of FDA's Center for Drug Evaluation and Research 
(CDER) issued a complete response letter to PMRS under Sec.  314.110(a) 
(21 CFR 314.110(a)) stating that NDA 209155 could not be approved in 
its present form, describing the specific deficiencies, and, where 
possible, recommending ways PMRS might remedy these deficiencies. The 
deficiencies include the following:
    1. The application in its present form is not approvable with the 
proposed labeling describing abuse-deterrent properties, for multiple 
reasons. In particular, (1) the oxycodone in the formulation can be 
readily extracted in commonly available solvents into a solution 
suitable for injection; (2) there were insufficient data showing the 
presence of excipients (including dye) in the formulation can be 
expected to deter abuse by injection; (3) the data submitted were 
insufficient to show the product was meaningfully resistant to 
manipulation for misuse or abuse; and (4) there were not data 
submitted, including data from pharmacokinetic and human abuse 
liability studies, fully characterizing the product's abuse potential 
by all relevant routes of abuse. Also, the data submitted were not 
sufficient to rule out the possibility that the proposed formulation 
could result in a greater proportion of abuse by injection of PMRS's 
product compared to a conventional IR oxycodone formulation. Abuse by 
injection carries greater risk of overdose and transmission of 
infectious disease than abuse by other routes.
    2. The safety and purity of the excipients intended (but not shown) 
to confer abuse deterrent properties were not adequately characterized, 
either by the intended oral route of use or by expected routes of 
abuse, including injection.
    3. An overall evaluation of elemental impurities in the final 
formulation and a risk assessment for each heavy metal (taking into 
consideration the maximum daily dose) were not provided.
    4. The application did not fully comply with the patent 
certification requirements applicable to applications submitted under 
section 505(b)(2) of the FD&C Act.
    5. The complete response letter describes additional deficiencies, 
which generally relate to chemistry, manufacturing, and controls and 
current good manufacturing practice requirements, that CDER determined 
preclude approval of the application in its present form. The complete 
response letter also noted that satisfactory resolution of 
objectionable inspection observations was required before the 
application could be approved. Due to applicable limitations on public 
disclosure of information contained in unapproved NDAs, including trade 
secret information, these specific deficiencies are not described in 
this notice.
    The complete response letter stated that PMRS is required to 
resubmit the application, fully addressing all deficiencies listed in 
the letter, or take other actions available under Sec.  314.110 (i.e., 
withdraw the application or request an opportunity for a hearing). 
Applicable regulations, including Sec.  10.75 (21 CFR 10.75), also 
provide a mechanism for applicants to obtain formal review of one or 
more decisions reflected in a complete response letter (see FDA's 
guidance for industry ``Formal Dispute Resolution: Sponsor Appeals 
Above the Division Level'' (November 2017) available at: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm343101.pdf).
    In response to the complete response letter, on November 17, 2017, 
PMRS submitted a request for an opportunity for a hearing under Sec.  
314.110(b)(3) on whether there are grounds under section 505(d) of the 
FD&C Act for denying approval of NDA 209155.

II. Notice of Opportunity for a Hearing

    For the reasons stated previously and others described in the 
complete response letter, notice is given to PMRS and to all other 
interested persons that the Center Director proposes to issue an order 
refusing to approve NDA 209155 on the grounds that the application 
fails to meet the criteria for approval under section 505(d) of the 
FD&C Act, including that: (1) PMRS has not provided sufficient data to 
show that the product would be safe (505(d)(1)); (2) PMRS has not shown 
that the methods used in, and the facilities and controls used for the 
manufacture, processing, or packing of the product are adequate to 
preserve its identity, strength, quality, and purity (505(d)(3)); and 
(3) the labeling PMRS proposed for the product is false or misleading 
(505(d)(7)).
    PMRS may request a hearing before the Commissioner of Food and 
Drugs (the Commissioner) on the Center Director's proposal to refuse to 
approve NDA 209155. If PMRS decides to seek a hearing, it must file: 
(1) A written notice of participation and request for a hearing (see 
the DATES section), and (2) the studies, data, information, and 
analyses relied upon to justify a hearing (see the DATES section), as 
specified in Sec.  [thinsp]314.200.
    As stated in Sec.  314.200(g), 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 to resolve. We note in this regard that because CDER 
proposes to refuse to approve NDA 209155 for multiple reasons, any 
hearing request from PMRS must address all of those reasons, including 
reasons described in the complete response letter but not described in 
this notice due to applicable limitations on public disclosure of 
information contained in unapproved NDAs, including trade secret 
information. Failure to request a hearing within the time provided and 
in the manner required by Sec.  314.200 constitutes a waiver of the 
opportunity to request a hearing. If a hearing request is not properly 
submitted, FDA will issue a notice refusing to approve NDA 209155.

[[Page 6198]]

    The Commissioner will grant a hearing if there exists a genuine and 
substantial issue of fact or if the Commissioner concludes that a 
hearing would otherwise be of public interest (Sec.  314.200(g)(6)). If 
a hearing is granted, it will be conducted according to the procedures 
provided in 21 CFR parts 10 through 16 (21 CFR 314.201).
    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, 
submissions may be seen in the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, and on the internet at https://www.regulations.gov. This notice is issued under section 505(c)(1)(B) 
of the FD&C Act, Sec. Sec.  314.110(b)(3) and 314.200.

    Dated: February 8, 2018.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 2018-02903 Filed 2-12-18; 8:45 am]
 BILLING CODE 4164-01-P