[Federal Register Volume 81, Number 194 (Thursday, October 6, 2016)]
[Notices]
[Pages 69532-69535]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-24234]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-N-2896]


Public Meeting on Pre-Market Evaluation of Abuse-Deterrent 
Properties of Opioid Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
meeting to discuss scientific and technical issues relating to 
formulation development and pre-market evaluation of opioid drug 
products with abuse-deterrent properties. The meeting is intended to 
give FDA the opportunity to discuss, and seek public input from 
stakeholders on, the approach to testing FDA recommended in its draft 
guidance ``General Principles for Evaluating the Abuse Deterrence of 
Generic Solid Oral Opioid Drug Products.'' The meeting will also 
provide an opportunity to discuss FDA's efforts to develop standardized 
in vitro testing methodologies for evaluating the abuse deterrence of 
opioid drug products. FDA is seeking input from all stakeholders, 
including patients, health care providers, health care payers, the 
pharmaceutical industry, patient advocates, academics, researchers, and 
other government entities.
    FDA may hold one or more additional meetings in the future to 
discuss the risk-benefit paradigm for opioid drug products to ensure 
that FDA is appropriately considering the full public health impact of 
prescription opioid drug products and the post-market impact (``real 
world effects'') of abuse-deterrent opioid drug products.

DATES: The public meeting will be held on October 31, 2016, from 8:30 
a.m. to 4:30 p.m. and November 1, 2016, from 8:30 a.m. to 4 p.m. The 
meeting may be extended or end early depending on the level of public 
participation. Individuals seeking to attend or to present at the 
meeting must register by October 17, 2016. Please register here for the 
meeting: http://www.cvent.com/d/wvq0sm/4W. Electronic or written 
comments regarding scientific and technical issues relating to 
formulation development and pre-market evaluation of abuse-deterrent 
properties of opioid drug products will be accepted until December 1, 
2016.

ADDRESSES: The public meeting will be held at College Park Marriott 
Hotel and Conference Center, 3501 University Blvd. East, Hyattsville, 
MD 20783.
    You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://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 http://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2016-N-2896 for ``Public Meeting on Pre-Market Evaluation of Abuse-
Deterrent Properties of Opioid Drug Products.'' Received comments will 
be placed in the docket and, except for those submitted as 
``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. If you do not 
wish your name and contact information to be made publicly available, 
you can provide this information on the cover sheet and not in the body 
of your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.
    FDA will post the agenda approximately 3 days before the public 
meeting at: http://www.fda.gov/Drugs/NewsEvents/ucm509853.htm. FDA will 
also post a link to the live Webcast of this public meeting on the day 
of the public meeting.

FOR FURTHER INFORMATION CONTACT: Michelle Eby, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6184, Silver Spring, MD 20993, 301-796-
4714, [email protected].

[[Page 69533]]


SUPPLEMENTARY INFORMATION:

I. Background

    Prescription opioid analgesics are an important component of modern 
pain management. Prescription opioid analgesic products such as 
oxycodone, hydrocodone, and morphine, are widely prescribed for the 
treatment of pain, and certain opioid drug products are also used in 
opioid dependence treatment programs. When used properly, opioid drug 
products can provide significant benefits for patients. Unfortunately, 
misuse and abuse of opioid drug products is a serious public health 
problem.
    When misused or abused, opioid drug products can cause serious 
harm, including addiction, overdose, and death. According to the 
Centers for Disease Control and Prevention (CDC), prescription opioid 
drug products were involved in over 14,000 deaths in 2014.\1\ FDA is 
determined to help defeat this epidemic through an adaptive, science-
based approach.
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    \1\ Wide-Ranging Online Data for Epidemiologic Research 
(WONDER), National Center for Health Statistics; available at http://wonder.cdc.gov.
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    In February 2016, FDA announced a comprehensive action plan to take 
concrete steps toward reducing the impact of opioid abuse on families 
and communities.\2\ As part of this plan, FDA strongly supports the 
development of, and transition to use of, opioid drug products with 
meaningful abuse-deterrent formulations. FDA has taken and is 
continuing to take steps to incentivize and support the development of 
opioid drug products with progressively better abuse-deterrent 
properties. These steps include working with individual sponsors on 
promising abuse-deterrent technologies, publishing guidance on the 
evaluation and labeling of abuse-deterrent drug products, and 
conducting and supporting research in developing appropriate pre-market 
testing methodologies for evaluating the abuse deterrence of both 
innovator and generic drugs.
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    \2\ http://www.fda.gov/NewsEvents/Newsroom/FactSheets/ucm484714.htm.
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    FDA believes abuse-deterrent technologies can and will improve 
substantially and can make a real impact in the fight against 
prescription opioid abuse. FDA hopes that as the market transitions to 
abuse-deterrent formulations, abuse rates will decrease and the most 
significant consequences of that abuse (addiction, overdose, and death) 
will diminish. To that end, fostering the development, marketing, and 
iterative improvement of abuse-deterrent formulations of opioid drug 
products, including generic opioid drug products, is a top priority. It 
is important that generic versions of opioids that reference approved 
opioids whose labeling describes abuse-deterrent properties are 
available to help ensure widespread access to safe and effective 
analgesics for patients who need them and to accelerate the prescribing 
of abuse-deterrent opioids. Such generic opioids should be no less 
abuse-deterrent than the opioids they reference; otherwise opioid 
abusers could preferentially seek out and abuse easier-to-abuse 
generics.
    FDA's work to date to support the development, marketing, and 
iterative improvement of abuse-deterrent formulations includes:
     Holding a public meeting in October 2014 to discuss the 
``Development and Regulation of Abuse-Deterrent Formulations of Opioid 
Medications;''
     Issuing a final guidance in April 2015 on the ``Abuse-
Deterrent Opioids--Evaluation and Labeling.'' This guidance explains 
FDA's current thinking about the studies, both pre- and post-marketing, 
that should be conducted to demonstrate that a given formulation for 
which a new drug application (NDA) is submitted has abuse-deterrent 
properties. It also makes recommendations about how those studies 
should be performed and evaluated and what information about a 
product's abuse-deterrent properties should be included in labeling;
     To date, approving seven opioid analgesic drug products 
with labeling describing abuse-deterrent properties \3\ consistent with 
the final guidance on evaluation and labeling of abuse-deterrent 
opioids;
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    \3\ A list of opioid medications with FDA-approved labeling 
describing abuse-deterrent properties can be found at http://www.fda.gov/NewsEvents/Newsroom/FactSheets/ucm514939.htm.
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     Seeking guidance from outside experts in the fields of 
pain management and drug abuse. For example, FDA has asked the National 
Academies of Sciences, Engineering, and Medicine to help develop a 
framework for opioid drug product review, approval, and monitoring that 
balances individual needs for pain control with the risk of addiction, 
as well as the broader public health consequences of opioid drug 
product misuse and abuse;
     Conducting or supporting research on opioid drug product 
formulations designed to deter abuse. This includes development of in 
vitro testing methodologies to assess purportedly abuse-deterrent 
formulations; and
     Issuing a draft guidance on the ``General Principles for 
Evaluating Abuse Deterrence of Generic Solid Oral Opioid Drug 
Products.''
    In the notice of availability for the draft guidance on evaluating 
abuse deterrence of generic opioid drug products, FDA announced its 
intent to hold a public meeting following the close of the comment 
period to discuss further the pre-market evaluation of the abuse 
deterrence of generic opioid drug products and related issues, as 
appropriate. FDA is opening a docket and holding this public meeting to 
further discuss pre-market evaluation of the abuse deterrence of 
generic opioid drug products and the development of standardized in 
vitro testing methodologies for evaluating the abuse deterrence of 
opioid drug products.
    Day 1 of this meeting will focus on scientific and technical issues 
related to the pre-market evaluation of the abuse deterrence of generic 
opioid drug products. It is important to have a viable pathway for 
approval of generic abuse-deterrent opioid drug products to further 
FDA's goal to transition to abuse-deterrent formulations as FDA looks 
forward to a future in which all or substantially all opioid 
medications are less susceptible to abuse than the formulations on the 
market today. The availability of generic versions of opioid drug 
products that reference listed drugs whose labeling describes abuse-
deterrent properties can help to ensure access to safe and effective, 
and affordable, opioid analgesics for patients who need them.
    Day 2 will focus on FDA's efforts to develop standardized in vitro 
testing methodologies for evaluating the abuse deterrence of opioid 
drug products. In vitro testing should, to the greatest extent 
possible, provide information sufficient to fully characterize a drug 
product's abuse-deterrent properties, including the degree of effort 
required to bypass or defeat those properties. In vitro studies should 
assess each potential route of abuse (including ingestion, injection, 
insufflation, and smoking) starting with simple and gentle mechanical 
and chemical manipulations progressing to complex and more destructive 
manipulations until a drug product's abuse-deterrent properties are 
defeated or compromised. To be sufficiently comprehensive, in vitro 
testing should address both the mechanisms by which abusers can be 
expected to attempt to deliberately overcome the abuse-deterrent 
properties of the product as well as the ways that patients may alter 
the formulation (intentionally or unintentionally) that

[[Page 69534]]

change the rate or amount of drug released.

A. Day 1: FDA's Evaluation of Generic Abuse-Deterrent Opioids

    Section 505(j) of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 355(j)) (FD&C Act) permits any person to submit to the FDA an 
abbreviated new drug application (ANDA) to seek approval to market a 
generic version of a previously approved drug product. To obtain 
approval, an ANDA applicant is not required to provide independent 
evidence of the safety and effectiveness of the proposed generic drug. 
Instead, the applicant relies on FDA's finding that a previously 
approved drug product, i.e, the reference listed drug (RLD), is safe 
and effective, and must demonstrate, among other things, that the 
proposed generic drug is the ``same'' as the RLD in certain ways and is 
bioequivalent.
    For FDA to approve an ANDA, the Agency must find, among other 
things, that the generic drug product has the same active 
ingredient(s), dosage form, route of administration, strength, 
conditions of use, and, with limited exceptions, labeling as the RLD, 
is bioequivalent to its RLD, that the methods used in, or the 
facilities and controls used for, the manufacture, processing, and 
packing of the drug are adequate to assure and preserve its identity, 
strength, quality, and purity, and that the inactive ingredients and 
composition of the generic drug are not unsafe under the conditions of 
use prescribed, recommended, or suggested in the labeling. See section 
505(j)(2)(A) and (j)(4) of the FD&C Act.
    FDA classifies as ``therapeutically equivalent'' those products 
that meet the following general criteria: (1) They are approved as safe 
and effective; (2) they are pharmaceutical equivalents in that they 
contain identical amounts of the same active ingredient(s) with the 
same route of administration and dosage form and meet compendial or 
other applicable standards of strength, quality, purity, and identity; 
(3) they are bioequivalent; (4) they are adequately labeled; and (5) 
they are manufactured in compliance with current good manufacturing 
practices regulations. See FDA's ``Approved Drug Products with 
Therapeutic Equivalence Evaluations'' (the Orange Book), Preface. FDA 
believes that a product classified as therapeutically equivalent can be 
substituted with the full expectation that the substituted product will 
produce the same clinical effect and safety profile as the reference 
product.
    If the RLD's labeling describes properties that are expected to 
deter misuse or abuse then the potential ANDA applicant should evaluate 
its proposed generic drug product in comparative in vitro studies and, 
in some cases, in relevant pharmacokinetic or other studies to show 
that it is no less abuse-deterrent than the RLD with respect to all 
potential routes of abuse.\4\
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    \4\ FDA's current thinking regarding the labeling of opioids is 
described in FDA's guidance for industry on ``Abuse-Deterrent 
Opioids--Evaluation and Labeling'' (April 2015). Any data relating 
to abuse-deterrent properties would be included in the DRUG ABUSE 
AND DEPENDENCE section of product labeling, 9.2 Abuse.
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    It is important that generic versions of opioid drug products 
referencing opioid drug products with FDA-approved labeling describing 
abuse-deterrent properties are available to help ensure availability of 
analgesics for patients who need them. FDA is interested in supporting 
the submission of ANDAs for which the RLD is an opioid drug product 
whose labeling describes abuse-deterrent properties and ensuring that 
generic opioid drug products are no less abuse-deterrent than the RLD 
in its efforts to combat the opioid epidemic.
    Topics for discussion during the open public comment period on Day 
1 and by the panel:
     Based on any testing you have attempted to perform or 
performed in accordance with the March 2016 draft guidance, are there 
any aspects of the guidance that need clarification or improvement?
     Are there any characteristics of the currently approved 
abuse-deterrent RLDs for which issuance of product specific guidance, 
beyond what is described in FDA's March 2016 draft guidance, would 
facilitate development of abuse-deterrent generic opioid drug products?
     Are there approaches or technologies for evaluating the 
abuse deterrence of generic opioid drug products that were not included 
in the March 2016 draft guidance that should be?
     What additional actions could FDA take to encourage the 
submission of ANDAs that reference an opioid drug product whose 
labeling describes abuse-deterrent properties?
     Are there potential consequences of the development and 
introduction of abuse-deterrent opioid drug products that warrant 
further consideration?

B. Day 2: Development of Standardized In Vitro Testing To Evaluate 
Abuse Deterrence

    The Office of Pharmaceutical Quality (OPQ) will discuss its vision 
for standardizing in vitro testing methodologies for evaluating 
purportedly abuse-deterrent formulations of opioid drug products. OPQ 
will also discuss the efforts being made to standardize in vitro 
testing conditions to apply to future products and some of the 
challenges being encountered. OPQ's Office of Testing and Research will 
then provide an update on its testing of abuse-deterrent formulations, 
including approaches being taken to simulate the ways individuals who 
abuse opioids manipulate opioid drug products for purposes of abuse 
(e.g., crushing, heating, dissolving). FDA recognizes that new 
technologies for deterring abuse of oral opioid drug products are 
rapidly evolving and is seeking public input on novel mechanisms and 
approaches being considered so that it may further consider how testing 
could be standardized.
    FDA intends to issue a general guidance describing FDA's 
recommendations for standardized in vitro testing to evaluate purported 
abuse-deterrent properties and considerations for a potential applicant 
as it develops an abuse-deterrent formulation of an opioid drug 
product. Building on the testing FDA has conducted and other available 
information including public input, FDA may recommend common protocols 
that incorporate standard test conditions, specified performance 
standards, control formulations and provide a tiered approach for 
determining when abuse-deterrent properties have been defeated and how 
that information may be used during drug development and for other 
relevant comparative situations. The guidance also may describe 
lifecycle considerations (e.g., the need for testing abuse deterrence 
throughout shelf life to determine if any product changes over time 
affect abuse-deterrence performance) and provide additional guidance on 
evaluating novel technological approaches used to deter abuse of oral 
opioid drug products.
    Topics for discussion during the open public comment period on Day 
2 and by the panel:
     What technical and quantitative issues should FDA consider 
as it develops guidance to recommend standardization of in vitro 
testing to evaluate the abuse deterrence of opioid drug product 
formulations for various routes of abuse, including ingestion, 
insufflation, injection, and smoking? For example, what should FDA 
consider with respect to mechanical manipulations (e.g., equipment, 
amount of effort, and time), chemical manipulations (e.g., solvent 
choice and availability), particle size distribution,

[[Page 69535]]

and volume of solvent used for extraction?
     How can FDA standardize in vitro testing to help 
substantiate appropriate and consistent product manufacture that 
assures abuse deterrence at release and through a drug product's shelf 
life?
     How can performance attributes measured by in vitro 
testing be quantified and linked to their impact on abuse deterrence? 
For example, discuss what amount of time delay in defeating an abuse-
deterrent property should be considered significant and the basis for 
the recommendation.
     How can FDA build flexibility into standardized testing so 
that it may be suitable for application to emerging technologies? Are 
there any specific emerging technologies that might require new types 
of testing?

II. Registration and Accommodations

    Registration: Registration is free and available on a first-come, 
first-served basis. Persons interested in attending this public meeting 
must register by close of business on October 17, 2016.
    If you need special accommodations because of a disability, please 
contact La'Shaune Morant, 240-316-3206, email: [email protected] 
no later than October 12, 2016.
    To register for the public meeting, please visit http://www.cvent.com/d/wvq0sm/4W (FDA has verified the Web address, but FDA is 
not responsible for subsequent changes to the Web site after this 
document publishes in the Federal Register) by October 17, 2016. Those 
without Internet access may register by contacting La'Shaune Morant, 
240-316-3206. Early registration is recommended because facilities are 
limited and, therefore, FDA may limit the number of participants from 
each organization. You will receive confirmation after you have 
registered and been accepted or you will be notified if you are on a 
waiting list. FDA may allow onsite registration if space is available. 
If registration reaches maximum capacity, FDA will post a notice 
closing registration at http://www.fda.gov/Drugs/NewsEvents/ucm509853.htm.
    Streaming Webcast of the Public Meeting: The meeting will also be 
Webcast. Persons interested in viewing the Webcast must register online 
by October 17, 2016. Early registration is recommended because Webcast 
connections may be limited. Organizations are requested to register all 
participants, but to view using one connection per location. A link to 
the live Webcast will be available at http://www.fda.gov/Drugs/NewsEvents/ucm509853.htm on the day of the public meeting. A video 
record of the public meeting will be available at http://www.fda.gov/Drugs/NewsEvents/ucm509853.htm following the meeting. 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.
    Requests for Oral Presentations: If you wish to present at the 
public meeting, you must register and indicate which topic(s) you wish 
to address: approach to testing FDA recommended in its draft guidance 
``General Principles for Evaluating the Abuse Deterrence of Generic 
Solid Oral Opioid Drug Products,'' new technologies for deterring abuse 
of oral opioid drug products, or standardization of in vitro testing 
methodologies for evaluating purportedly abuse-deterrent formulations 
of opioid drug products. This will help FDA organize the presentations. 
FDA will do its best to accommodate requests to make public comments. 
Individuals and organizations with common interests are urged to 
consolidate or coordinate their presentations, and request time for a 
joint presentation. Following the close of the registration, FDA will 
determine the amount of time allotted to each presenter and the 
approximate time each oral presentation is to begin, and will select 
and notify participants by October 24, 2016. All requests to make oral 
presentations must be received by the close of registration, October 
17, 2016. If you are selected, any presentation materials must be 
emailed to Michelle Eby (see FOR FURTHER INFORMATION CONTACT) no later 
than October 27, 2016. No commercial or promotional material will be 
permitted to be presented or distributed at the public meeting.
    FDA is holding this public meeting to obtain information on 
scientific and technical issues relating to formulation development and 
pre-market evaluation of opioid drug products with abuse-deterrent 
properties. In order to permit the widest possible opportunity for 
public comment, FDA is soliciting either electronic or written comments 
on all aspects of the public meeting topics. The deadline for 
submitting comments related to this public meeting is December 1, 2016.
    Accommodations: Attendees are responsible for their own hotel 
accommodations. Attendees making reservations at the College Park 
Marriott Hotel and Conference Center, 3501 University Blvd. East, 
Hyattsville, MD 20783, are eligible for a reduced rate of $231/night, 
not including applicable taxes. To receive the reduced rate, please 
reference ``FDA Opioid Drug Meeting'' if you make your reservation by 
calling 1-800-676-6137, or book your reservation at http://www.marriott.com/meeting-event-hotels/group-corporate-travel/groupCorp.mi?resLinkData=FDA%20Opioid%20Drug%20Meeting%5Ewasum%60FDGFDGA%60231.00%60USD%60false%602%6010/30/16%6011/1/16%6010/12/16&app=resvlink&stop_mobi=yes.
    If you need special accommodations because of a disability, please 
contact La'Shaune Morant, 240-316-3206, [email protected] no 
later than October 12, 2016.

III. Transcript Request

    Transcripts of the meeting will be available for review at the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20850, and on the Internet 
at http://www.regulations.gov approximately 30 days after the meeting. 
A transcript will also be available in either hard copy or on CD-ROM, 
after submission of a Freedom of Information request. The Freedom of 
Information office address is available on the Agency's Web site at 
http://www.fda.gov.

    Dated: September 30, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-24234 Filed 10-5-16; 8:45 am]
BILLING CODE 4164-01-P