Development and Regulation of Abuse-Deterrent Formulations of Opioid Medications; Public Meeting, 56810-56814 [2014-22514]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 79, Number 184 (Tuesday, September 23, 2014)]
[Notices]
[Pages 56810-56814]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-22514]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-N-1359]


Development and Regulation of Abuse-Deterrent Formulations of 
Opioid Medications; Public Meeting

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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

SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
meeting to discuss the development, assessment, and regulation of 
abuse-deterrent formulations of opioid medications. The meeting will 
focus on scientific and technical issues related to the development and 
in vitro assessment of these products, as well as FDA's approach 
towards assessing the benefits and risks of all opioid medications, 
including those with abuse-deterrent properties.
    FDA is seeking input on these issues from all stakeholders, 
including patients, health care providers, the pharmaceutical industry, 
patient advocates, academics, researchers, and other governmental 
entities.

DATES: The public meeting will be held on October 30, 2014, from 8:30 
a.m. to 5 p.m. and October 31, 2014, from 8:30 a.m. to 3 p.m. The 
public meeting may be extended or may end early depending on the level 
of public participation. Individuals who wish to present at the meeting 
must register by October 14, 2014. Individuals who wish to attend the 
meeting but do not wish to make a presentation should register by 
October 24, 2014. See section III under the SUPPLEMENTARY INFORMATION 
section for information on how to register to speak at the meeting. 
Submit either electronic or written comments by January 9, 2015.

ADDRESSES: The public meeting will be held at the Sheraton Silver 
Spring Hotel, 8777 Georgia Ave., Silver Spring, MD 20910, 301-589-0800, 
FAX: 301-587-4791.
    Submit electronic comments to https://www.regulations.gov. Submit 
written comments to the Division of Dockets Management (HFA-305), Food 
and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 
20852. Identify all comments with the docket number found in brackets 
in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Mary C. Gross, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20903, 301-796-3519, FAX: 301-796-
9899, email: mary.gross@fda.hhs.gov; or Brutrinia D. Cain, Center for 
Drug Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20993, 301-796-4633, email: 
Brutrinia.cain@fda.hhs.gov; or Georgiann Ienzi, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20993, 301-796-3515, FAX: 301-847-
8737, email: Georgiann.Ienzi@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Introduction

    Opioid analgesics are important medications that are widely 
prescribed for the treatment of pain, and certain opioids are also used 
in drug treatment programs. When used properly, opioid drugs provide 
significant benefits for patients. However, they also carry a risk of 
misuse, abuse, addiction, overdose, and death. According to an analysis 
from the Centers for Disease Control and Prevention (CDC), in 2010, 
opioid analgesics were involved in 16,651 overdose deaths, which 
represented a 313 percent increase over the past decade (Ref. 1). The 
Substance Abuse and Mental Health Services Administration (SAMHSA) 
reports that for each overdose death, there were an additional 11 
treatment admissions (Ref. 2), 33 emergency department visits (Ref. 3), 
and 880 non-medical users of these drugs (Ref. 4).
    The development of and transition to use of opioids with meaningful 
abuse-deterrent properties is one important component of a multipronged 
approach to addressing abuse of opioid medications. FDA looks forward 
to a future in which most or all opioid medications are available in 
formulations that are less susceptible to abuse than the formulations 
that are on the market today.
    To achieve this goal, FDA is taking steps to incentivize and 
support the development of opioid medications with progressively better 
abuse-deterrent properties. These steps include working with individual 
sponsors on promising abuse-deterrent technologies, developing 
appropriate testing methodologies for both innovator and generic 
products, and publishing guidance on the development and labeling of 
abuse-deterrent opioids.
    FDA understands that the iterative innovation in abuse-deterrent 
technologies we envision could have implications for generic opioid 
medications. It is important that generic options remain available to 
ensure widespread access to effective analgesics for patients who need 
them.
    The transition to abuse-deterrent formulations of opioid 
medications presents a number of complex scientific and regulatory 
challenges. The purpose of this public meeting is to share and solicit 
comments on the Agency's ongoing work to identify and address these 
challenges.

II. Background

    Opioid analgesics (e.g., hydrocodone, oxycodone, morphine, and 
fentanyl) play a vital role in treating both chronic and acute pain. 
The Institute of Medicine reports that millions of Americans are living 
with chronic pain, including those suffering from back pain, 
neuropathic pain, and pain associated with cancer, with an annual 
economic cost of approximately $600 billion in health care expenses and 
lost productivity (Ref. 5). Millions more suffer from acute pain 
following common medical procedures performed every day across the 
country, such as dental and orthopedic procedures. While FDA is working 
to support the efficient development of safer, non-opioid alternatives 
for treating pain, opioids are currently an indispensable component of 
the pain treatment armamentarium, and will remain so for some time to 
come.
    Unfortunately, the abuse and misuse of opioid medications has 
become a public health crisis. Opioid-involved drug overdose death 
rates in the United States have increased four-fold from 1999 to 2008 
(Ref. 6). Emergency department visits, substance abuse treatment 
admissions, and economic costs associated with opioid abuse have also 
increased dramatically over the same period (Ref. 7). This rise in 
adverse events has largely paralleled the

[[Page 56811]]

rise in the number of prescriptions for these products (Ref. 7). A 
comprehensive approach is needed to address this crisis--one that 
involves other Federal agencies, State governments, professional 
medical organizations, academic institutions, and other stakeholders. 
FDA, as one part of the Federal response to this crisis, is working to 
improve the safe use of opioids.
    As part of this work, FDA strongly supports the development of 
opioid medications with meaningful abuse-deterrent properties. Although 
this field holds great promise, it is relatively new. Currently 
available abuse-deterrent formulations are expected to provide 
improvements over existing formulations, but their impact on the abuse 
epidemic may be limited. For example, even though some abuse-deterrent 
technologies have been demonstrated to deter some forms of abuse (e.g., 
injection or intranasal) to varying degrees in controlled settings, as 
yet no marketed opioid formulation has been demonstrated to deter the 
simplest and most common form of abuse--swallowing a number of intact 
tablets or capsules. Further, all currently available formulations 
designed to deter abuse can be defeated with sufficient time, 
equipment, and expertise. These limitations may be impossible to 
completely overcome as these products must release the opioids they 
contain to have their intended therapeutic effects.
    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 for opioid 
medications 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 medications is a top priority. FDA's 
work in support of this priority includes the following:
     Established an Opioids Taskforce to coordinate and support 
FDA work on abuse-deterrent formulations of opioids.
     Consulted with advisory committees in connection with the 
development, evaluation, and labeling of opioids with abuse-deterrent 
technologies. For example, in October 2010, a joint meeting of the 
Anesthetic and Life Support Drugs Advisory Committee and the Drug 
Safety and Risk Management Advisory Committee was held to discuss, 
among other things, how sponsors should design and conduct postmarket 
epidemiological or observational studies to evaluate whether and to 
what extent products designed to reduce the likelihood and incidence of 
abuse actually do so.
     Issued draft guidance to assist industry in developing and 
assessing abuse-deterrent opioid formulations (``Draft Guidance for 
Industry: Abuse-Deterrent Opioids--Evaluation and Labeling,'' 78 FR 
2676; January 14, 2013). FDA participated in the Abuse-Deterrence 
Formulation Science meeting held on September 30 and October 1, 2013, 
which provided a forum to discuss the draft guidance. FDA is committed 
to publishing a final version of this guidance as soon as possible.
     Met and worked with sponsors regarding approval of 
potentially abuse-deterrent formulations and reviewed applications 
seeking approval, or, subsequent to such approval, seeking inclusion of 
language in product labeling regarding the products' purportedly abuse-
deterrent properties.
     Determined that the original formulation of OXYCONTIN 
posed an increased potential for abuse by certain routes of 
administration compared to reformulated OXYCONTIN. Based on the 
totality of the data and information available, FDA concluded that the 
benefits of original OXYCONTIN no longer outweighed its risks. The 
Agency determined that original OXYCONTIN was withdrawn for reasons of 
safety and effectiveness, and accordingly will not accept abbreviated 
new drug applications (ANDAs) that refer to original OXYCONTIN.
     Conducted or supported research on opioid formulations 
designed to deter abuse. This includes development of in vitro testing 
methodologies to assess purportedly abuse-deterrent opioid 
formulations.
     Sought public comment on innovative packaging, storage, 
and disposal systems that could help deter prescription opioid abuse 
(see https://www.gpo.gov/fdsys/pkg/FR-2014-04-09/pdf/2014-07909.pdf).

III. Scope of the Public Meeting

    FDA is opening a docket and holding a public meeting to obtain 
public input on issues related to abuse-deterrent formulations of 
opioid medications. The first session of the meeting will focus on 
scientific and technical issues related to the development and in vitro 
assessment of these products. The second session will focus on FDA's 
approach to assessing the benefits and risks of the opioids, including 
opioids with abuse-deterrent properties. The second session will cover 
both FDA's relevant actions to date as well as how FDA can continue to 
and further support advances in this field.

A. Session 1: Development and Evaluation of Abuse-Deterrent Opioid 
Formulations

    In this session FDA personnel and others will give presentations on 
the manufacturing and formulation science related to abuse-deterrent 
formulations, including methods used to evaluate the in vitro 
performance of such formulations. FDA's goal is to develop 
scientifically rigorous methods for assessing how well purportedly 
abuse-deterrent opioid formulations--whether submitted in connection 
with a new drug application (NDA) or an ANDA--actually deter abuse. As 
discussed in the ``Draft Guidance for Industry: Abuse-Deterrent 
Opioids--Evaluation and Labeling,'' for NDA products evidence from in 
vitro studies, bioavailability studies, human abuse liability studies, 
and/or epidemiological studies may be needed to fully evaluate a 
product's potentially abuse-deterrent properties. In this session, 
however, we are focusing only on the first category of testing--in 
vitro studies.
    FDA will discuss its internal research in this area. This 
discussion will include the manufacturing science behind the design of 
abuse-deterrent formulations, a variety of manipulation techniques, and 
the results of testing approved products and placebo formulations under 
a range of different manipulation conditions. FDA will also discuss 
results from its research contract with the National Institute for 
Pharmaceutical Technology and Education on identifying excipient 
material attributes that impact abuse-deterrent properties. As we will 
discuss, these results show that while currently available technologies 
have promise with regard to reducing abuse, additional work is needed, 
as they also have significant limitations and vulnerabilities.
    FDA is developing standardized in vitro test methodologies to 
assess how well purportedly abuse-deterrent formulations perform under 
conditions designed to simulate the ways individuals who abuse opioids 
manipulate opioid products for purposes of abuse (e.g., crushing, 
heating, dissolving).

[[Page 56812]]

    For both NDAs and ANDAs, these methodologies could be used to 
identify the critical performance attributes of the drug potentially 
related to abuse-deterrence (e.g., crush-resistance, extraction-
resistance). For NDAs, these methodologies could be used to assess 
comparative performance with predecessor products or appropriate 
controls (e.g., a non-abuse-deterrent immediate-release (IR) 
formulation with the same active ingredient). For ANDAs, FDA is still 
considering the best approach, but these methodologies could be used to 
assess the proposed generic product's critical performance attributes 
related to abuse deterrence relative to those of the reference listed 
drug (RLD).>
    For both NDAs and ANDAs, FDA intends to issue general guidance 
defining common protocols for in vitro testing. FDA is considering 
whether to provide more detailed, product-specific in vitro testing 
recommendations for ANDAs as well, possibly by including such guidance 
together with product-specific bioequivalence testing recommendations 
where appropriate.
    Topics for Discussion:
     Please comment on the limitations of currently available 
abuse-deterrent technologies and what next-generation technologies or 
products might be able to overcome these limitations and provide 
improved protection against abuse and misuse. Please comment both on 
the development of iterative improvements in abuse-deterrent 
technologies for solid oral dose forms of opioids and on the 
development of abuse-deterrent formulation technologies for non-solid 
oral dosage forms (e.g., transdermal patches, solutions, and buccal 
films).
     Please comment on the approach discussed above whereby FDA 
would focus on a given RLD's critical performance attributes related to 
abuse deterrence for purposes of evaluating an ANDA referencing that 
formulation. How would these critical performance attributes be 
identified for a given product? What if certain attributes are not 
described in the RLD's approved labeling?
     Please comment on the approach discussed above whereby FDA 
develops and publishes a standard battery of in vitro test 
manipulations to be conducted on all, or some appropriate subset of, 
potentially abuse-deterrent formulations.
    [cir] Specifically, please comment on the utility of step-wise 
testing, moving from simple manipulations to more complex ones. If the 
abuse-deterrent features are compromised or defeated by simple 
manipulations, would further testing that is more complex (e.g., 
involving more than one manipulation) and more destructive (e.g., 
higher temperatures, harsher solvents, etc.) be valuable?
    [cir] Please also comment on the availability and use of common 
solvents in which extraction studies should be conducted.
    [cir] Please comment on the appropriate controls for in vitro 
assessments of proposed generic abuse-deterrent formulations. Should 
the proposed generic abuse-deterrent formulation only be compared with 
the RLD formulation with abuse-deterrent properties or is the use of an 
additional negative control necessary to ensure that the test is 
sufficiently discriminatory? Please comment on the selection and 
standardization of a negative control, and what degree of superiority 
compared with the negative control should be viewed as meaningful.
    [cir] Please comment on what performance attributes should be 
considered ``critical'' in assessing whether and to what extent a 
formulation effectively deters abuse, such as the time delay or the 
amount of effort needed by the abuser under controlled conditions to 
access the drug for purposes of abuse. How can these performance 
attributes be quantified and linked to their impact on abuse 
deterrence? For example, an abuse-deterrent technology may only delay--
rather than completely prevent--access to the opioid for purposes of 
abuse. Please comment on the amount of time delay that should be 
considered significant and the basis for your recommendation.
    [cir] Please comment on how FDA should adapt and expand its testing 
methodologies as new abuse-deterrent technologies become available. Are 
there any specific emerging technologies that might require new types 
of testing?

B. Session 2: FDA's Regulation of Abuse-Deterrent Opioid Formulations

    FDA assesses each opioid drug product's safety and efficacy on a 
case-by-case basis. Abuse potential is one aspect of a product's safety 
that the Agency considers, together with all other appropriate factors, 
in determining whether a product's benefits outweigh its risks. As part 
of this determination, FDA considers the benefit/risk profile of 
available therapies.
    For instance, FDA determined that original OXYCONTIN, which lacked 
abuse-deterrent properties, posed an increased potential for abuse by 
certain routes of administration compared to reformulated OXYCONTIN. 
After reformulated OXYCONTIN was approved, FDA concluded that the 
benefits of original OXYCONTIN no longer outweighed its risks. The 
Agency determined that original OXYCONTIN was withdrawn for reasons of 
safety and effectiveness, and accordingly will not accept ANDAs that 
refer to original OXYCONTIN.
    Regarding the labeling of opioid products with potentially abuse-
deterrent properties, FDA's current thinking is described in the 
``Draft Guidance for Industry: Abuse-Deterrent Opioids--Evaluation and 
Labeling.'' Studies designed to evaluate a product's purportedly abuse-
deterrent properties should be scientifically rigorous. In order to 
support a description of such properties in labeling, the data should 
predict or show that these properties can be expected to, or actually 
do, result in a meaningful reduction in that product's abuse potential 
(Ref. 8). To date, only two products--TARGINIQ and reformulated 
OXYCONTIN--have obtained labeling for their abuse-deterrent properties 
consistent with this thinking.
    Regarding generic versions of opioids designed to deter abuse, FDA 
is still carefully considering its approach and much remains to be 
worked out. See Session 1 above for a discussion of how comparative in 
vitro testing may be used to assess these products.
    As abuse-deterrent technologies continue to improve and new opioid 
products are developed and approved that meaningfully reduce abuse, FDA 
expects the market for opioid medications to continue to transition to 
abuse-deterrent formulations. Ultimately, FDA looks forward to a future 
in which all or substantially all opioid medications are less 
susceptible to abuse than the conventional formulations that dominate 
the market today.
    Although FDA has received requests to require all opioid 
medications, or some subset of them, to be formulated with abuse-
deterrent technologies, we have said that a class-wide requirement is 
not feasible or in the interests of public health at this time (Ref. 
9). This field is still in its early stages. Both the technologies 
involved and the clinical, epidemiological, and statistical methods for 
evaluating those technologies are new and rapidly evolving. As 
discussed above, we have limited experience with these formulations and 
currently available abuse-deterrent technologies have significant 
limitations.
    Accordingly, FDA currently applies the product-by-product approach 
described in Session 2, with a goal of incentivizing an incremental, 
sponsor-

[[Page 56813]]

driven market transition from conventional opioid formulations to 
formulations with meaningful abuse-deterrent properties. We anticipate, 
however, that at some point--after abuse-deterrent formulations have 
become available for a number of different opioid active moieties and 
after we have obtained more experience with this field--FDA may 
determine that the risks of all or most opioid products that lack 
abuse-deterrent properties outweigh the benefits in light of available 
therapies. We pose several questions about these approaches below.
    Finally, given that currently marketed abuse-deterrent technologies 
have significant limitations, FDA is interested in appropriately 
incentivizing and supporting meaningful improvements in abuse-deterrent 
technologies so that progressively better abuse-deterrent formulations 
become available. We pose questions about this below as well.
    Topics for Discussion:
     As described in the ``Draft Guidance for Industry: Abuse-
Deterrent Opioids--Evaluation and Labeling,'' FDA intends to approve 
language in NDA product labeling that accurately and fairly describes 
the abuse-deterrent properties of an opioid product if adequately 
supported by data (Ref. 8). We hope that the availability of such 
labeling claims will incentivize development and use of those products 
preferentially where appropriate. Please comment on this approach, 
including its impact on encouraging the development of generic opioids 
with abuse-deterrent formulations.
     What does it mean for a product to have meaningful abuse-
deterrent properties? Please comment on what data should be provided to 
support that determination.
     FDA is considering under what circumstances the benefit/
risk assessment methodology discussed in Session 2 would support a 
refusal to approve, or withdrawal of approval for, an NDA for an opioid 
formulation lacking meaningful abuse-deterrent properties if an 
available therapy or therapies with meaningful abuse-deterrent 
properties exist. Please comment on this approach and its implications 
for the development of abuse-deterrent opioid formulations, patient 
access to opioid medications, generic competition, and potential drug 
shortages. What other considerations should pertain?
     One aspect of the benefit/risk assessment relates to the 
consideration of available therapies. Please comment on FDA's 
consideration of available therapies in assessing (or re-assessing) the 
benefit/risk profile of an opioid drug product. What product or 
products should FDA consider to be ``available therapies'' when 
assessing or re-assessing the benefit/risk profile of an opioid 
product?
     Much of the focus in developing abuse-deterrent 
formulations has been on extended-release and long-acting (ER/LA) 
opioids. As more ER/LA opioid products are reformulated with abuse-
deterrent technologies, individuals who abuse opioids may shift their 
attention to opioid drugs lacking abuse-deterrent properties, including 
IR products. Are there special considerations associated with IR 
products that do not apply to ER/LA opioids? Also, please comment on 
whether there are subclasses of opioid medications for which a shift to 
abuse-deterrent formulations may be of limited public health benefit.
     As discussed above, FDA does not think a class-based, 
abuse-deterrent formulation requirement is feasible or appropriate at 
this time. Under what circumstances would it be appropriate to impose 
such a requirement and on what classes or subclasses of opioid 
products? What considerations should be taken into account to help 
ensure that such an approach does not conflict with public health needs 
for continued access to important medications?
     If FDA were to determine that the risks of an opioid 
product--or, in the case of a class-based approach, many such 
products--that lacks abuse-deterrent properties outweigh the benefits 
in light of available therapies, how could the Agency minimize any 
negative impact on patient access and on generic and innovator drug 
development? One possible option would be to apply a delayed 
implementation date (e.g., 2 years) to give affected sponsors a 
``phase-out'' period to either reformulate or withdraw products lacking 
abuse-deterrent properties. Please comment.
     As noted above, FDA is interested in encouraging the 
development and introduction of opioid products with progressively 
better abuse-deterrent properties, as well as the phase-out of products 
with less meaningful properties, as abuse-deterrent technologies 
improve. What actions could FDA take to support this goal? Under what 
circumstances would it be appropriate to refuse to approve or initiate 
withdrawal of a product with, for example, ``first generation'' abuse-
deterrent properties?
     Finally, FDA is aware of the importance of identifying 
ways to measure the impacts (positive or negative) of the actions we 
take to incentivize and support the development and introduction of 
abuse-deterrent formulations of opioid medications. Are there specific 
potential impacts of our actions that we need to consider in addition 
to those addressed above?

III. Attendance and Registration

    Attendance is free and will be on a first-come, first served basis. 
Individuals who wish to present at the public meeting must register on 
or before October 14, 2014, at https://fda-abuse-deterrent-public-meeting.eventbrite.com. FDA will accommodate requests to speak, as time 
permits, and will determine the amount of time allotted to each 
presenter based on the numbers of speaker requests. Speakers should 
plan on arriving to the meeting prior to the assigned time in order to 
avoid forfeiting your assigned time should the agenda move ahead of 
schedule. An agenda and additional meeting background material will be 
available approximately 3 days before the meeting at https://www.fda.gov/Drugs/NewsEvents/ucm408607.htm.
    Individuals who wish to attend the meeting but do not wish to make 
a presentation should also register at https://fda-abuse-deterrent-public-meeting.eventbrite.com by October 24, 2014. Onsite registration 
on the day of the meeting will be based on space availability.
    If you need special accommodations due to a disability, please 
contact Mary Gross, Brutrinia Cain, or Georgiann Ienzi (see FOR FURTHER 
INFORMATION CONTACT) at least 7 days in advance.
    Information about how to view the live Web cast of this meeting 
will posted at https://www.fda.gov/Drugs/NewsEvents/ucm408607.htm. A 
video recording of the meeting will be available at the same Web 
address for 1 year.

IV. Comments

    Interested persons may submit either electronic comments regarding 
this document to https://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. To ensure 
consideration, submit comments by January 9, 2015. Comments may be seen 
in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at https://www.regulations.gov.

[[Page 56814]]

V. Transcripts

    As soon as possible after a transcript of the public meeting is 
available, it will be accessible at https://www.regulations.gov. It may 
be viewed at the Division of Dockets Management (see ADDRESSES). A 
transcript will also be available in either hardcopy or on CD-ROM, 
after submission of a Freedom of Information request. Written requests 
are to be sent to the Division of Freedom of Information (ELEM-1029), 
Food and Drug Administration, 12420 Parklawn Dr., Element Bldg., 
Rockville, MD 20857.

VI. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen between 
9 a.m. and 4 p.m., Monday through Friday. (FDA has verified the Web 
site addresses, but FDA is not responsible for any subsequent changes 
to the Web sites after this document publishes in the Federal 
Register.)

    1. CDC, ``Opioids Drive Continued Increase in Drug Overdose 
Deaths'', 2013, available at https://www.cdc.gov/media/releases/2013/
p0220drugoverdosedeaths.html.
    2. SAMHSA, Center for Behavioral Health Statistics and Quality. 
Treatment Episode Data Set (TEDS): 2001-2011. National Admissions to 
Substance Abuse Treatment Services. BHSIS Series S-65, HHS 
Publication No. (SMA) 13-4772. Rockville, MD, 2013, available at 
https://www.samhsa.gov/data/2k13/TEDS2011/TEDS2011N.pdf.
    3. SAMHSA, Center for Behavioral Health Statistics and Quality, 
``Drug Abuse Warning Network,'' 2011, available at https://
samhsa.gov/data/dawn/nations/Nation2011AllMA.xls.
    4. SAMHSA, ``Results from the 2012 National Survey on Drug Use 
and Health,'' detailed table 1.1A, NSDUH Series H-46, HHS 
Publication No. (SMA) 13-4795. Rockville, MD, 2013, available at 
https://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/NationalFindings/NSDUHresults2012.pdf.
    5. Institute of Medicine, ``Relieving Pain in America: A 
Blueprint for Transforming Prevention, Care, Education, and 
Research,'' available at https://www.iom.edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-Transforming-Prevention-Care-Education-Research.aspx.
    6. CDC, ``Vital Signs: Overdoses of Prescription Opioid Pain 
Relievers--United States, 1999-2008,'' available at https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6043a4.htm.
    7. Department of Health and Human Services, ``Addressing 
Prescription Drug Abuse in the United States--Current Activities and 
Future Opportunities,'' available at https://www.cdc.gov/
HomeandRecreationalSafety/pdf/
HHSPrescriptionDrugAbuseReport
09.2013.pdf.
    8. ``Draft Guidance for Industry: Abuse-Deterrent Opioids--
Evaluation and Labeling,'' January 2013, available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM334743.pdf.
    9. Janet Woodcock, M.D., letter to Center for Lawful Access and 
Abuse Deterrence et al., dated October 25, 2013, in Docket No. FDA-
2013-P-0703, available at https://www.regulations.gov/#!documentDetail;D=FDA-2013-P-0703-0004.

    Dated: September 17, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-22514 Filed 9-22-14; 8:45 am]
BILLING CODE 4164-01-P