82 FR 55617 - General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products; Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 82, Issue 224 (November 22, 2017)

Page Range		55617-55619
FR Document		2017-25248

The Food and Drug Administration (FDA or Agency) is announcing the availability of a guidance for industry entitled ``General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.'' This guidance is intended to assist a person who plans to develop and submit an abbreviated new drug application (ANDA) to seek approval of a generic version of a solid oral opioid drug product that references an opioid drug product with abuse- deterrent properties described in its labeling. The guidance recommends studies, including comparative in vitro and pharmacokinetic (PK) studies, that a potential ANDA applicant should conduct and submit to FDA to demonstrate that a generic solid oral opioid drug product is no less abuse deterrent than its reference listed drug (RLD) with respect to all potential routes of abuse.

Federal Register, Volume 82 Issue 224 (Wednesday, November 22, 2017)

[Federal Register Volume 82, Number 224 (Wednesday, November 22, 2017)]
[Notices]
[Pages 55617-55619]
From the Federal Register Online [www.thefederalregister.org]
[FR Doc No: 2017-25248]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-D-0785]

General Principles for Evaluating the Abuse Deterrence of Generic
Solid Oral Opioid Drug Products; Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the availability of a guidance for industry entitled ``General
Principles for Evaluating the Abuse Deterrence of Generic Solid Oral
Opioid Drug Products.'' This guidance is intended to assist a person
who plans to develop and submit an abbreviated new drug application
(ANDA) to seek approval of a generic version of a solid oral opioid
drug product that references an opioid drug product with abuse-
deterrent properties described in its labeling. The guidance recommends
studies, including comparative in vitro and pharmacokinetic (PK)
studies, that a potential ANDA applicant should conduct and submit to
FDA to demonstrate that a generic solid oral opioid drug product is no
less abuse deterrent than its reference listed drug (RLD) with respect
to all potential routes of abuse.

DATES: Submit either electronic or written comments on Agency guidances
at any time.

ADDRESSES: You may 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-2016-D-0785 for ``General Principles for Evaluating the Abuse
Deterrence of Generic Solid Oral Opioid Drugs; Guidance for Industry;
Availability.'' Received comments 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.thefederalregister.org/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.
Submit written requests for single copies of this guidance to the
Division of Drug Information, Center for Drug Evaluation and Research,
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale
Building, 4th Floor, Silver Spring, MD 20993-0002. Send one self-
addressed adhesive label to assist that office in processing your
requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Gail Schmerfeld, Office of Generic
Drugs, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002,
301-796-9291, email: gail.schmerfeld@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of a guidance for industry
entitled ``General Principles for Evaluating the

[[Page 55618]]

Abuse Deterrence of Generic Solid Oral Opioid Drug Products.''
Prescription opioid analgesics are an important component of modern
pain management. However, abuse and misuse of these drug products have
created a serious and widespread public health problem. Addressing this
public health crisis is an FDA priority. One potentially important step
toward the goal of creating safer opioid analgesics has been the
development of opioid drug products that are formulated to deter abuse.
``Abuse-deterrent properties,'' as that term is used in the guidance to
which this notice applies are those properties shown to meaningfully
deter abuse; abuse-deterrent properties do not fully prevent abuse or
addiction. FDA considers the development of these products a high
public health priority. It is important that less costly generic
versions of opioids that reference listed drugs whose labeling
describes abuse-deterrent properties are available to ensure access to
safe and effective analgesics for patients who need them.
If the summary in section 9.2 of the approved labeling for the RLD
indicates that FDA has concluded that the RLD has properties that are
expected to (or have been shown through postmarketing studies to) deter
abuse, the potential ANDA applicant should evaluate its proposed
generic drug to show that it is no less abuse deterrent than the RLD
with respect to all of the potential routes of abuse. This will ensure
the generic drug is no less abuse-deterrent than the RLD with respect
to all potential routes of abuse and minimize the risk of shifting
abuse to other, potentially more dangerous routes. This guidance
describes FDA's current thinking on the studies that should be
conducted by a potential ANDA applicant and submitted to FDA in an ANDA
to demonstrate that a generic solid oral opioid drug product is no less
abuse deterrent than its RLD with respect to all potential routes of
abuse. These studies are in addition to other studies that may be
needed to support ANDA approval (e.g., as described in product-specific
guidances).
The final guidance, like the draft guidance, focuses on the general
principles for developing and evaluating the abuse deterrence of
generic solid oral opioid drug products formulated to incorporate
physical or chemical barriers, agonist/antagonist combinations,
aversive agents, or a combination of two or more of these technologies.
FDA will continue to assess the state of science and, as novel
technologies develop, will address them by issuing additional guidance,
as appropriate.
In the Federal Register of March 25, 2016, FDA announced the
availability of the draft guidance for industry ``General Principles
for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug
Products'' (81 FR 16186). FDA subsequently announced in the Federal
Register of October 6, 2016, and held on October 31-November 1, 2016, a
public meeting to discuss scientific and technical issues relating to
formulation development and premarket evaluation of opioid drug
products with abuse-deterrent properties (81 FR 69532). This final
guidance reflects our consideration of comments made in the dockets for
the draft guidance (Docket No. FDA-2016-D-0785) and for the public
meeting (Docket No. FDA-2016-N-2896) and comments made during the
public meeting, and provides the Agency's current thinking with respect
to the general principles for evaluating the abuse deterrence of
generic solid oral opioid drug products.
Among other changes, the final guidance eliminates the
recommendation to use a control to identify discriminatory study
conditions for comparing the proposed generic opioid drug product (the
test (T) product) and the RLD (reference (R) product). Instead, FDA
recommends that a potential ANDA applicant conduct extraction studies
to assess the particular vulnerabilities of T and R products to inform
the comparison of their abuse deterrence. The final guidance also
provides more detailed recommendations regarding the conduct of in vivo
studies, specifically comparative PK studies of manipulated T and R
products to evaluate the potential for abuse by the oral and nasal
routes of administration.
Appendix 1 of the final guidance continues to describe some of the
ways in which the T and R products can be physically manipulated and
provides recommendations for conducting extraction studies to assess
the particular vulnerabilities of the T and R products to inform the
comparison of their abuse deterrence. FDA continues to recommend
potential ANDA applicants follow a tier-based approach to
extractability testing to efficiently compare a T product to its R
product and limit the number of tests required for evaluating the abuse
deterrence of the T product, but has modified some of the initial
recommendations regarding solvents.
Appendix 2 provides recommendations for evaluating abuse by
ingestion. In the final guidance, FDA clarifies the circumstances under
which a potential applicant should conduct a comparative oral PK study.
Appendices 3, 4, and 5 provide modified recommendations for evaluating
abuse by injection, insufflation, and smoking, respectively.
The guidance addresses the general principles for evaluating abuse
deterrence in generic solid oral opioid drug products. FDA may provide
additional testing recommendations in future product-specific
guidances. For example, FDA may recommend in a product-specific
guidance that a potential ANDA applicant evaluate human abuse potential
(for example, evaluate a study subject's willingness to take drug
again) if R product contains a known aversive agent. Further, FDA will
continue to assess the state of the science and, as novel technologies
develop, will address them by issuing revised or additional guidance,
as appropriate.
Potential ANDA applicants may pose questions regarding evaluation
of abuse deterrence for a generic solid oral opioid drug product
through FDA's pre-ANDA program. The goals of the pre-ANDA program are
to clarify regulatory expectations for prospective applicants early in
the development process, assist applicants in developing more complete
submissions, promote a more efficient and effective ANDA review
process, and reduce the number of review cycles required to obtain ANDA
approval, particularly for complex products. FDA considers abuse-
deterrent opioids to be products that fall within the definition of
complex product as that term has been defined in the GDUFA
Reauthorization Performance Goals and Program Enhancements Fiscal Years
2018-2022, which can be found at https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM525234.pdf. The pre-ANDA
program provides for, among other things, submission of controlled
correspondence and requests for formal meetings between FDA and
applicants on complex generic drug development issues.
This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
current thinking of FDA on ``General Principles for Evaluating the
Abuse Deterrence of Generic Solid Oral Opioid Drug Products.'' It does
not establish any rights for any person and is not binding on FDA or
the public. You can use an alternative approach if it satisfies the
requirements of the applicable statutes and regulations. This guidance
is not subject to Executive Order 12866.

[[Page 55619]]

II. Electronic Access

Persons with access to the internet may obtain the guidance at
either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or
https://www.regulations.gov.

Dated: November 16, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-25248 Filed 11-21-17; 8:45 am]
BILLING CODE 4164-01-P

55618 Federal Register / Vol. 82, No. 224 / Wednesday, November 22, 2017 / Notices

Abuse Deterrence of Generic Solid Oral by issuing additional guidance, as a potential applicant should conduct a
Opioid Drug Products.’’ Prescription appropriate. comparative oral PK study. Appendices
opioid analgesics are an important In the Federal Register of March 25, 3, 4, and 5 provide modified
component of modern pain 2016, FDA announced the availability of recommendations for evaluating abuse
management. However, abuse and the draft guidance for industry ‘‘General by injection, insufflation, and smoking,
misuse of these drug products have Principles for Evaluating the Abuse respectively.
created a serious and widespread public Deterrence of Generic Solid Oral Opioid The guidance addresses the general
health problem. Addressing this public Drug Products’’ (81 FR 16186). FDA principles for evaluating abuse
health crisis is an FDA priority. One subsequently announced in the Federal deterrence in generic solid oral opioid
potentially important step toward the Register of October 6, 2016, and held on drug products. FDA may provide
goal of creating safer opioid analgesics October 31–November 1, 2016, a public additional testing recommendations in
has been the development of opioid meeting to discuss scientific and future product-specific guidances. For
drug products that are formulated to technical issues relating to formulation example, FDA may recommend in a
deter abuse. ‘‘Abuse-deterrent development and premarket evaluation product-specific guidance that a
properties,’’ as that term is used in the of opioid drug products with abuse- potential ANDA applicant evaluate
guidance to which this notice applies deterrent properties (81 FR 69532). This human abuse potential (for example,
are those properties shown to final guidance reflects our consideration evaluate a study subject’s willingness to
meaningfully deter abuse; abuse- of comments made in the dockets for the take drug again) if R product contains a
deterrent properties do not fully prevent draft guidance (Docket No. FDA–2016– known aversive agent. Further, FDA
abuse or addiction. FDA considers the D–0785) and for the public meeting will continue to assess the state of the
development of these products a high (Docket No. FDA–2016–N–2896) and science and, as novel technologies
public health priority. It is important comments made during the public develop, will address them by issuing
that less costly generic versions of meeting, and provides the Agency’s revised or additional guidance, as
opioids that reference listed drugs current thinking with respect to the appropriate.
whose labeling describes abuse- general principles for evaluating the Potential ANDA applicants may pose
deterrent properties are available to abuse deterrence of generic solid oral
questions regarding evaluation of abuse
ensure access to safe and effective opioid drug products.
deterrence for a generic solid oral opioid
analgesics for patients who need them. Among other changes, the final
guidance eliminates the drug product through FDA’s pre-ANDA
If the summary in section 9.2 of the program. The goals of the pre-ANDA
recommendation to use a control to
approved labeling for the RLD indicates program are to clarify regulatory
identify discriminatory study conditions
that FDA has concluded that the RLD for comparing the proposed generic expectations for prospective applicants
has properties that are expected to (or opioid drug product (the test (T) early in the development process, assist
have been shown through postmarketing product) and the RLD (reference (R) applicants in developing more complete
studies to) deter abuse, the potential product). Instead, FDA recommends submissions, promote a more efficient
ANDA applicant should evaluate its that a potential ANDA applicant and effective ANDA review process, and
proposed generic drug to show that it is conduct extraction studies to assess the reduce the number of review cycles
no less abuse deterrent than the RLD particular vulnerabilities of T and R required to obtain ANDA approval,
with respect to all of the potential routes products to inform the comparison of particularly for complex products. FDA
of abuse. This will ensure the generic their abuse deterrence. The final considers abuse-deterrent opioids to be
drug is no less abuse-deterrent than the guidance also provides more detailed products that fall within the definition
RLD with respect to all potential routes recommendations regarding the conduct of complex product as that term has
of abuse and minimize the risk of of in vivo studies, specifically been defined in the GDUFA
shifting abuse to other, potentially more comparative PK studies of manipulated Reauthorization Performance Goals and
dangerous routes. This guidance T and R products to evaluate the Program Enhancements Fiscal Years
describes FDA’s current thinking on the potential for abuse by the oral and nasal 2018–2022, which can be found at
studies that should be conducted by a routes of administration. https://www.fda.gov/downloads/
potential ANDA applicant and Appendix 1 of the final guidance ForIndustry/UserFees/GenericDrugUser
submitted to FDA in an ANDA to continues to describe some of the ways Fees/UCM525234.pdf. The pre-ANDA
demonstrate that a generic solid oral in which the T and R products can be program provides for, among other
opioid drug product is no less abuse physically manipulated and provides things, submission of controlled
deterrent than its RLD with respect to recommendations for conducting correspondence and requests for formal
all potential routes of abuse. These extraction studies to assess the meetings between FDA and applicants
studies are in addition to other studies particular vulnerabilities of the T and R on complex generic drug development
that may be needed to support ANDA products to inform the comparison of issues.
approval (e.g., as described in product- their abuse deterrence. FDA continues This guidance is being issued
specific guidances). to recommend potential ANDA consistent with FDA’s good guidance
The final guidance, like the draft applicants follow a tier-based approach practices regulation (21 CFR 10.115).
guidance, focuses on the general to extractability testing to efficiently The guidance represents the current
principles for developing and evaluating compare a T product to its R product thinking of FDA on ‘‘General Principles
asabaliauskas on DSKBBXCHB2PROD with NOTICES

the abuse deterrence of generic solid and limit the number of tests required for Evaluating the Abuse Deterrence of
oral opioid drug products formulated to for evaluating the abuse deterrence of Generic Solid Oral Opioid Drug
incorporate physical or chemical the T product, but has modified some of Products.’’ It does not establish any
barriers, agonist/antagonist the initial recommendations regarding rights for any person and is not binding
combinations, aversive agents, or a solvents. on FDA or the public. You can use an
combination of two or more of these Appendix 2 provides alternative approach if it satisfies the
technologies. FDA will continue to recommendations for evaluating abuse requirements of the applicable statutes
assess the state of science and, as novel by ingestion. In the final guidance, FDA and regulations. This guidance is not
technologies develop, will address them clarifies the circumstances under which subject to Executive Order 12866.

VerDate Sep<11>2014 18:57 Nov 21, 2017 Jkt 244001 PO 00000 Frm 00066 Fmt 4703 Sfmt 4703 E:\FR\FM\22NON1.SGM 22NON1

Document Created: 2017-11-22 00:48:43
Document Modified: 2017-11-22 00:48:43

Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Notices
Action		Notice of availability.
Dates		Submit either electronic or written comments on Agency guidances at any time.
Contact		Gail Schmerfeld, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, 301-796-9291, email: [email protected]
FR Citation		82 FR 55617

82 FR 55617 - General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products; Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 82, Issue 224 (November 22, 2017)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration