[Federal Register Volume 82, Number 224 (Wednesday, November 22, 2017)]
[Notices]
[Pages 55617-55619]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.
    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: [email protected].

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


