81 FR 78605 - Non-Inferiority Clinical Trials To Establish Effectiveness; Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 216 (November 8, 2016)

Page Range		78605-78606
FR Document		2016-26931

The Food and Drug Administration (FDA or Agency) is announcing the availability of a guidance for industry entitled ``Non-Inferiority Clinical Trials to Establish Effectiveness.'' This document provides guidance to sponsors and applicants submitting investigational new drug applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or supplemental applications on the appropriate use of non-inferiority (NI) study designs to provide evidence of the effectiveness of a drug or biologic. The guidance gives advice on when NI studies demonstrating effectiveness of an investigational drug can provide interpretable results, how to choose the NI margin, and how to test the NI hypothesis.

Federal Register, Volume 81 Issue 216 (Tuesday, November 8, 2016)

[Federal Register Volume 81, Number 216 (Tuesday, November 8, 2016)]
[Notices]
[Pages 78605-78606]
From the Federal Register Online [www.thefederalregister.org]
[FR Doc No: 2016-26931]

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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2010-D-0075]

Non-Inferiority Clinical Trials To Establish Effectiveness;
Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the availability of a guidance for industry entitled ``Non-Inferiority
Clinical Trials to Establish Effectiveness.'' This document provides
guidance to sponsors and applicants submitting investigational new drug
applications (INDs), new drug applications (NDAs), biologics licensing
applications (BLAs), or supplemental applications on the appropriate
use of non-inferiority (NI) study designs to provide evidence of the
effectiveness of a drug or biologic. The guidance gives advice on when
NI studies demonstrating effectiveness of an investigational drug can
provide interpretable results, how to choose the NI margin, and how to
test the NI hypothesis.

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: 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-2010-D-0075 for ``Non-Inferiority Clinical Trials to Establish
Effectiveness; Guidance for Industry.'' 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.
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 or the Office of
Communication, Outreach and Development, Center for Biologics
Evaluation and Research (CBER), Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 71, Rm. 3128, 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: Scott Goldie, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire

[[Page 78606]]

Ave., Bldg. 21, Rm. 3557, Silver Spring, MD 20993-0002, 301-796-2055;
or Robert Temple, Center for Drug Evaluation and Research, Food and
Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 4212,
Silver Spring, MD 20993-0002, 301-796-2270; or Stephen Ripley, Center
for Biologics Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-
0002, 240-402-7911.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of a guidance for industry
entitled ``Non-Inferiority Clinical Trials to Establish
Effectiveness.'' This guidance consists of four parts. The first part
is a general discussion of regulatory, study design, scientific, and
statistical issues associated with the use of NI studies to establish
the effectiveness of a drug or biologic. The second part focuses on
some of these issues in more detail, notably the statistical approaches
used to determine the NI margin and to test for non-inferiority. The
third part addresses commonly asked questions about NI studies. The
fourth part includes four examples of successful and unsuccessful
efforts to define NI margins and test for non-inferiority.
This guidance finalizes the draft guidance for industry, ``Non-
Inferiority Clinical Trials,'' published in 2010. In addition, it
supersedes the guidance for industry, ``Antibacterial Drug Products:
Use of Noninferiority Trials to Support Approval,'' also published in
2010, which will be withdrawn.
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 NI clinical trials to establish
effectiveness. 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.

II. Electronic Access

Persons with access to the Internet may obtain the guidance at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm; http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm; or
http://www.regulations.gov.

Dated: November 3, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-26931 Filed 11-7-16; 8:45 am]
BILLING CODE 4164-01-P

78606 Federal Register / Vol. 81, No. 216 / Tuesday, November 8, 2016 / Notices

Ave., Bldg. 21, Rm. 3557, Silver Spring, Dated: November 3, 2016. Therapeutic Equivalence Evaluations,’’
MD 20993–0002, 301–796–2055; or Leslie Kux, which is known generally as the
Robert Temple, Center for Drug Associate Commissioner for Policy. ‘‘Orange Book.’’ Under FDA regulations,
Evaluation and Research, Food and [FR Doc. 2016–26931 Filed 11–7–16; 8:45 am] drugs are removed from the list if the
Drug Administration, 10903 New BILLING CODE 4164–01–P
Agency withdraws or suspends
Hampshire Ave., Bldg. 22, Rm. 4212, approval of the drug’s NDA or ANDA
Silver Spring, MD 20993–0002, 301– for reasons of safety or effectiveness or
796–2270; or Stephen Ripley, Center for DEPARTMENT OF HEALTH AND if FDA determines that the listed drug
Biologics Evaluation and Research, HUMAN SERVICES was withdrawn from sale for reasons of
Food and Drug Administration, 10903 safety or effectiveness (21 CFR 314.162).
Food and Drug Administration A person may petition the Agency to
New Hampshire Ave., Bldg. 71, Rm.
determine, or the Agency may
7301, Silver Spring, MD 20993–0002, [Docket No. FDA–2016–P–2674] determine on its own initiative, whether
240–402–7911. a listed drug was withdrawn from sale
Determination That CALAN SR
SUPPLEMENTARY INFORMATION: for reasons of safety or effectiveness.
(Verapamil Hydrochloride) Extended-
This determination may be made at any
I. Background Release Oral Tablet, 180 Milligrams,
time after the drug has been withdrawn
Was Not Withdrawn From Sale for
FDA is announcing the availability of from sale, but must be made prior to
Reasons of Safety or Effectiveness
approving an ANDA that refers to the
a guidance for industry entitled ‘‘Non-
AGENCY: Food and Drug Administration, listed drug (§ 314.161 (21 CFR 314.161)).
Inferiority Clinical Trials to Establish
HHS. FDA may not approve an ANDA that
Effectiveness.’’ This guidance consists does not refer to a listed drug.
of four parts. The first part is a general ACTION: Notice.
CALAN SR (verapamil hydrochloride)
discussion of regulatory, study design, extended-release oral tablet, 180 mg, is
SUMMARY: The Food and Drug
scientific, and statistical issues Administration (FDA or Agency) has the subject of NDA 019152 held by
associated with the use of NI studies to determined that CALAN SR (verapamil Pfizer Inc. CALAN SR is indicated for
establish the effectiveness of a drug or hydrochloride) extended-release oral the treatment of hypertension, to lower
biologic. The second part focuses on tablet, 180 milligrams (mg), was not blood pressure. CALAN SR (verapamil
some of these issues in more detail, withdrawn from sale for reasons of hydrochloride) extended-release oral
notably the statistical approaches used safety or effectiveness. This tablet, 180 mg, is currently listed in the
to determine the NI margin and to test determination will allow FDA to ‘‘Discontinued Drug Product List’’
for non-inferiority. The third part approve abbreviated new drug section of the Orange Book.
addresses commonly asked questions applications (ANDAs) for verapamil Heritage Pharma Labs, Inc., submitted
about NI studies. The fourth part hydrochloride extended-release oral a citizen petition dated August 31, 2016
includes four examples of successful tablet, 180 mg, if all other legal and (Docket No. FDA–2016–P–2674), under
and unsuccessful efforts to define NI regulatory requirements are met. 21 CFR 10.30, requesting that the
margins and test for non-inferiority. Agency determine whether CALAN SR
FOR FURTHER INFORMATION CONTACT:
(verapamil hydrochloride) extended-
This guidance finalizes the draft Stacy Kane, Center for Drug Evaluation release oral tablet, 180 mg, was
guidance for industry, ‘‘Non-Inferiority and Research, Food and Drug withdrawn from sale for reasons of
Clinical Trials,’’ published in 2010. In Administration, 10903 New Hampshire safety or effectiveness.
addition, it supersedes the guidance for Ave., Bldg. 51, Rm. 6236, Silver Spring, After considering the citizen petition
industry, ‘‘Antibacterial Drug Products: MD 20993–0002, 301–796–8363. and reviewing Agency records, and
Use of Noninferiority Trials to Support SUPPLEMENTARY INFORMATION: In 1984, based on the information we have at this
Approval,’’ also published in 2010, Congress enacted the Drug Price time, FDA has determined under
which will be withdrawn. Competition and Patent Term § 314.161 that CALAN SR (verapamil
This guidance is being issued Restoration Act of 1984 (Pub. L. 98–417) hydrochloride) extended-release oral
consistent with FDA’s good guidance (the 1984 amendments), which tablet, 180 mg, was not withdrawn for
practices regulation (21 CFR 10.115). authorized the approval of duplicate reasons of safety or effectiveness. The
The guidance represents the current versions of drug products under an petitioner has identified no data or other
thinking of FDA on NI clinical trials to ANDA procedure. ANDA applicants information suggesting that CALAN SR
establish effectiveness. It does not must, with certain exceptions, show that (verapamil hydrochloride) extended-
the drug for which they are seeking release oral tablet, 180 mg, was
establish any rights for any person and
approval contains the same active withdrawn for reasons of safety or
is not binding on FDA or the public.
ingredient in the same strength and effectiveness. We have carefully
You can use an alternative approach if
dosage form as the ‘‘listed drug,’’ which reviewed our files for records
it satisfies the requirements of the
is a version of the drug that was concerning the withdrawal of CALAN
applicable statutes and regulations.
previously approved. ANDA applicants SR (verapamil hydrochloride) extended-
II. Electronic Access do not have to repeat the extensive release oral tablet, 180 mg, from sale.
clinical testing otherwise necessary to We have also independently evaluated
Persons with access to the Internet gain approval of a new drug application relevant literature and data for possible
may obtain the guidance at http:// (NDA). postmarketing adverse events. We have
mstockstill on DSK3G9T082PROD with NOTICES

www.fda.gov/Drugs/Guidance The 1984 amendments include what found no information that would
ComplianceRegulatoryInformation/ is now section 505(j)(7) of the Federal indicate that this drug product was
Guidances/default.htm; http:// Food, Drug, and Cosmetic Act (21 U.S.C. withdrawn from sale for reasons of
www.fda.gov/BiologicsBloodVaccines/ 355(j)(7)), which requires FDA to safety or effectiveness.
GuidanceComplianceRegulatory publish a list of all approved drugs. Accordingly, the Agency will
Information/Guidances/default.htm; or FDA publishes this list as part of the continue to list CALAN SR (verapamil
http://www.regulations.gov. ‘‘Approved Drug Products With hydrochloride) extended-release oral

VerDate Sep<11>2014 16:27 Nov 07, 2016 Jkt 241001 PO 00000 Frm 00042 Fmt 4703 Sfmt 4703 E:\FR\FM\08NON1.SGM 08NON1

Document Created: 2018-02-14 08:23:49
Document Modified: 2018-02-14 08:23:49

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		Scott Goldie, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 21, Rm. 3557, Silver Spring, MD 20993-0002, 301-796-2055; or Robert Temple, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Rm. 4212, Silver Spring, MD 20993-0002, 301-796-2270; or Stephen Ripley, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993- 0002, 240-402-7911.
FR Citation		81 FR 78605

81 FR 78605 - Non-Inferiority Clinical Trials To Establish Effectiveness; Guidance for Industry; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICESFood and Drug Administration

Federal Register Volume 81, Issue 216 (November 8, 2016)

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration