Federal Register / Vol. 80, No. 30 / Friday, February 13, 2015 / Notices 8089 

opioid antagonist with high affinity for 

the mu opioid receptor. The naloxone is 

intended to be inactive when 

SUBOXONE is used appropriately, but 

to precipitate more severe withdrawal 

symptoms if the product is crushed and 

injected by an individual dependent on 

full opioid agonists. A variety of factors 

such as degree of opioid dependence, 

relative amount of buprenorphine 

exposure, and route of administration 

influence the antagonist effect of 

naloxone. As a result, buprenorphine/ 

naloxone combination products may not 

have the same effect on non-dependent 

opioid abusers or abusers of 

buprenorphine. As stated in the 

approved SUBOXONE labeling in 

section 12.2, ‘‘naloxone in 

buprenorphine/naloxone tablets may 

deter injection of buprenorphine/ 

naloxone tablets by persons with active 

substantial heroin or other full muopioid dependence,’’ but ‘‘some opioiddependent persons, particularly those 

with a low level of full mu-opioid 

physical dependence or those whose 

opioid physical dependence is 

predominantly to buprenorphine, abuse 

buprenorphine/naloxone combinations 

by the intravenous or intranasal route.’’ 

SUBUTEX has important therapeutic 

benefits for certain patient populations 

that may not tolerate or should not be 

exposed to the naloxone in SUBOXONE. 

Specifically, as explained in section 

5.11 of the approved labeling for 

SUBOXONE, ‘‘[b]uprenorphine/ 

naloxone products are not 

recommended in patients with severe 

hepatic [liver] impairment and may not 

be appropriate for patients with 

moderate hepatic impairment.’’ Section 

5.11 further states that ‘‘hepatic 

impairment results in a reduced 

clearance of naloxone to a much greater 

extent than buprenorphine,’’ and thus, 

‘‘patients with severe hepatic 

impairment will be exposed to 

substantially higher levels of naloxone 

than patients with normal hepatic 

function.’’ SUBUTEX also is preferred to 

SUBOXONE for patients transitioning 

from treatment with methadone or other 

long-acting opioid products because 

they are at higher risk for precipitated 

and prolonged withdrawal, and the 

naloxone in buprenorphine/naloxone 

combination products may cause worse 

withdrawal in this population. 

Although Reckitt has publicly stated 

that SUBUTEX ‘‘creates a greater risk of 

misuse, abuse, and diversion’’ than 

SUBOXONE (please refer to letter from 

Reckitt to Health Care Providers, 

available at http:// 

buprenorphine.samhsa.gov/ 

SubutexDiscontinuation9-16-11.pdf), 

Reckitt has not submitted any data, 

information, or analysis to support this 

claim. Based on our independent review 

of the available data and the published 

studies on the relative abuse liability of 

SUBUTEX and SUBOXONE, we do not 

have sufficient information at this time 

to determine that SUBUTEX poses an 

increased potential for abuse or misuse 

relative to SUBOXONE. Furthermore, as 

discussed previously, SUBUTEX has 

important therapeutic benefits for 

certain patient populations that may not 

tolerate or should not be exposed to the 

naloxone in SUBOXONE. 

For these reasons, based on the data 

and information available to the Agency 

at this time, we find that the benefits of 

SUBUTEX continue to outweigh the 

risks. Therefore, we conclude that 

SUBUTEX was not withdrawn from sale 

for reasons of safety or effectiveness. 

Accordingly, the Agency will 

continue to list SUBUTEX in the 

‘‘Discontinued Drug Product List’’ 

section of the Orange Book. The 

‘‘Discontinued Drug Product List’’ 

delineates, among other items, drug 

products that have been discontinued 

from marketing for reasons other than 

safety or effectiveness. FDA will not 

begin procedures to withdraw approval 

of ANDAs that refer to SUBUTEX. Such 

ANDAs may continue to be approved by 

the Agency as long as they meet all 

other legal and regulatory requirements 

for the approval of ANDAs. 

Dated: February 9, 2015. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2015–03001 Filed 2–12–15; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2014–N–2187] 

Identifying Potential Biomarkers for 

Qualification and Describing Contexts 

of Use To Address Areas Important to 

Drug Development; Request for 

Comments 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice; request for comments. 

SUMMARY: The Food and Drug 

Administration (FDA or Agency) is 

seeking information to facilitate 

development and qualification of 

biomarkers in areas related to human 

drug therapeutics. Towards this goal, 

FDA is encouraging interested groups 

and individuals to submit information 

on specific medical and biological areas 

where novel biomarkers can be 

identified that would meaningfully 

advance drug development. FDA 

encourages respondents to describe 

evidentiary considerations that are 

important to qualify these biomarkers 

for a specific context of use. Details of 

information that should be provided to 

the Agency are described in the survey. 

DATES: Submit either electronic or 

written comments by April 14, 2015. 

ADDRESSES: You may submit comments 

by any of the following methods: 

Electronic Submissions 

Submit electronic comments in either 

of the following ways: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

• SurveyMonkey Link: https://

www.surveymonkey.com/s/RHJLHS7. 

This survey may be used to provide 

feedback on answers to questions 

regarding potential biomarkers for 

qualification and to describe contexts of 

use to address areas important to drug 

development. 

Written Submissions 

Submit written submissions in the 

following ways: 

• Mail/Hand delivery/Courier (for 

paper submissions): Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852. 

Instructions: All submissions received 

must include the Docket No. FDA– 

2014–N–2187 for this document. All 

comments received may be posted 

without change to http://

www.regulations.gov, including any 

personal information provided. It is 

only necessary to send one set of 

comments. For additional information 

on submitting comments, see the 

‘‘Request for Information’’ heading of 

the SUPPLEMENTARY INFORMATION section 

of this document. 

Docket: For access to the docket to 

read background documents or 

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, between 9 

a.m. and 4 p.m., Monday through 

Friday. 

FOR FURTHER INFORMATION CONTACT: 

Marianne Noone, Center for Devices and 

Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 21, Rm. 4528, Silver Spring, 

MD 20993–0002, 301–796–7495. 


tkelley on DSK3SPTVN1PROD with NOTICES
8090 Federal Register / Vol. 80, No. 30 / Friday, February 13, 2015 / Notices 

SUPPLEMENTARY INFORMATION: 

I. Background 

The President signed into law the 

Food and Drug Administration Safety 

and Innovation Act (FDASIA) (Pub. L. 

112–144) on July 9, 2012. Title I of 

FDASIA reauthorizes the Prescription 

Drug User Fee Act (PDUFA) and 

provides FDA with the user fee 

resources necessary to maintain an 

efficient review process for human drug 

and biological products. The 

reauthorization of PDUFA added 

performance goals and procedures for 

the Agency that represent FDA’s 

commitments during fiscal years 2013 

through 2017. These commitments are 

fully described in the document entitled 

‘‘PDUFA Reauthorization Performance 

Goals and Procedures Fiscal Years 2013 

through 2017’’ (PDUFA Goals Letter), 

available on FDA’s Web site at http://

www.fda.gov/downloads/ForIndustry/

UserFees/PrescriptionDrugUserFee/

UCM270412.pdf. Section IX of the 

PDUFA Goals Letter entitled 

‘‘Enhancing Regulatory Science and 

Expediting Drug Development’’ 

references support for the identification 

and advancement of biomarkers. 

A biomarker is an objective 

characteristic that is measured and 

evaluated as an indicator of normal 

biologic processes, pathogenic 

processes, or pharmacologic responses 

to treatment. Biomarkers can serve 

many purposes in clinical drug 

development, including the following: 

Defining the appropriate patient 

populations for study, as well as those 

who should receive the drug in clinical 

practice; pharmacodynamic markers for 

proof of concept and dose selection; and 

pharmacodynamic markers of adverse 

effects. A subset of pharmacodynamic 

biomarkers can serve as replacements 

for clinical efficacy endpoints that 

reflect how a patient feels, functions, or 

survives. The path to development of 

promising therapeutics can be enabled 

by the availability of biomarkers that are 

analytically validated and clinically 

qualified for a specific context of use 

(i.e., a comprehensive, clear, and precise 

statement that describes the manner of 

use, interpretation, and purpose of use 

of a biomarker in drug development). 

Qualification is based on a body of 

evidence that demonstrates that the 

biomarkers are fit for purpose in drug 

development and evaluation (http://

www.fda.gov/Drugs/ 

DevelopmentApprovalProcess/Drug

DevelopmentToolsQualification

Program/ucm284076.htm). Further, 

qualification is dependent on the 

specific proposed context of use. 

Biomarkers that are qualified can help 

to progressively reduce uncertainty 

about the outcome of clinical 

development programs. 

Public/private partnerships involving 

regulatory, academic, and industry 

scientists, collaborating within a 

precompetitive framework, are essential 

to catalyzing progress. Because of 

limitations in resources, such efforts 

must be focused on the opportunities 

that offer the greatest potential for 

impact. 

FDA intends to facilitate 

identification of the most promising 

biomarkers and the areas important to 

drug development and to promote 

efforts that will aid in the qualification 

and regulatory adoption of the drug 

development framework. 

II. Request for Information 

FDA is seeking public feedback to 

identify promising biomarker 

candidates in areas important to drug 

development and to identify 

considerations for evidence needed to 

qualify various types of biomarkers for 

specific contexts of use. FDA requests 

identification of specific biomarkers 

with a proposed context of use and of 

the type of evidence needed to support 

qualification. After reviewing the 

information provided, FDA will post the 

collated information on its Web site. 

A. Information Requirements 

In general, submitted information 

should include the following for each 

biomarker nominated, as well as any 

other relevant information: 

• Areas that have a critical need for 

biomarkers to assist drug development; 

• The name of the biomarker; 

• The proposed context of use for the 

biomarker (if known); 

• The reason why the biomarker 

should be considered, taking into 

account its usefulness as a drug 

development tool; and 

• Any evidence that should be 

developed to support qualification of 

the biomarker. 

B. Questions and Requests 

Specific questions and requests are as 

follows: 

1. Are there specific aspects of drug 

development that could be enhanced 

through the development of biomarkers? 

a. Please list the specific applications 

of biomarkers that address areas 

important to drug development. 

b. Please list the specific areas (for 

example, a specific disease area or an 

organ toxicity) needed for development 

of biomarkers important to drug 

development. 

c. Is there information or efforts 

which could be leveraged to advance 

these areas? If yes, please describe. 

d. Are there areas that appear to be 

promising for the development of new 

biomarkers and for which collaborative 

engagement from stakeholders offers a 

path forward? If so, please explain. 

• Are there groups positioned to 

accomplish this? If yes, please describe. 

e. Are there barriers that preclude 

engagement or investment in biomarkers 

for these priority areas? If yes, please 

explain. 

2. In each of these priority areas that 

are important to drug development, 

please provide the following 

information: 

a. Biomarker: What specific 

biomarkers do you believe represent the 

greatest near-term opportunity to 

establish utility in drug development 

(i.e., that could be substantially 

advanced by facilitating discussion and 

consensus building)? 

b. Rationale: Why should the 

biomarker(s) be included on the list, 

taking into account its usefulness in 

regulatory decisionmaking as a drug 

development tool? 

c. Context of use: Can you please 

describe/propose a specific context of 

use for the biomarker(s)? 

d. Evidentiary gaps: To support the 

proposed context of use, what do you 

see as the largest evidentiary gaps that 

need to be addressed to permit ‘‘fit for 

purpose’’ qualification? 

e. How can these evidentiary gaps be 

addressed? 

f. Collaborative data sharing: Can any 

of these gaps be addressed by 

collaborative data sharing of existing 

data versus prospective studies 

specifically dedicated to addressing the 

gap? 

3. Please indicate your affiliation from 

the following list: Academia, 

pharmaceutical sector, biotechnology 

sector, government, professional 

organization, non-profit organization, 

clinician, patient advocacy group, 

patient, or other (please provide 

specifics, if you choose other). 

III. Paperwork Reduction Act 

This Federal Register notice requests 

input from biomarker experts from 

academia, the pharmaceutical industry, 

and government organizations on the 

evidentiary standards for biomarkers or 

on the expectations about data for 

qualification of different types of 

biomarkers. 

This request is exempt from the Office 

of Management and Budget’s review 

under 5 CFR 1320.3(h)(4): Facts or 

opinions submitted in response to 

general solicitations of comments from 

the public, published in the Federal 

Register or other publications, 

regardless of the form or format thereof, 


tkelley on DSK3SPTVN1PROD with NOTICES
Federal Register / Vol. 80, No. 30 / Friday, February 13, 2015 / Notices 8091 

provided that no person is required to 

supply specific information pertaining 

to the commenter, other than that 

necessary for self-identification, as a 

condition of the Agency’s full 

consideration of the comment. 

Dated: February 5, 2015. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2015–02976 Filed 2–12–15; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2014–N–1049] 

Conditional Approval of New Animal 

Drugs; Public Meeting; Request for 

Comments 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notification of public meeting; 

request for comments. 

The Food and Drug Administration 

(FDA) is announcing a public meeting to 

explore the use of statutory changes to 

expand the use of conditional approval 

to additional categories of new animal 

drugs. This policy exploration is 

consistent with a stated performance 

goal in the Animal Drug User Fee 

Amendments of 2013 (ADUFA III) goals 

letter. FDA is requesting that you submit 

any comments related to this issue by 

September 30, 2015. 

Date and Time: The public meeting 

will be held on March 16, 2015, from 1 

p.m. until 4 p.m. 

Location: The public meeting will be 

held at the Center for Veterinary 

Medicine, Food and Drug 

Administration, 7519 Standish Pl., 3rd 

Floor, Rockville, MD 20855. Parking is 

free. 

Contact Person: Laura Bradbard, 

Center for Veterinary Medicine, Food 

and Drug Administration, 7519 Standish 

Pl., Rm. 159, Rockville, MD 20855, 240– 

276–9109, FAX: 240–276–9020, email: 

Laura.Bradbard@fda.hhs.gov. 

Registration: Registration is free and 

available on a first-come, first-served 

basis. Persons interested in attending 

this meeting must register by March 10, 

2015. For general questions about the 

meeting, for assistance to register for the 

meeting, to request an opportunity to 

make an oral presentation, or to request 

special accommodations due to a 

disability, contact Laura Bradbard (see 

Contact Person). Please include your 

name, organization, and contact 

information. If you are requesting an 

opportunity to speak, please send a brief 

summary of your comments. Early 

registration for the meeting is 

encouraged due to limited time and 

space. 

SUPPLEMENTARY INFORMATION: 

I. Background 

FDA considers the timely review of 

the safety and effectiveness of new 

animal drugs to be central to the 

Agency’s mission to protect and 

promote the public health. Before 2004, 

the timeliness and predictability of the 

new animal drug review program was a 

concern. The Animal Drug User Fee Act 

enacted in 2003 (Pub. L. 108–130; 

hereinafter referred to as ‘‘ADUFA I’’), 

authorized FDA to collect user fees for 

5 years—fiscal year (FY) 2004 to FY 

2008—that were to be dedicated to 

expediting the review of new animal 

drug applications according to certain 

performance goals and to expand and 

modernize the new animal drug review 

program. The Agency agreed to meet a 

comprehensive set of performance goals 

established to show significant 

improvement in the timeliness and 

predictability of the new animal drug 

review process. The implementation of 

ADUFA I provided a significant funding 

increase that enabled FDA to increase 

the number of staff dedicated to the new 

animal drug application review process. 

In 2008, before ADUFA I expired, 

Congress passed the Animal Drug User 

Fee Amendments of 2008 (Pub. L. 110– 

316; hereinafter referred to as ‘‘ADUFA 

II’’), which included an extension of 

ADUFA for an additional 5 years—FY 

2009 to FY 2013. ADUFA II 

performance goals were established 

based on ADUFA I FY 2008 review 

timeframes. In addition, FDA provided 

program enhancements to reduce review 

cycles and improve communications 

during reviews. 

In 2013, before ADUFA II expired, 

Congress passed ADUFA III (Pub. L. 

113–14), which was signed by the 

President on June 13, 2013. Like its 

predecessors, ADUFA III includes its 

own comprehensive set of performance 

goals. One such goal, as stated in the 

ADUFA III goals letter, is: Beginning in 

early FY 2014, the Agency agrees to 

explore, in concert with industry, the 

feasibility of pursuing statutory 

revisions, consistent with the Agency’s 

mission to protect and promote the 

public health, that may expand the use 

of conditional approvals to other 

appropriate categories of new animal 

drug applications and develop 

recommendations by September 30, 

2015. 

Currently, the conditional approval 

provisions allow an applicant to market 

a new animal drug intended for a minor 

species or a minor use in a major 

species after the applicant has 

demonstrated that the drug is safe and 

can be manufactured according to 

standards applicable to approval of 

applications under section 512(b)(1) of 

the Federal Food, Drug, and Cosmetic 

Act (21 U.S.C. 360b(b)(1)). FDA and 

members of regulated industry jointly 

agreed to explore, as part of the 

performance goals outlined in the 

ADUFA III goals letter, statutory 

changes to expand the use of 

conditional approval to other 

appropriate categories of new animal 

drugs. 

This public meeting is intended to 

provide an additional opportunity for 

public comment. The Agency is 

especially interested in receiving 

comments during the meeting on the 

categories of new animal drug 

applications that would be considered 

‘‘appropriate’’ and why; concerns, if 

any, that might arise due to the 

expansion of the Conditional Approval 

process; and the length of marketing 

exclusivity, if any, that should be 

associated with the expansion of the 

Conditional Approval process. 

FDA will consider comments received 

at this meeting as it moves forward with 

this process. 

FDA has already opened public 

docket FDA Docket No. FDA–2014–N– 

1049 to receive comments on the issue 

(79 FR 53430, September 9, 2014). 

Although you can comment on this 

document at any time, to ensure that the 

Agency considers your comment before 

finalizing work on the exploration 

process described in this document, 

submit either electronic or written 

comments by September 30, 2015. 

II. Participation in a Public Meeting 

While oral presentations from specific 

individuals and organizations may be 

limited due to time constraints during 

the public meeting, stakeholders may 

submit electronic or written comments 

discussing any issues of concern to the 

administration record (the docket). All 

relevant data and documentation should 

be submitted with the comments to 

Docket No. FDA–2014–N–1049. Submit 

electronic comments to http:// 

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. It is only 

necessary to send one set of comments. 

Identify comments with the docket 

number FDA–2014–N–1049. Received 

comments may be seen in the Division 


tkelley on DSK3SPTVN1PROD with NOTICES