Notice: Draft Guidance for Industry on Use of Histology in Biomarker 
Qualification Studies; Availability

Federal Register: Volume 76, Number 251 (Friday, December 30, 2011)
                  Pages 82306-82308

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a draft guidance for industry entitled ``Use of 
Histology in Biomarker Qualification Studies.'' This guidance is 
intended to assist sponsors that conduct biomarker qualification 
studies for which histology is a reference standard. This guidance 
discusses the processes that should be considered to ensure the quality 
and integrity of histology data in biomarker studies, and outlines the 
scientific standards for histology used in biomarker characterization 
and qualification. The recommendations in this guidance are intended 
for studies in biomarker qualification designated to justify the 
proposed context of use, where scientifically rigorous evaluation of 
biomarker performance in relation to histologic changes is essential. 
The principles outlined in this guidance are also applicable to 
exploratory biomarker studies.

DATES: Although you can comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that the Agency considers your comment on this 
draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by March 29, 2012.
    Submit either electronic or written comments concerning the 
proposed collection of information by February 28, 2012.

ADDRESSES: Submit written requests for single copies of the draft 
guidance to the Division of Drug Information, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002. Send 
one self-addressed adhesive label to assist that office in processing 
your requests. See the SUPPLEMENTARY

[[Page 82307]]

INFORMATION section for electronic access to the draft guidance 
document.
    Submit electronic comments on the draft guidance to http://www.regulations.gov.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.

FOR FURTHER INFORMATION CONTACT: Elizabeth Hausner, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 4145, Silver Spring, MD 20993-0002, (301) 
796-1084.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Use of Histology in Biomarker Qualification Studies.'' The 
discovery, characterization, qualification, and implementation of 
biomarkers have been identified by the FDA Critical Path Initiative as 
an important means for improving the efficiency and success rate of 
medical product development. Biomarkers have been broadly applied to 
describe the following:
     Structural features from the molecular to the anatomic 
level (e.g., genetic composition, receptor expression patterns, 
radiographic appearances);
     Biochemical measurements (e.g., serum levels of 
electrolytes, enzyme activity levels, prostate-specific antigen);
     Physiologic organ system function (e.g., creatinine 
clearance, pulmonary function tests, cardiac ejection fraction, 
electrocardiography).
    The studies to be submitted in support of a biomarker qualification 
will depend upon the proposed context of use and the ultimate goal of 
the submission. If a biomarker becomes qualified, analytically valid 
measurements of it can be relied upon to have a specific and 
interpretable meaning (e.g., physiologic, toxicologic, pharmacologic, 
or clinical) in drug development and regulatory decisionmaking. 
Industry can then employ the biomarker for the qualified context of use 
during premarketing drug development, and FDA reviewers can be 
confident about the qualified context of use without the need to 
reconfirm its applicability or utility. Accordingly, biomarker 
qualification studies are held to the same Good Laboratory Practice 
standards as are other premarketing studies.
    Traditionally, histology has been used to identify morphologic 
changes in the context of nonclinical safety assessment, clinical 
diagnosis, and evaluation of response to therapy. There is a strong 
correlation between specific histology findings, clinical outcomes, and 
some clinical chemistry parameters. Because of this history, histology 
is currently used in biomarker qualification as a reference standard to 
evaluate the sensitivity and specificity of potential biomarkers and 
their ability to indicate temporal correlation with the evolution and 
reversibility of morphologic changes. Because of the many variations in 
the practice of histology, this guidance is offered to facilitate 
quality, consistency, and scientific rigor in biomarker qualification 
studies where histology is used as a reference standard.
    Although great benefit may accrue from use of a qualified 
biomarker, a poorly characterized biomarker can do considerable harm. A 
poorly characterized biomarker may lead to inappropriate removal of a 
drug from development, encourage development of a drug that is unlikely 
to be approved, or lead to an erroneous perception of safety. Thus, for 
biomarkers to achieve the desired goal, the science that identifies, 
characterizes, and informs the biomarker use should be unbiased and of 
the highest quality.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the Agency's current thinking on the use of 
histology in biomarker qualification studies. It does not create or 
confer any rights for or on any person and does not operate to bind FDA 
or the public. An alternative approach may be used if such approach 
satisfies the requirements of the applicable statutes and regulations.

II. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

III. Paperwork Reduction Act of 1995

    Under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 
3501-3520), Federal Agencies must obtain approval from the Office of 
Management and Budget (OMB) for each collection of information that 
they conduct or sponsor. ``Collection of information'' is defined in 44 
U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes Agency requests or 
requirements that members of the public submit reports, keep records, 
or provide information to a third party. Section 3506(c)(2)(A) of the 
PRA (44 U.S.C. 3506(c)(2)(A)), requires Federal Agencies to provide a 
60-day notice in the Federal Register for each proposed collection of 
information before submitting the collection to OMB for approval. To 
comply with this requirement, FDA is publishing this notice of the 
proposed collection of information set forth in this document.
    With respect to the collection of information associated with this 
draft guidance, FDA invites comments on the following topics: (1) 
Whether the proposed information collected is necessary for the proper 
performance of FDA's functions, including whether the information will 
have practical utility; (2) the accuracy of FDA's estimated burden of 
the proposed information collected, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information collected; and (4) ways to 
minimize the burden of information collected on the respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    This draft guidance refers to previously approved collections of 
information found in FDA regulations. Sections II, IV, V, and VI of the 
guidance request that certain information be submitted to FDA and 
certain records be maintained by the sponsor. We may request this 
information under 21 CFR 58.81, 58.120, 58.185, 312.23, and 312.53. The 
collections of information for 21 CFR parts 58 and 312 have been 
approved under OMB control numbers 0910-0119 and 0910-0014, 
respectively.
    The draft guidance discusses certain information that should be 
described in the standard operating procedures (SOPs) and recommends 
that sponsors document and maintain records of the SOPs. In addition to 
the SOPs already covered by previously approved collections of 
information, the draft guidance recommends that two new procedures be 
included in the SOPs. The new procedures that require OMB approval for 
the collection of information are as follows: (1) Procedures for 
describing and documenting the type and extent of background lesions 
and (2) a detailed description of the pathology peer review process, 
including how disagreements among reviewers will be adjudicated.

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Based on FDA's data on the number of sponsors that would be covered by 
the draft guidance, we estimate that approximately 180 SOPs related to 
histologic evaluation will include the new procedures, and that 
sponsors will need approximately 30 minutes to document, maintain, and 
update their SOPs with the new procedures.
    FDA estimates the burden of this collection of information as 
follows:

                                                       Table 1--Estimated Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                  Average burden per
                                                           Number of       Number of records     Total annual      recordkeeping (in      Total hours
                                                         recordkeepers     per recordkeeper         records             hours)
--------------------------------------------------------------------------------------------------------------------------------------------------------
SOP New Procedures..................................                 30                   6                 180                 0.5                  90
                                                     ---------------------------------------------------------------------------------------------------
    Total...........................................  ..................  ..................  ..................  ..................                 90
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.

IV. Electronic Access

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

    Dated: December 22, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-33553 Filed 12-29-11; 8:45 am]
BILLING CODE 4160-01-P