[Federal Register Volume 81, Number 164 (Wednesday, August 24, 2016)]
[Proposed Rules]
[Pages 58341-58380]
[FR Doc No: 2016-19875]

Vol. 81

Wednesday,

No. 164

August 24, 2016

Part VI

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Parts 16 and 58

Good Laboratory Practice for Nonclinical Laboratory Studies; Proposed
Rule

Federal Register / Vol. 81 , No. 164 / Wednesday, August 24, 2016 /
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 16 and 58

[Docket No. FDA-2010-N-0548]

Good Laboratory Practice for Nonclinical Laboratory Studies

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the regulations for good laboratory practice (GLP) for nonclinical
laboratory studies to require a complete quality system approach,
referred to as a GLP Quality System, when safety and toxicity studies
support or are intended to support applications or submissions for
products regulated by FDA. We are proposing additional management
responsibilities and standard operating procedures (SOPs) consistent
with the proposed requirement for a GLP Quality System. We also propose
to revise the testing facility definition to reflect current practices
for the conduct of nonclinical laboratory studies, particularly
multisite studies. These proposals are intended to build quality into
planning, conducting, and reporting a nonclinical laboratory study and
to help ensure data quality and integrity.

DATES: Submit either electronic or written comments on the proposed
rule by November 22, 2016. Submit comments on information collection
issues under the Paperwork Reduction Act of 1995 by September 23, 2016
see section IX). See section VII for the proposed effective date of a
final rule based on this proposed rule.

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-N-0548 for ``Good Laboratory Practice for Nonclinical
Laboratory Studies.'' 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 comments on information collection issues to the Office of
Management and Budget (OMB) in the following ways:
    Fax to the Office of Information and Regulatory Affairs, OMB, Attn:
FDA Desk Officer, FAX:<PHONE_NUMBER>, or email to
<EMAIL_ADDRESS>All comments should be identified with the
title, ``Reporting and Recordkeeping Requirements for Good Laboratory
Practice for Nonclinical Laboratory Studies.''

FOR FURTHER INFORMATION CONTACT: Vernon Toelle, Office of Surveillance
and Compliance, Center for Veterinary Medicine, Food and Drug
Administration, 7519 Standish Pl., MPN4-142, Rockville, MD 20855, 240-
402-5637; or Kristin Webster Maloney, Office of Policy and Risk
Management, Office of Regulatory Affairs, Food and Drug Administration,
10903 New Hampshire Ave., Bldg. 32, Rm. 4373, Silver Spring, MD 20993,
240-402-4993.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Introduction
    A. What is the background for this rule?
    B. Why is FDA proposing this rule?
III. Description of the Part 58 Proposal
    A. What did FDA consider when drafting this rule?
    B. Part 58, Subpart A--General Provisions
    C. Part 58, Subpart B--Organization and Personnel
    D. Part 58, Subpart C--Facilities
    E. Part 58, Subpart D--Equipment
    F. Part 58, Subpart E--Nonclinical Laboratory Study Operations

    G. Part 58, Subpart F--Test, Control, and Reference Articles
    H. Part 58, Subpart G--Protocol for and Conduct of a Nonclinical
Laboratory Study
    I. Part 58, Subpart J--Records and Reports
    J. Part 58, Subpart K--Disqualification of Any Person Conducting
a Phase of a Nonclinical Laboratory Study
IV. Regulatory Hearing Before FDA
V. Analysis of Environmental Impact
VI. Legal Authority
VII. Proposed Implementation Plan
VIII. Economic Analysis of Impacts
    A. Introduction
    B. Summary
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. References

I. Executive Summary

A. Purpose of the Proposed Rule

    Nonclinical laboratory studies, often referred to as preclinical
studies when conducted before first-in-human clinical studies, provide
safety or toxicity information, or both, that is essential for the
development of FDA-regulated products and help determine the safety of
new food ingredients. For drugs administered to animals whose products
will be consumed by humans, nonclinical laboratory studies are critical
for determining safe levels of residual drug product. For tobacco
products, nonclinical laboratory studies may provide evidence regarding
the relative toxicities of new or modified risk tobacco products. FDA's
regulation of the conduct of nonclinical laboratory studies is
important to help ensure the quality and integrity of data derived from
those studies, the protection of human subjects, and that marketing
decisions are based on accurate and reliable data.
    Therefore, FDA proposes to amend the GLP regulations to require the
use of a complete quality system approach (proposed GLP Quality System)
when a nonclinical laboratory study supports or is intended to support
an application or submission to FDA. Part 58 (21 CFR part 58) presently
includes many aspects of a quality system approach. However, certain
fundamentals of a fully implemented GLP Quality System considered
essential to a quality system, such as certain SOPs and adequate
management roles, responsibilities, and accountability, are not
presently required. We therefore propose a fully implemented GLP
Quality System as the proper framework for building quality into
planning, conducting, and reporting a nonclinical laboratory study to
help ensure the quality and integrity of the resulting data used to
support FDA regulatory decisions.
    We also propose to amend the GLP regulations to reflect current
practices for the conduct of nonclinical laboratory studies,
particularly multisite studies, while allowing industry flexibility to
meet the proposed requirements.

B. Summary of the Major Provisions of the Proposed Rule

    Under the proposed GLP Quality System, FDA intends to enhance the
current quality system approach for nonclinical laboratory studies. The
GLP Quality System will provide additional responsibilities for testing
facility management and new responsibilities for maintaining SOPs. We
propose modifications to the definition of a testing facility to be
applicable to all nonclinical laboratory studies, whether they are
conducted at a single facility or at multiple sites. We propose
amending roles and functions consistent with the revised testing
facility definition. FDA expects that a GLP Quality System will provide
the appropriate framework for building quality into a nonclinical
laboratory study and will result in more reliable data for FDA to
consider when making regulatory decisions.

C. Legal Authority

    FDA proposes to issue this rule under the authority of the
provisions in sections 351 and 354-360F of the Public Health Service
Act (PHS Act) and the provisions in the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) applicable to the conduct of nonclincial
laboratory studies, specifically under section 701(a) of the FD&C Act
(21 U.S.C. 371(a), as essential to enforcement of the Agency's
responsibilities under sections 402, 406, 408, 409, 501, 502, 503, 505,
510, 512-516, 518-520, 571, 721, 801, 905, 910, and 911 of the FD&C Act
(21 U.S.C. 342, 346, 348, 349, 351, 352, 353, 355, 360, 360b-360f,
360h-360j, 360ccc, 379, 381, 387e, 387j, and 387k).

D. Costs and Benefits

    Costs estimates of the rule include annual costs from the
additional reporting and recordkeeping responsibilities required under
the proposed GLP Quality System. One-time costs include reading and
understanding the rule, updating existing SOPs, writing new SOPs, and
training. We estimate annualized costs, over a 10-year period, at a 7-
percent discount rate would average $51.9 million, or $51.5 million
with a 3-percent discount rate. We lack sufficient information to
quantify the benefits of the proposed rule, but we anticipate that it
would result in better quality and more reliable data to support
applications and submissions to us. The table summarizes these
estimates along with their ranges.

                                         Summary of Benefits, Costs and Distributional Effects of Proposed Rule
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                                                                                Units
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                Category                      Primary      Low estimate    High estimate                                      Period           Notes
                                             estimate                                      Year dollars    Discount rate      covered
                                                                                (%)           (years)
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Benefits:
    Annualized..........................  ..............  ..............  ..............            2014               7              10
    Monetized $millions/year............  ..............  ..............  ..............            2014               3              10
    Annualized..........................  ..............  ..............  ..............            2014               7              10
    Quantified..........................  ..............  ..............  ..............            2014               3              10
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    Qualitative.........................  The proposed rule would clarify GLP standards
                                          to facilitate a more consistent approach and
                                          provide greater international consistency. As
                                          a result, we anticipate improvements in the
                                          integrity and quality of data submitted for
                                          FDA review decisions.
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Costs:

    Annualized..........................           $51.9           $34.4           $69.3            2014               7              10
    Monetized $millions/year............            51.5            34.2            68.9            2014               3              10
    Annualized..........................  ..............  ..............  ..............            2014               7              10
    Quantified..........................  ..............  ..............  ..............            2014               3              10
                                         ---------------------------------------------------------------------------------------------------------------
Qualitative:
    Federal.............................  ..............  ..............  ..............            2014               7              10
    Annualized..........................  ..............  ..............  ..............            2014               3              10
                                         ---------------------------------------------------------------------------------------------------------------
    Monetized millions/year.............  From:
                                          To:
                                         ---------------------------------------------------------------------------------------------------------------
Transfers:
    Other...............................  ..............  ..............  ..............            2014               7              10
    Annualized..........................  ..............  ..............  ..............            2014               3              10
                                         ---------------------------------------------------------------------------------------------------------------
    Monetized millions/year.............  From:
                                          To:
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Effects:                                  State, Local or Tribal Government: None estimated.
                                          Small Business: The proposed requirements would likely impose a significant burden on small entities employing
                                          fewer than 10 workers in ``Dental Equipment and Supplies'' (between 1.87 and 8.94 percent of average annual
                                          sales). However, we do not have data on how many of these dental-equipment small entities perform nonclinical
                                          laboratory studies to support, or intended to support, an application or submission regulated by us; only such
                                          entities would be affected by the rule.
                                          Wages: None estimated.
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II. Introduction

    FDA is proposing to amend the GLP regulations in part 58 to require
the use of a complete quality system approach, referred to as a GLP
Quality System, for the conduct of nonclinical laboratory studies when
safety or toxicity studies, or both, support or are intended to support
applications or submissions to FDA. FDA proposes to define a GLP
Quality System as the organizational structure, responsibilities,
procedures, processes, and resources for implementing quality
management in the conduct of nonclinical laboratory studies.
    While many aspects of a quality system approach are presently
included in part 58, we expect that implementation of a GLP Quality
System will provide an improved framework that is more flexible and
will help ensure quality in planning, conducting, and reporting
nonclinical laboratory studies. Consistent with the proposed
requirement for a GLP Quality System, we propose additional management
responsibilities, with accompanying SOPs, to ensure management's
responsibility for establishing and maintaining the quality system. We
also propose to revise the definition of a testing facility to reflect
current practices for the conduct of nonclinical laboratory studies,
particularly the conduct of multisite studies. Conforming modifications
are proposed for consistency with the proposed GLP Quality System and
today's prevalence of multisite studies.
    FDA is proposing these changes to help ensure the quality and
integrity of data from nonclinical laboratory studies conducted in
support of applications and submissions to FDA. We also are modernizing
the regulations to further the Agency's efforts to encourage the
implementation of the principles of the ``3Rs,'' to reduce, refine, and
replace animal use in testing. This approach seeks to minimize the use
of animals in such testing and promote more humane, appropriate, and
specific test methods for evaluating product safety. These proposed
changes will clarify and update the regulations. In particular, we are
proposing changes recognizing the current prevalence of multisite
studies while adding flexibility consistent with current practices and
the use of ever-changing technology.

A. What is the background for this rule?

    On December 21, 2010, FDA published an advanced notice of proposed
rulemaking (ANPRM), ``Good Laboratory Practice for Nonclinical
Laboratory Studies'' (December 2010 ANPRM) (75 FR 80011), to solicit
stakeholder input regarding FDA's intention to modify the GLP
regulations in part 58. As stated in the December 2010 ANPRM, FDA is
proposing to require that all facilities conduct nonclinical laboratory
studies under a GLP Quality System when those studies support or are
intended to support an application or submission to FDA.
    The December 2010 ANPRM addressed nine specific areas to consider
for amending part 58. Those nine areas are: (1) The GLP Quality System,
(2) Multisite Studies, (3) Electronic/Computerized Systems, (4) Sponsor
Responsibilities, (5) Animal Welfare, (6) Information on Quality
Assurance Inspection Findings, (7) Process-Based Systems Inspections,
(8) Test and Control Article Information, and (9) Sample Storage
Container Retention.
    FDA received about 90 comments to the December 2010 ANPRM. Most of
the comments address the nine specific areas; however, a number of the
comments include additional areas for FDA's consideration. All comments
were reviewed and considered by a working group with representatives
from all FDA Centers, along with representatives from the U.S.
Environmental Protection Agency (EPA), the Animal and Plant Health
Inspection Service of the U.S.

Department of Agriculture (USDA/APHIS), and the Office of Laboratory
Animal Welfare at the National Institutes of Health (NIH/OLAW).
    In addition to the December 2010 ANPRM comments, we reviewed and
considered the documents of the working group on GLP of the
Organisation for Economic Co-operation and Development (OECD),
including the general principles of GLP and consensus and advisory
documents (Ref. 1). The United States is a signatory to OECD's GLP
Mutual Acceptance of Data agreement (Ref. 2) and, as an OECD member
country, FDA participated in the development of OECD's GLP documents.
For this proposal, we strive for consistency with the relevant OECD
documents whenever possible.

B. Why is FDA proposing this rule?

    The proposed GLP Quality System would help to provide a flexible
framework for building quality into planning, conducting, and reporting
a nonclinical laboratory study, and would help ensure the integrity of
data submitted to FDA to support FDA regulatory decisions. The present
regulations do not require certain fundamentals considered essential to
a complete quality system. For example, the present regulations do not
specifically require SOPs for developing and maintaining SOPs, or SOPs
for developing and periodically assessing a quality system, nor do they
provide for adequate management roles, responsibilities, and
accountability. We note that a major principle of a complete quality
system is management's ultimate responsibility for establishing and
maintaining the quality system.
    This proposal also is intended to update the regulations to reflect
today's conduct of nonclinical laboratory studies, particularly the
conduct of multisite studies. For multisite studies that may have
multiple contracts and subcontracts for various study phases, effective
communication is essential, especially considering the proposed
requirement for a single final study report. We agree with the numerous
comments to the December 2010 ANPRM that support a clear delineation of
study responsibilities and effective communication among all parties
involved in multisite studies.
    Some stakeholders suggest that certain provisions in part 58 are
outdated and hamper efficient use of present technology (for example,
requiring hard copies of records and documentation instead of allowing
computerized options). Several industry organizations approached FDA
after the announcement of the Bioresearch Monitoring (BIMO)
Modernization Initiative in 2006 (Ref. 3), requesting that we modernize
the GLP regulations. One request, among others, was to remove the
requirement that the quality assurance unit (QAU) must maintain the
master schedule and copies of protocols. These requests were echoed in
several comments to the December 2010 ANPRM. FDA agrees with those
comments and proposes to update part 58 to help address the use of
present technology.
    Because the number of FDA inspections is limited by competing
priorities and limited resources, we look to sponsors and nonclinical
laboratory management to help ensure that data submitted to FDA in
support of applications and submissions are reliable. For those
nonclinical laboratory studies that are the bases for allowing a new
medical product into first-in-human clinical studies, the quality and
integrity of the data are crucial to human subject protection.
    This proposal complements the intent of the original GLP proposed
rule to ensure the quality and integrity of the resulting data (41 FR
51206 at 51210, November 19, 1976) (Ref. 4). FDA expects that requiring
a GLP Quality System will help ensure data quality and integrity. The
proposed GLP Quality System also will allow the flexibility to develop
site-specific procedures for related SOPs. Because of the great
diversity in institutions, research activities, and organizational
structures covered by these regulations, it is important to have
sufficient flexibility in the regulations to allow the regulated
parties to meet these requirements in a manner that best suits their
organizational needs.

III. Description of the Part 58 Proposal

A. What did FDA consider when drafting this rule?

1. Animal Rule
    Several comments to the December 2010 ANPRM requested that FDA
modify part 58 to accommodate studies conducted in animals to support
the effectiveness of human drugs or biological products when human
efficacy studies are not ethical or feasible. Those comments refer to
the ``Animal Rule'' (21 CFR parts 314 and 601) (67 FR 37988, May 31,
2002).
    The Animal Rule provides a pathway for FDA to grant marketing
approval based on adequate and well-controlled animal efficacy studies
when the results of those studies establish that the drugs or
biological products are reasonably likely to produce clinical benefit
in humans. Products evaluated for efficacy under the Animal Rule should
be evaluated for safety under the existing requirements for
establishing the safety of new drugs and biological products. The
provisions in part 314, subpart I for drugs and part 601, subpart H for
biological products apply only to situations when adequate and well-
controlled human efficacy studies cannot ethically be conducted because
they would involve deliberate exposure of healthy human volunteers to a
potentially lethal or permanently disabling toxic chemical, biological,
radiological, or nuclear substance, and field trials to study the
product's effectiveness after an accidental or hostile exposure have
not been feasible.
    In the past, FDA has said that ``All studies subject to this rule
must be conducted in accordance with preexisting requirements under the
good laboratory practices (21 CFR part 58) regulations'' (67 FR 37988
at 37989, May 31, 2002). FDA made this statement because part 58
includes requirements for a quality system structure to ensure the
quality and integrity of animal study data. These studies are intended
to generate data that are essential for the approval or licensure of
products intended for human use. Thus, ensuring the quality and
integrity of data from these studies is critical as they serve as
substantial evidence of effectiveness of the product.
    Part 58 was issued to ensure the quality and integrity of
nonclinical laboratory studies conducted to assess the safety of FDA-
regulated products. In response to comments made to the ANPRM, FDA
questions whether any requirement presently in part 58 or in this
proposal poses a unique or disproportionate obstacle or burden on the
conduct of certain animal studies specific to product development under
the Animal Rule.
    FDA, however, tentatively concludes there may be justifiable
limitations to applying GLP regulations when conducting Animal Rule-
specific studies, especially for studies using challenge agents that
require high-containment facilities (for example, biosafety level 4
(BSL-4) \1\ laboratory environments). Therefore, although part 58
embodies critical elements of a quality system to ensure data quality

and integrity, FDA also recognizes that some current part 58
requirements may not be appropriate, or may require modification to
address adequately data quality practices for the Animal Rule-specific
studies.
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    \1\ BSL-4 refers to the practices, safety equipment, and
safeguards required for laboratories that work with highly
infectious and lethal pathogenic microbes which cause, for example,
such lethal diseases in humans as smallpox, Ebola, or Marburg virus
hemorrhagic fever. BSL-4 is the highest biosafety level designation
possible and means that the most stringent safeguards are in place
to protect researchers, non-laboratory building occupants, the
general public, and the environment from exposure to exotic or
lethal agents.
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    Accordingly, although not included in the regulatory text portion
of this proposal, FDA is considering expanding part 58 to include the
conduct of certain Animal Rule studies that support approval or
licensure of products for human use under the established data quality
and integrity standards. We seek comment on this proposal. In
particular, we invite comment on the possibility of amending the scope
of the regulation in Sec.  58.1(a) to encompass not only nonclinical
laboratory studies, but also to include certain Animal Rule-specific
studies. Correspondingly, we are considering adding a definition in
Sec.  58.3 for ``Animal Rule-specific studies subject to GLP'' (for
purposes of this document, ``Animal Rule-specific studies subject to
GLP'' are referred to as ``covered Animal Rule studies'').
    Specifically, FDA is considering including within the definition of
covered Animal Rule studies only the following types of studies to
support product approval under the Animal Rule: (1) The adequate and
well-controlled animal efficacy studies that serve as substantial
evidence of the effectiveness necessary for approval or licensure of
human drugs or biological products, respectively; (2) pharmacokinetic
and/or pharmacodynamic studies in animals used to select a dose and
regimen in humans; and (3) if seeking qualification through FDA's
Animal Model Qualification Program,\2\ the model-defining natural
history studies.3 4
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    \2\ The Animal Model Qualification Program is part of FDA's Drug
Development Tool (DDT) Qualification Program. The DDT Program
provides a framework for development and regulatory acceptance of
scientific tools for use in drug development programs. Qualification
of an animal model is not required for the approval of drugs or
licensure of biologics under the Animal Rule. For more information
about this program, see FDA's guidance for industry and FDA staff
Qualification Process for Drug Development Tools (January 2014)
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm230597.pdf),
and the Animal Model Qualification Program Web site: http://inside.fda.gov:9003/CDER/OfficeofTranslationalSciences/BiomarkerQualifications/ucm271856.htm.
    \3\ In the context of animal model qualification, the model-
defining natural history studies are the animal studies that
establish the ranges of values of key parameters of the disease or
condition that will be specified in the context of use statement for
the qualified model and that will be used as measures of quality
control and quality assurance when the model is replicated.
    \4\ Natural history studies that will not be used to support the
qualification of an animal model, as defined in footnote 2, would
not be subject to GLP regulations.
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    FDA seeks comment on the impact of expanding part 58 to include
these covered Animal Rule studies. We also request comment on what
other changes to the regulations, beyond amending the scope and
definitions, are needed to address issues unique to covered Animal Rule
studies. FDA specifically requests comments in response to the
following questions:
    1. Would amending part 58 to expand the scope to include covered
Animal Rule studies establish an appropriate quality system approach to
the conduct of such studies to ensure data quality and integrity? If
not, what gaps or shortcomings would remain, and how should they be
addressed?
    2. Would such an amendment provide sufficient clarity and
flexibility to sponsors and investigators? If not, what alternatives or
changes to this approach are needed?
    3. FDA is considering adding a definition in part 58 for ``Animal
Rule-specific studies subject to GLP'' (referred to as ``covered Animal
Rule studies''). As discussed in section III.A.1., the proposed
definition contains three specific types of studies that would be
subject to part 58. Is the term ``Animal Rule-specific studies subject
to GLP,'' as defined in Sec.  58.3, clear and appropriately inclusive?
    4. What are the benefits, challenges, and burdens of amending part
58 to include covered Animal Rule studies?
    a. Would this proposed expansion of the scope in Sec.  58.1(a)
impact entities conducting covered Animal Rule studies?
    b. Would the proposed expansion of the scope in Sec.  58.1(a)
impact those entities engaged in conducting nonclinical laboratory
studies to assess product safety?
    c. What could be done to minimize burdens or costs, including costs
or burdens on small entities, associated with part 58 compliance for
covered Animal Rule studies?
    5. Are there any challenges or differences involved in the conduct
of covered Animal Rule studies (versus nonclinical laboratory studies)
that merit different standards or establishment of a separate
regulation? If so, what are those challenges or differences, and what
alternative(s) would be preferable?
    6. Based on possible differences identified in question 5, are
there any particular aspects in the current or proposed part 58 that
would be unduly difficult to meet? What changes to current part 58, or
the proposed amendments, could be made to address or accommodate these
issues? For example:
    a. Would it be satisfactory to include a provision to allow on a
case-by-case basis a covered Animal Rule study sponsor to seek FDA
agreement on deviations from certain part 58 requirements that may not
be practicable to meet as follows: ``When the study is an Animal Rule-
specific study subject to GLP, FDA may agree to deviations from any
requirement of this part that it finds unnecessary to ensure the
quality and integrity of the study by written agreement with the
sponsor before the conduct of the study. In such cases, FDA's
acceptance of deviations from the requirements will be contingent upon
compliance with any alternative requirements included in that
agreement.''
    b. Would it be workable or appropriate to entirely exempt covered
Animal Rule studies from certain requirements of part 58? If so, what
exemption(s) would be necessary or appropriate?
    As discussed in section III.A.1., FDA considers GLP regulations to
be a well-established and relevant system for ensuring data quality and
integrity for covered Animal Rule studies. Therefore, until a final
rule is published, FDA recommends the use of the current GLP framework
(for example, definitions, procedures, roles and responsibilities, and
controls) for covered Animal Rule studies to the extent practicable,
and intends to provide more information about FDA's expectations for
adapting a GLP framework to these studies.
    Before initiating covered Animal Rule studies, sponsors should
identify aspects of the studies anticipated to be challenging with
regard to GLP and propose methods for adapting the studies to ensure
the quality and integrity of the resulting data. Sponsors should submit
this information to FDA for concurrence on the data quality and
integrity plan before the studies are initiated. A guidance document is
available regarding the essential elements necessary to address
efficacy under the Animal Rule.\5\
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    \5\ See FDA's guidance for industry Product Development Under
the Animal Rule (October 2015), at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM399217.pdf.
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2. ISO 9001 and GLP Quality System
    Many comments to the December 2010 ANPRM note that the
International Organization for Standardization (ISO) 9001 is very
general and not all aspects outlined in ISO 9001 are applicable to
GLPs. FDA acknowledges this.

However, ISO 9001 is an internationally recognized standard for quality
systems. Also, FDA's Quality System Regulation (QSR) in part 820 (21
CFR part 820) for current good manufacturing practice requirements for
medical devices was harmonized, to the extent possible, with the ISO
9001: 1994 ``Quality Systems--Model for Quality Assurance in Design,
Development, Production, Installation and Servicing.''
    Some comments to the December 2010 ANPRM state that consistency
with the ISO 9001 standard would be acceptable if we retained what they
perceived as the present flexibility of the regulations. A number of
comments state that it would be beneficial to borrow elements of a
quality system from the QSR requirements in part 820 rather than
reference ISO 9001:1994. Many comments also request that we define the
operational areas necessary for broader adoption of a quality system
approach.
    In this proposal, we incorporate aspects of ISO 9001:1994 that are
consistent with part 820 and our desire to propose a complete quality
system approach. For example, we propose to address establishing and
maintaining a GLP quality system by adding to part 58 certain
definitions, relevant SOPs, and management roles and responsibilities
modeled after the part 820 requirements. Our proposed additions to more
fully enable a GLP quality system will help expand the present
flexibility in part 58. Our proposals also are consistent with OECD
guidance documents for GLP wherever possible and, at the very least, do
not conflict with them.
3. Animal Welfare
    Many comments to the December 2010 ANPRM note that Sec.  58.90
covers animal care and thus, FDA investigators review documentation of
animal care during GLP inspections. This is true. If animal care is not
compliant with appropriate standards, there is a high likelihood that
such noncompliance could confound the results of affected studies.
Since the good laboratory practice regulations were published, the
Animal Welfare Act has been amended and the public's perception of
animal welfare has changed. Therefore, we propose specific
responsibilities regarding animal welfare because the humane treatment
of animals in research settings is essential to the quality and
integrity of GLP studies.
    Many comments to the December 2010 ANPRM state that addressing
animal welfare in part 58 would be a duplication of USDA/APHIS or the
NIH regulations. That is not our intention. FDA has a Memorandum of
Understanding (MOU) (Ref. 5) with USDA/APHIS and NIH/OLAW regarding
animal welfare oversight. FDA forwards to the relevant regulatory
agency any concerns regarding animal welfare observed during FDA
inspections for their followup. Those animal welfare observations are
not included on a Form FDA 483 (Inspectional Observations) that may be
issued at the close of an FDA inspection, unless the observations also
show noncompliance with Sec.  58.90.
    While this proposal addresses animal welfare concerns, FDA supports
the use of non-animal testing methods when scientifically valid
alternatives are available. We encourage sponsors with questions about
non-animal testing methods to approach FDA early in the development
process for consultation on the suitability and acceptability of non-
animal tests for their particular product. This approach reflects FDA's
position in its May 20, 2010, citizen petition response to the
Mandatory Alternatives Petition Coalition and subsequent Agency
statements. That petition requested that FDA require only non-animal
test methods instead of corresponding animal test methods whenever such
scientifically satisfactory methods are available. (See Docket No. FDA-
2007-P-0109.)
4. Multisite Studies
    As stated in the December 2010 ANPRM, FDA's intent was simply to
add new definitions relevant to roles and responsibilities specific to
multisite studies. Many comments to the December 2010 ANPRM state that
the present regulations are basically adequate and suggested only
minimal modifications.
    Since publication of the December 2010 ANPRM, we have changed our
thinking concerning regulatory changes needed to address multisite
studies. For example, we have determined that amending the definition
of a testing facility will help address the current conduct of
multisite studies. We discuss in section III.B.2. our proposed changes
to that definition.
    Many comments to the December 2010 ANPRM suggest that we align our
requirements regarding multisite studies with the OECD consensus
document entitled, The Application of the OECD Principles of GLP to the
Organisation and Management of Multi-Site Studies (Ref. 6). The
comments also requested that we not be as prescriptive as those OECD
directives. We agree with those comments. We reviewed and considered
this OECD consensus document and incorporated into our proposal the
same general concepts, where applicable.
5. GLP Roles and Responsibilities
    We propose to maintain the current GLP roles for management, study
director, and QAU. We propose that the overarching responsibilities of
those who fulfill these roles remain as follows: Management is
responsible for establishing and maintaining conditions and procedures
necessary for the conduct of nonclinical laboratory studies compliant
with GLPs; the study director, as the sole point of study control, is
responsible for implementing those procedures in specific studies; and
the QAU is responsible for inspecting and general oversight of studies,
verifying that they are GLP compliant or recommending changes needed
for bringing them into compliance.
    These responsibilities complement each other and sometimes overlap
in multiple areas, providing for a system of checks and balances. We
intend for this proposal to maintain the authority necessary for
fulfilling each of these roles while allowing maximum flexibility for
the conduct of a GLP-compliant nonclinical laboratory study.
    We are interested in feedback about whether this proposal will
accomplish our goal of maintaining the necessary interrelationships
among these roles, and whether our proposal undermines any one of these
roles or fails to provide adequate flexibility.

B. Part 58, Subpart A--General Provisions

1. Scope (Sec.  58.1)
    We propose to expand the scope of FDA-regulated nonclinical
laboratory studies to specifically include toxicity studies. For
purposes of this proposal, toxicity means the acute or long-term
adverse effects that could result from use of the FDA-regulated
product. While some nonclinical laboratory studies of FDA-regulated
products evaluate a product's safety, including toxicity, most are
conducted solely to determine a product's toxicity. For example, when
combined with the results of clinical trials, determination of toxicity
at various doses can inform an appropriate risk-to-benefit analysis
when relevant to FDA's consideration of a product's marketing
application or submission.
    For drugs administered to animals whose products will be consumed
by humans, toxicity studies are critical for determining safe levels of
residual drug product. Nonclinical laboratory studies of food
ingredients and food contact substances provide the basis for

establishing levels at which a substance will not, with reasonable
certainty, be harmful under its intended conditions of use. In the
evaluation of tobacco products, FDA could use the data derived from
nonclinical laboratory studies to evaluate relative toxicity as opposed
to evaluating safety.
    Additional proposed modifications to the scope in Sec.  58.1 expand
the language to include FDA jurisdictional oversight of tobacco
products as specified in the FD&C Act, sections 905, 910, and 911. We
also propose to modify and broaden ``medical devices for human use'' to
``devices'' to include FDA's Center for Veterinary Medicine (CVM),
which has jurisdiction over devices used in veterinary medicine.
    In addition, we propose changing the provision ``for research and
marketing permits'' to ``applications or submissions'' for FDA-
regulated products. This proposed change will include the applications
and submissions to FDA listed in the definitions section of this
proposal.
    As stated in both the preamble to the original proposed regulations
(original GLP proposed rule) (41 FR 51206 at 51210) and the preamble to
the original GLP final rule (43 FR 59986 at 59988), the GLP
``regulations are intended to ensure, as far as possible, the quality
and integrity of test data that are submitted to FDA and become the
basis for regulatory decisions made by the Agency.'' Therefore, the
phrase ``intended to support'' in present and proposed Sec.  58.1(a)
means that any nonclinical laboratory study included within the
proposed expanded scope of Part 58 that is conducted with the intent
that it may support an application or submission to FDA should be
conducted in compliance with the GLP regulations.
    Also, we propose adding Sec.  58.1(c) to describe what we mean by
``where appropriate'' when used in the part 58 regulatory text. This
proposal addresses studies conducted at a single testing facility as
well as at multiple sites. We propose using ``where appropriate'' in
many of the revised or added provisions because not all requirements
are applicable to all studies. For example, a test site tasked only
with interpreting a study's histopathology would not require all of the
SOPs required for a test site responsible for multiple phases.
2. Definitions (Sec.  58.3)
    The current Sec.  58.3 Definitions, is not alphabetized and
includes paragraphs (a) through (p). We propose to remove the paragraph
designations, add new definitions, modify certain current definitions,
and alphabetize the complete listing of definitions.
    We propose modifying current Sec.  58.3(e) to change the defined
term from ``Application for research or marketing permit'' to
``Applications and Submissions to FDA''. We propose this change because
nonclinical laboratory studies can support applications and submissions
to FDA other than those for research and marketing. Also, in the
definition for ``Applications and Submissions to FDA'' proposed
paragraphs (1) through (35), we add certain relevant statutory or
regulatory citations for consistency.
    We propose including applications and submissions for tobacco
products described in the FD&C Act. We note that FDA plans to issue
regulations under section 910(g), providing conditions under which
tobacco products intended for investigational use may be exempted from
the requirements of chapter IX of the FD&C Act. It is our intent that
applications for such investigational tobacco products will be included
within the scope of Sec.  58.3.
    We also propose adding those applications and submissions for FDA-
regulated products that include nonclinical laboratory study results
but are not currently specifically included. For example, Humanitarian
Device Exemption applications are new since publishing in 1987 the last
final rule modifying part 58. We also propose expressly adding the
medical device Premarket Notification (also known as a ``510(k)''
submission).
    Attending Veterinarian: We propose adding a definition for an
attending veterinarian. Our proposed definition is the same as the
definition in USDA's Animal Welfare Regulations (9 CFR 1.1) but without
specifics about educational requirements. We propose defining an
attending veterinarian as a veterinarian with training, experience, or
both in the care and management of the species being attended, with
direct or delegated authority for activities involving animals. We
propose this definition because we propose in part 58 certain
provisions about animal welfare. For example, we propose that the study
director must defer to the attending veterinarian when decisions
regarding animal welfare arise, particularly when animals are in pain
or distress.
    Batch: We propose changing the definition of batch currently in
Sec.  58.3(n) to reference the relevant provisions in Sec.  58.105
(Test, control, and reference article characterization) and Sec.
58.107 (Test, control, and reference article handling). We also add
that batch means a specific quantity or lot of a reference article (see
section III.B.2.), we discuss the addition of a reference article
definition.
    Contracted Person: We propose adding a definition for contracted
person to mean a person that assumes, either directly or indirectly as
an independent contractor, one or more of the responsibilities for
conducting a nonclinical laboratory study. Several comments to the
December 2010 ANPRM state that the responsibilities of all persons (any
legal entity) involved in multisite studies need to be addressed in the
regulations. We propose the use of this term to allow us to address the
comments without specifically identifying all possible contracted
entities.
    The comments also request that FDA include specifics for multisite
studies as to how responsibilities are to be met and by whom. In
response to these comments, we intend that a contracted person includes
any person (for example, testing facility or individual) that the
sponsor contracts with to conduct a phase (defined activity or set of
activities) of a nonclinical laboratory study. Also, the term
contracted person includes any person that is under a subcontract to
conduct a phase of a nonclinical laboratory study.
    Contributing Scientist: We propose adding and defining the term
contributing scientist. A contributing scientist is an individual
responsible for conducting, interpreting, analyzing, or performing any
service for a phase of a nonclinical laboratory study. The current
regulation in Sec.  58.185 for reporting study results refers to
``individual scientists or other professionals involved in the study''
(see Sec.  58.185(a)(12)). Our proposal replaces these scientists or
other professionals with the term contributing scientist. In addition,
when a contributing scientist is a contracted independent expert or
specialist, we use the term independent contributing scientist. See,
also, section III.C.6. where we discuss Sec.  58.37 (Contributing
scientist).
    Control Article: We propose modifying the definition of control
article currently in Sec.  58.3(c) by changing ``medical device for
human use'' to ``device'' to expand the regulations to include devices
used in veterinary medicine. Also, the revised definition proposes to
include a ``tobacco product''.
    Establish: For this part 58 proposal, the meaning of establish is
to define, document (in writing or electronically), and implement. We
propose adding a definition for establish to help eliminate repeating
in the applicable regulatory text the words that define establish. Our
proposed definition is identical to the

definition of establish in the part 820 quality system regulation in
Sec.  820.3(k).
    Facility-Based Inspection: We propose introducing the term
facility-based inspection to mean a QAU inspection that covers the
general facilities and activities; for example, installations, support
systems, computer systems, training, environmental monitoring, and
equipment maintenance and calibration. This addition, along with the
definition of process-based inspection (see section III.B.2.) would
allow for greater efficiency instead of duplicating, for each study,
inspection of those general facilities and activities. Our proposed
definition also is consistent with the definition for facility-based
inspection in the OECD document, Quality Assurance and GLP (Ref. 7).
    GLP Quality System: We propose adding a definition for GLP Quality
System to mean the organizational structure, responsibilities,
procedures, processes, and resources for implementing quality
management in the conduct of nonclinical laboratory studies. As
discussed in section II.B., we consider a fully implemented GLP Quality
System the proper framework for building quality into planning,
conducting, and reporting a nonclinical laboratory study while allowing
flexibility for site-specific procedures.
    Lead Quality Assurance Unit: We propose adding a definition for a
lead quality assurance unit (lead QAU) meaning the QAU responsible for
quality assurance (QA) in a multisite nonclinical laboratory study. We
propose that testing facility management with executive responsibility
selects the lead QAU. The location of the lead QAU may be at the
testing facility, with another person conducting a phase of the study,
or provided through a contractual relationship. This definition is
consistent with the definition for lead QAU in the OECD consensus
document, The Application of the OECD Principles of GLP to the
Organisation and Management of Multi-Site Studies (Ref. 6).
    Management with Executive Responsibility: We propose adding a
definition for management with executive responsibility to mean senior
employees of the testing facility or test site who have the authority
to establish or make changes to the quality policy and GLP Quality
System at their testing facility or test site. We note that part 820
(see Sec.  820.3(n)) adopted this term describing senior management to
be consistent with the quality system specifications in ISO 9001:1994
(61 FR 52602 at 52609, October 7, 1996).
    Master Schedule: We propose adding a definition for master schedule
that means a compilation of information used for assessment of workload
and the tracking of nonclinical laboratory studies. The master schedule
will include information about all nonclinical laboratory studies
conducted. For multisite studies, the master schedule also will include
the phases conducted (see proposed 58.31(k)). Our proposed definition
of master schedule is consistent with the definition in the OECD GLP
document, OECD Principles on Good Laboratory Practice (Ref. 8). When we
discuss Sec.  58.31 (Management with executive responsibility, section
III.C.2.), we elaborate on requirements concerning the master schedule.
    Multisite Study: We propose adding a definition for multisite study
to mean any study that has phases (defined in section III.B.2.)
conducted at more than one site. Our proposed definition of multisite
study is consistent with the definition in the OECD consensus document,
The Application of the OECD Principles of GLP to the Organisation and
Management of Multi-Site Studies (Ref. 6).
    Nonclinical Laboratory Study: We propose modifying the current
definition in Sec.  58.3(d) for a nonclinical laboratory study to add
after ``under laboratory conditions'' the phrase ``or in the applicable
environment''. This addition recognizes that the conduct of a
nonclinical laboratory study is not limited to a traditional laboratory
environment. We propose to make clear that the purpose for conducting
nonclinical laboratory studies may be to determine relative toxicity.
For example, because tobacco products are not safe, nonclinical
laboratory studies help FDA evaluate the relative toxicities of those
products. We also propose to update the regulations by changing ``field
trials in animals'' to ``clinical investigational use in animals'',
which more accurately describes our intent. We propose a sentence
structure change in the last sentence in this definition to clarify our
intent, which is often misinterpreted due to the current sentence
structure.
    Phase: We propose adding a definition for phase to mean a defined
activity or set of activities in the conduct of a nonclinical
laboratory study. We propose this new definition to aid in
understanding the new proposed definition of multisite study, which is
any study that has phases conducted at more than one site. Our proposed
definition is consistent with the definition of phase in the OECD
consensus document, The Application of the OECD Principles of GLP to
the Organisation and Management of Multi-Site Studies (Ref. 6).
    Principal Investigator: We propose adding a definition for
principal investigator to mean an individual with specific
responsibilities delegated by the study director for a phase of a
nonclinical laboratory study. We propose defining principal
investigator in general terms rather than specifying the principal
investigator's single role in a multisite study as defined in the OECD
document, OECD Principles on Good Laboratory Practice (Ref. 8).
However, we propose that principal investigator responsibilities are
those delegated by the study director, which is consistent with OECD
principles. See, also, section III.C.7. where we discuss Sec.  58.39
(Principal investigator).
    Process-based Inspection: We propose adding a definition for
process-based inspection to mean inspecting repetitive, frequently
performed procedures and processes (for example, certain mutagenicity
studies). This definition recognizes present practice and allows for
greater efficiency, as noted elsewhere (section III.B.2.). Our proposed
definition is consistent with the definition for process-based
inspection in the OECD document, Quality Assurance and GLP (Ref. 7).
    Quality: We propose adding a definition for quality, meaning the
totality of features and characteristics bearing on the ability of a
nonclinical laboratory study to provide reliable data.
    Quality Assurance Unit (QAU): We propose modifying the current
definition in Sec.  58.3(l) to remove ``except the study director'' and
``designation by testing facility management''. Also, we propose adding
a sentence ``The QAU must be entirely separate from and independent of
the personnel engaged in the direction and conduct of the particular
study.'' We propose these changes for clarity and to be consistent with
our inclusion of multisite studies and with the statement currently in
Sec.  58.35.
    Quality Policy: We propose adding a definition for quality policy
that is identical to the definition in Sec.  820.3(u), meaning ``the
overall intentions and direction of an organization with respect to
quality, as established by management with executive responsibility.''
    Raw Data: We propose modifying the current definition in Sec.
58.3(k) to update the regulations to address copying requirements and
computerized systems, and to specifically include the pathology report.
We propose adding to the definition that raw data means ``all
nonclinical laboratory study records and

documentation or exact copies that maintain the original intent and
meaning and are made according to the person's certified copy
procedures.'' This additional regulatory text eliminates the need to
provide examples of what we consider a copy. We also propose adding
``correspondence'' and ``other documentation (regardless of capture
medium)'' to the examples of raw data. The addition of ``regardless of
capture medium'' eliminates the need to provide examples of possible
capture media. Also, we propose including as raw data ``the signed and
dated pathology report'' to clarify what we consider as raw data.
    Reference Article: We propose adding a definition for reference
article consistent with EPA's GLP regulations in 40 CFR 160.3 and 792.3
for defining a ``reference substance'' to mean an article used to
establish a basis for comparison of the test article for known chemical
or biological measurements. We propose this addition to acknowledge the
use of reference articles in certain studies.
    Short-Term Study: We propose adding a definition for short-term
study to mean when the in-life period (study period during which data
are collected) is completed within several days or, at most, a week.
Since the pre-specified, periodic timing of process-based inspections
can result in the lack of an inspection of a short-term study, this
definition is necessary to address our proposed addition of process-
based inspections (see also the discussion of the definition of
process-based inspection in section III.B.2.).
    Specimen: We propose adding ``or retention'' to the end of the
current definition of specimen in Sec.  58.3(j) to read, ``Specimen
means any material derived from a test system for examination,
analysis, or retention.'' We propose this change because a specimen may
be collected solely for retention purposes. Also, this proposed change
is consistent with the definition in the OECD GLP document, OECD
Principles on Good Laboratory Practice (Ref. 8).
    Sponsor: We propose modifying the current definition of sponsor in
Sec.  58.3(f) consistent with our proposal to expand the scope of part
58, and to address possible roles of the sponsor in multisite studies.
We propose revising the current definition in Sec.  58.3(f)(3) to
include the possible roles a sponsor could play in a multisite study in
addition to initiating and supporting the study. Those roles and
applicable requirements are the same as those for a testing facility,
test site, or contributing scientist as we propose to define those
terms.
    See, also, section III.B.3. where we discuss Sec.  58.5 (Sponsor
responsibilities).
    Standard Operating Procedures (SOPs): We propose adding a
definition for SOPs to mean documented procedures describing how to
perform tests or activities normally not specified in detail in study
protocols. We propose this addition because many proposed modifications
in Sec.  58.31 refer to required SOPs. This definition is consistent
with the OECD GLP document, OECD Principles on Good Laboratory Practice
(Ref. 8).
    Study-based Inspection: We propose adding a definition for study-
based inspection to mean the same QAU inspection specified currently in
Sec.  58.35(b)(3) for inspecting a critical operation of the study that
is scheduled according to the study's chronology or sequence of events.
Our proposed definition is consistent with the definition for study-
based inspection in the OECD consensus document, Quality Assurance and
GLP (Ref. 7).
    Test Article: We propose modifying the current definition of test
article in Sec.  58.3(b) to change ``medical device for human use'' to
``device'' and to add ``tobacco product''. As discussed in section
III.B.1. concerning the scope of part 58, we propose these changes to
broaden devices to include FDA's CVM and to include FDA's jurisdiction
of tobacco products.
    Test Site: We propose adding a definition for test site to mean a
``person'' (currently defined in Sec.  58.3(h)) responsible for a phase
of a multisite nonclinical laboratory study. We propose that a test
site includes management with executive responsibility and supporting
SOPs for the conduct of a nonclinical laboratory study. For a different
nonclinical laboratory study, a test site could function as a testing
facility.
    Test System: We propose modifying the current definition of test
system in Sec.  58.3(i) to add ``reference'' article consistent with
our other proposed changes. See elsewhere in section III.B.2. for our
proposed definition and explanation for adding a definition of
reference article.
    Testing Facility: We propose removing and replacing most of the
current definition of testing facility in current Sec.  58.3(g) to
update the regulations consistent with the conduct of multisite
nonclinical laboratory studies. Our proposed definition is as follows:
``Testing facility means a person responsible for conducting,
coordinating, or completing a nonclinical laboratory study, or any
combination thereof. The testing facility designates the study
director.''
    We propose this change because, in a multisite study, the testing
facility might not be the person treating the test system with the test
article as specified in the current definition. Rather, the person
treating the test system with the test article might be a contracted or
subcontracted person. Therefore, this general definition of a testing
facility is necessary to capture all possible contractual relationships
in a multisite study.
    Validation: We propose adding a definition for validation to mean
confirmation by examination and provision of objective evidence that
the particular requirements for a specific intended use of a system or
process can be consistently fulfilled. This proposed definition is
similar to the definition in Sec.  820.3(z), and addresses comments to
the December 2010 ANPRM requesting a definition for validation of a
system or process.
    Vehicle: We propose adding a definition for vehicle to mean any
agent that serves as a carrier and is used to mix, disperse, or
solubilize the test, control, or reference article for administration
or application to the test system. This proposal recognizes the use of
vehicles in the conduct of nonclinical laboratory studies. Our proposed
definition is consistent with the definition of vehicle in the OECD GLP
document, OECD Principles on Good Laboratory Practice (Ref. 8), for
describing a carrier for test, control, or reference articles.
3. Sponsor Responsibilities (Sec.  58.5)
    The present regulations in Sec.  58.10 cover only a sponsor's
responsibilities to notify a consulting laboratory, contractor, or
grantee that their service ``is part of a nonclinical laboratory study
that must be conducted in compliance with the provisions of this part
[part 58]''. FDA received many comments to the December 2010 ANPRM
noting that there are other sponsor responsibilities implicit
throughout the present regulations, and stating that the study sponsor
must share in the responsibility for complying with part 58. We agree
with those comments.
    Therefore, we propose adding Sec.  58.5 Sponsor responsibilities,
that provides explicit provisions for the presently implied sponsor
responsibilities and adds new sponsor responsibilities. Our proposed
sponsor responsibilities are consistent with the preamble to the
original GLP proposed rule stating that the adequacy and validity of
nonclinical laboratory tests remain the responsibility of the sponsor
of the product as part of establishing the marketability of the product
(41 FR

51206 at 51206) (Ref. 4). In addition, we propose adding provisions
consistent with the OECD advisory document, The Role and
Responsibilities of the Sponsor in the Application of the Principles of
GLP (Ref. 9).
    For each nonclinical laboratory study, we propose that the sponsor
must ensure the study protocol meets the requirements specified in
Sec.  58.120 (Protocol (see proposed Sec.  58.5(a) regulatory text,
elsewhere in this document). Also, we propose that the sponsor must
ensure the study protocol provides for the humane care of animals \6\
(see proposed Sec.  58.5(b)). We propose these additions because the
sponsor is responsible for developing the study protocol, either
directly or through a contracted person. To indicate the sponsor's
approval of the study protocol, we propose that the sponsor must sign
and date the study protocol (see proposed Sec.  58.5(c)).
---------------------------------------------------------------------------

    \6\ The document, ``International Guiding Principles for
Biomedical Research Involving Animals,'' last revised in December
2012, advocates among other principles, the ``Three Rs'' of the
ethical use of animals--replacement, refinement, and reduction (Ref.
10). Additionally, the protocol must meet the requirements in Sec.
58.90 for animal care. USDA's Animal Welfare Act regulations (Code
of Federal Regulations, Title 9, Chapter1, Subchapter A, Parts 1-4)
and the Institute for Laboratory Animal Research's Guide for the
Care and Use of Laboratory Animals (Ref. 11), provide specifics
regarding the veterinary care expected when animals are used for
research.
---------------------------------------------------------------------------

    For any phase of a nonclinical laboratory study that includes the
use of animals, we propose that the sponsor contract with persons
accredited as following appropriate animal welfare procedures. If, for
any reason, the sponsor does not use an accredited person for a phase
that includes the use of animals, we propose that the sponsor must
document the reason for using the non-accredited person. (See proposed
Sec.  58.5(d).) If the study supports an application or submission to
FDA, we propose requiring in the application or submission the reason
for using a non-accredited person, along with supporting information to
show the qualifications of that person, such as a copy of SOPs showing
the application of current animal welfare laws, regulations, policies,
and guidelines. This information must be included in the compliance
statement. (See proposed Sec.  58.5(d) and (k).) We are proposing these
requirements to help ensure animal welfare concerns are adequately
addressed, and to help safeguard the reliability of study results.
    A sponsor may transfer to another party responsibility for any or
all of the obligations set forth in this part. A party that assumes any
obligation of a sponsor must comply with the specific regulations in
this chapter applicable to this obligation and must be subject to the
same regulatory action as a sponsor for failure to comply with any
obligation assumed under these regulations. Although a sponsor might
transfer certain responsibilities, the sponsor is still ultimately
responsible for compliance with all sponsor responsibilities provided
in this chapter. When referring to the sponsor throughout this
proposal, we also mean any person that assumes, as an independent
contractor with the sponsor, one or more of the obligations of a
sponsor.
    We propose that the sponsor must document that the contracted
person conducting a phase of the nonclinical laboratory study is
qualified according to the provisions in part 58 applicable for the
phase or phases that person is contracted to perform. (See proposed
Sec.  58.5(e).) Using qualified contracted persons is essential for
ensuring GLP compliance and the quality and integrity of the resulting
data.
    We propose adding communication requirements to sponsor
responsibilities. The OECD consensus document, The Application of the
OECD Principles of GLP to the Organisation and Management of Multi-Site
Studies (Ref. 6), states that many problems associated with the conduct
of multisite studies ``can be prevented by clear allocation of
responsibilities and effective communication among all parties involved
in the conduct of the study.'' This includes the sponsor, study
director, management, principal investigators, QAU, and all other study
personnel. Many comments to the December 2010 ANPRM repeat this
opinion. We agree and propose that the sponsor must ensure appropriate
lines of communication are established (defined, documented in writing
or electronically, and implemented) among all persons conducting any
phase of the nonclinical laboratory study. We also propose that
communications established among persons conducting a phase of the
study that involve the sponsor must be documented by the sponsor. (See
proposed Sec.  58.5(f).)
    We propose that the sponsor must document that test, control, and
reference articles are prepared, characterized, and labeled according
to part 58, subpart F, and are appropriately shipped. In addition, the
sponsor must obtain, and provide to the study director as soon as
available, information about test, control, and reference article
characterization as specified in Sec.  58.105. (See proposed Sec.
58.5(g).) We propose this requirement in Sec.  58.5(g), because the
study director must have characterization information to help ensure
appropriate dosing of the test article and to interpret study results
in the final study report.
    We propose that the sponsor inform the study director of any known
potential risks of the test article to human health or to the
environment, and any measures necessary to protect study personnel.
(See proposed Sec.  58.5(h).) Since the sponsor is most familiar with
test article characteristics because of either direct testing or
receiving results from a contracted person that characterized the test
article, we propose this requirement as a sponsor responsibility. If
there are known or suspected risks to human health or the environment,
it is essential that the study director, as the single point of study
control, is aware of the risks and the measures necessary to protect
study personnel and the environment. This is consistent with OECD's
advisory document, The Role and Responsibilities of the Sponsor in the
Application of the Principles of GLP (Ref. 9).
    We propose that the sponsor must review, approve, sign, and date
each protocol amendment before implementation. (See proposed Sec.
58.5(i).) Many comments to the December 2010 ANPRM recommend this
requirement and we agree. After initiating the study, the sponsor must
be aware of proposed study protocol changes and why the changes are
proposed. This requirement is part of our proposed checks and balances
in part 58 and will help ensure that the amended protocol complies with
GLP.
    We propose that the sponsor must document and update, as necessary,
the archive location of all raw data and records described in proposed
Sec. Sec.  58.190 and 58.195. When we conduct BIMO GLP inspections as a
result of an application or submission to FDA, we rely on the sponsor
to provide the location of the study archives. (See proposed Sec.
58.5(j).)
    We propose that the sponsor must include, in any application or
submission to FDA that contains the results of a nonclinical laboratory
study, the final study report of the nonclinical laboratory study and
all amendments to the final report described in proposed Sec.  58.185.
Also, we propose that the sponsor must include either a statement that
the study was conducted in compliance with the requirements in part 58
or, if not conducted in compliance with part 58, a brief statement of
the reason for noncompliance. (See proposed Sec.  58.5(k)). We propose
this requirement,

consistent with the proposed expansion of the scope, to include all
applications and submissions to FDA supported by data from nonclinical
laboratory studies.
4. Transfer of Responsibilities (Sec.  58.10)
    We propose significant changes to current Sec.  58.10 to help
address the possibility of multiple contractual relationships,
including subcontracting, in multisite nonclinical laboratory studies,
and to conform as much as possible to the regulations in 21 CFR 312.52,
Transfer of obligations to a contract research organization, and 21 CFR
511.1(f), Contract research organizations. Many comments to the
December 2010 ANPRM suggest that we specify in part 58 the parties
responsible in a multisite study and how any transfer of
responsibilities is accomplished. We agree with those suggestions. We
also propose the changes because the current regulations address
explicitly only testing facilities.
    We propose changing the title of Sec.  58.10 from ``Applicability
to studies performed under grants and contracts'' to ``Transfer of
responsibilities'' to reflect the proposed changes to this section. We
also propose adding paragraph designations (a), (b), and (c).
    In Sec.  58.10(a), we propose to require written documentation of
any transfer of responsibilities to a ``contracted person'', as that
term is proposed in Sec.  58.3, referring to any person a sponsor
utilizes to provide a service for the conduct of a nonclinical
laboratory study. Contracted persons may, for example, serve as the
study director, management with executive responsibility, the QAU, a
testing facility, a test site, or an independent contributing
scientist. These contracted persons may further contract with other
individuals or entities. Specifically, we propose that any
responsibility required by the regulations that is transferred must be
described in writing, and that any responsibility not covered by the
written description is considered not transferred.
    We propose to add in Sec.  58.10(b) that any person transferring to
a contracted person any regulatory responsibility for a phase of a
nonclinical laboratory study must inform that contracted person that
the transferred responsibility is required to be performed in
compliance with the provisions in part 58. Proposed paragraph (b)
therefore includes what is currently in Sec.  58.10.
    In Sec.  58.10(c), we propose adding that a contracted person
assuming any regulatory responsibility for a phase of a nonclinical
laboratory study must comply with the regulations in chapter I (21 CFR
chapter I) applicable to the transferred responsibility. That
contracted person will be subject to the same regulatory requirements
as those regulated persons transferring the responsibility.
    We propose these requirements for transfer of responsibilities in a
nonclinical laboratory study to help ensure contracted persons perform
any transferred responsibilities in compliance with part 58 and to help
ensure the quality and integrity of data supporting applications and
submissions to FDA. Also, our proposal is consistent with industry's
desire for flexible relationships among persons conducting phases of a
nonclinical laboratory study.
5. Inspection of Any Person Conducting a Phase of a Nonclinical
Laboratory Study (Sec.  58.15)
    We propose revising Sec.  58.15 to clarify FDA's inspection
authority to include inspecting any person that conducts a phase of a
nonclinical laboratory study of an FDA-regulated product. This includes
all contracted and subcontracted persons that agree to assume one or
more regulatory responsibilities. We propose revising the heading of
Sec.  58.15 to be consistent with these proposed changes.
    Also, we propose modifying the provision about FDA inspection of
QAU records. In the preamble to the original GLP final rule (43 FR
59986 at 59998, December 22, 1978) (Ref. 12) and repeated in FDA's
compliance policy guide (CPG 7151.02) (Ref. 13), we state our policy
that FDA investigators will not routinely inspect QAU records.
Exceptions when FDA will inspect QAU records include ``for cause'' FDA
inspections, or inspections conducted under an inspection warrant, or
when necessary for litigation purposes. Therefore, we propose modifying
Sec.  58.15(a) to specifically state that the ``records inspection and
copying requirements do not routinely apply to QAU records of findings
and problems, or to actions recommended and taken''. We propose adding
for clarity, that ``FDA retains the authority to inspect all QAU
records when necessary to ensure compliance with this part [part 58]''.
    In Sec.  58.15(b), we propose changing certain terms for
consistency within this proposal. For example, we propose changing
``the testing facility'' to ``any person conducting a phase of the
nonclinical laboratory study''.

C. Part 58, Subpart B--Organization and Personnel

1. Personnel (Sec.  58.29)
    We propose no changes to the intent of current Sec.  58.29(a).
However, we propose adding to the end of this provision clarifying
sentences, ``This must include training and experience with GLP
requirements. Personnel who work with animals must have both general
and species-specific training and experience.''
    Several comments to the December 2010 ANPRM state that training on
GLP requirements is essential for all personnel in a nonclinical
laboratory study. This proposed training requirement also is consistent
with the personnel requirements in the OECD Principles on Good
Laboratory Practice (Ref. 8). Therefore, we propose requiring GLP
training to ensure all personnel in a nonclinical laboratory study
understand how to comply with GLP and all aspects of a nonclinical
laboratory study are GLP compliant.
    As we state elsewhere in section III.A.3., we propose specific
responsibilities regarding animal welfare because compliance with
animal care requirements helps ensure the quality and integrity of
study data. Therefore, we propose that all personnel involved with
animal treatment and care must have relevant training and experience,
including species-specific training when applicable.
    In Sec.  58.29(b), we propose adding a requirement that all study
personnel must have access to and comply with the study protocol and
applicable protocol amendments and SOPs, and any protocol deviation
must be reported to the study director. In Sec.  58.29(c), we propose
adding a requirement that all study personnel must record raw data
promptly and accurately as required by a new regulatory provision in
Sec.  58.180 Data quality and integrity. We propose these new
provisions to help ensure compliance with GLPs and to update the
regulations consistent with current practices and the prevalence of
multisite studies. This proposal also is consistent with personnel
responsibilities in the OECD Principles on Good Laboratory Practice
(Ref. 8).
    In proposed Sec.  58.29(d) (currently, Sec.  58.29(b)), we replace
``Each testing facility'' with ``Any person conducting a phase of a
nonclinical laboratory study''. We propose this and other conforming
changes in Sec.  58.29 to address the occurrence of contracting and
subcontracting in multisite studies, to update the regulations, and for
consistency with our proposals in part 58.

2. Testing Facility Management With Executive Responsibility (Sec.
58.31)
    We propose significant changes in Sec.  58.31 consistent with our
proposal requiring a GLP Quality System. To clarify who is responsible
for the proposed requirements in Sec.  58.31, we propose adding ``with
executive responsibility'' to the current heading of ``Testing facility
management.'' We propose this change to specify that upper management
at a testing facility or test site is ultimately responsible for GLP
compliance. We also propose summarizing in the introductory paragraph
the expanded responsibilities of management consistent with the
regulatory text in part 820 (see Sec.  820.20).
    The current provisions in Sec.  58.31(c) through (g) require only
assurances that certain activities are available, performed,
understood, or communicated. For those responsibilities currently in
Sec.  58.31, we propose clarifying and expanding them, requiring
actions and referencing specific SOPs (where applicable). We also
propose adding new responsibilities consistent with a GLP Quality
System and the conduct of multisite studies.
    We propose a new Sec.  58.31(a) requiring testing facility
management with executive responsibility to establish and update
written GLP Quality System SOPs. For continuing oversight of the GLP
Quality System, in new Sec.  58.31(b), we propose requiring testing
facility management with executive responsibility to review at
specified and sufficient intervals and document that the GLP Quality
System meets the requirements in proposed part 58. We propose that
testing facility management with executive responsibility is
responsible for overseeing the implementation of the requirements in
proposed Sec.  58.31(b), according to established procedures to be
included in proposed Sec.  58.81(b)(2) (establishment and periodic
review of a GLP Quality System).
    In Sec.  58.31(e), we propose that testing facility management with
executive responsibility appoint and document the appointment of a
management representative who is a member of the testing facility
management with authority over and responsibility for documenting that
GLP Quality System requirements are effectively established and
maintained. We also propose that this appointed member reports to
management with executive responsibility about the performance of the
GLP Quality System, which includes reports from the QAU. Appointment of
this individual is an organizational responsibility of the testing
facility management with executive responsibility such as in part 820,
Quality System Regulation, the model for the GLP Quality System.
    In Sec.  58.31(f), we propose that testing facility management with
executive responsibility is responsible for documenting that all
persons in a multisite study follow adequate equipment-related SOPs. In
Sec.  58.31(h), we propose this same management is responsible for
documenting that all study personnel are trained to perform their
assigned functions. In Sec.  58.31(k), we propose this same management
is responsible for appointing a person to maintain the master schedule
along with other requirements concerning the master schedule, such as
requiring in a master schedule the core information presently specified
under QAU responsibilities in Sec.  58.35(b)(1). This core information
is essential on each master schedule to ensure consistent
identification across all persons (individuals or entities) in a
multisite study. We propose adding Sec.  58.31(m), requiring testing
facility management with executive responsibility to review all
protocols to ensure that environmental, animal welfare, or work
resource issues or issues with scientific methodology do not affect or
bias any phase of the study's conduct.
    We propose adding Sec.  58.31(r) to require testing facility
management with executive responsibility to review the suitability and
effectiveness of the QAU or lead QAU, as applicable, at defined
intervals and with sufficient frequency, according to established SOPs
as required in proposed Sec.  58.81(b)(17). Periodic review of the
QAU's capability to fulfill their responsibilities helps to ensure the
quality and integrity of study data and is also consistent with a
quality system.
    We propose adding Sec.  58.31(u), requiring testing facility
management with executive responsibility to establish SOPs for
archiving records and materials generated during the course of a
nonclinical laboratory study, including the designation and replacement
of the archivist and any supporting staff. This archiving process is an
essential aspect of compliance with GLPs because maintenance of raw
data and specimens from a specific study enables reconstruction of that
study for verification of the information in the final study report and
confirmation of the study's compliance with part 58.
    These and other proposals in Sec.  58.31 are consistent with the
preamble to the original GLP final rule that states, ``A determination
of the adequacy of each standard operating procedure is the
responsibility of the management'' (43 FR 59986 at 60002) (Ref. 12).
Also, our proposals are responsive to many comments to the December
2010 ANPRM asking that we define operational areas necessary for
broader adoption of a quality system approach to the conduct of
nonclinical laboratory studies.
    Rather than specifying how essential activities of a GLP Quality
System must be conducted, we propose requiring management with
executive responsibility at testing facilities and test sites to
establish essential SOPs. This flexible approach would allow testing
facilities and test sites to establish SOPs best suited to their
specific organizational structure.
3. Test Site Management With Executive Responsibility (Sec.  58.32)
    We propose updating the regulations by adding Sec.  58.32. This new
provision would address the current prevalence of multisite studies and
require test site management with executive responsibility to comply
with relevant requirements in proposed Sec.  58.31 and develop and
maintain SOPs described in Sec.  58.81, ``where appropriate'', as that
term is proposed in Sec.  58.1(c).
    We expect that a test site, like a testing facility, has management
with executive responsibility and appropriate SOPs. Therefore, while a
test site might be conducting a phase of a particular multisite study,
for a different study the same test site could function as a testing
facility by coordinating, conducting, or completing the entire study.
4. Study Director (Sec.  58.33)
    In Sec.  58.33, we propose modifying and adding study director
requirements to update the regulations and to address the prevalence of
multisite studies. We propose certain study director requirements for
consistency with our other proposals in part 58 (for example, our
proposals for a GLP Quality System and for checks and balances to help
ensure data quality and integrity).
    In Sec.  58.33(a), we propose keeping the current requirement that
the study director is the single point of study control. We propose
adding that the study director cannot delegate overall responsibility
for a nonclinical laboratory study. This proposed addition clarifies
and emphasizes that a study director cannot delegate oversight of an
entire nonclinical laboratory study, even though a study director may
delegate to a principal investigator certain responsibilities.
    This proposed change is consistent with FDA's longstanding
interpretation

of a study director's responsibilities and consistent with present FDA
and EPA GLP regulations. This proposed addition also is consistent with
the OECD consensus document, The Role and Responsibilities of the Study
Director in GLP Studies (Ref. 14). Many comments to the December 2010
ANPRM stress the importance of the study director remaining the single
point of study control.
    We propose in Sec.  58.33(a)(2) the study director's responsibility
for implementing procedures that ensure adequate communication among
all study personnel and with the sponsor, as applicable, because
communication is essential in a nonclinical laboratory study.
    In Sec.  58.33(b), we propose new requirements for the study
director for documenting, consulting, signing, and archiving (see
proposed Sec. Sec.  58.33(b)(2) through (7) and (12) through (14)). In
Sec.  58.33(b)(13), we propose that the study director must sign and
date the final study report. FDA agrees with OECD's discussion in this
regard in both the OECD Principles on Good Laboratory Practice (Ref. 8)
and the consensus document, The Role and Responsibilities of the Study
Director in GLP Studies (Ref. 14). The study director's signature on
the final study report indicates acceptance of responsibility for the
validity of the data and the extent to which the study complies with
GLP principles. We also recognize that we use the terms retain and
archive interchangeably throughout this proposal (see, for example,
proposed Sec.  58.33(b)(14)), and we seek comment on which term is
preferred by industry.
    We propose adding in Sec.  58.33(b)(5) and (6) new study director
responsibilities affecting the welfare of test animals. When a protocol
and its amendments impact test animal use, we propose the study
director must document that a committee whose function is ensuring the
appropriate and humane care of animals must first review and approve
the protocol and applicable amendments before initiating the study or
implementing the amendments. The study director also must document that
such a committee has reviewed and approved general procedures for
commonly conducted animal tests. Any protocol requiring only those
tests, with their approved parameters, would not require additional
review before study initiation. However, if a protocol increases the
numbers of animals to be used or alters any of the approved testing
parameters, specific review and approval of that protocol would be
required before study initiation.
    We propose in 58.35(b)(6), that the study director must consult
with the attending veterinarian during review of proposed study
protocols to determine potential animal welfare concerns and
appropriate responses to likely contingencies. Early identification of
potential animal welfare concerns benefits the test animals because
they will receive prompt care, which improves the quality of the data
collected.
    In 58.33(b)(11), we propose adding that the study director must
document that all applicable GLP regulations are followed and include a
study compliance statement in the final study report. FDA agrees with
the statement in the OECD consensus document, The Role and
Responsibilities of the Study Director in GLP Studies (Ref. 14) that
the study director should ascertain that GLP requirements are fully
complied with in every phase of a study, that the study protocol is
faithfully followed, and that all observations, including any
deviations from the protocol, are fully documented.
    In Sec.  58.33(b)(14), we propose adding a timeframe for archiving
of no later than 2 weeks after the study completion date. We think that
timely archiving of raw data, documents, protocols, specimens, and
final reports will help prevent their loss or destruction. Stakeholders
requesting modernizing part 58 asked specifically for a reasonable time
period after the study completion date to complete study archiving.
Numerous comments to the December 2010 ANPRM agree, particularly with
regard to archiving computerized systems. We propose the 2-week
timeframe to allow flexibility for archiving material without
jeopardizing study material integrity.
5. Quality Assurance Unit (QAU) (Sec.  58.35)
    In Sec.  58.35, we propose keeping the QAU functions currently in
the regulations. We propose modifying Sec.  58.35(a) by separating it
into paragraph (1) QAU function and paragraph (2) QAU location. We
propose this change for consistency with our other proposals in part 58
(for example, to address the location of the lead QAU for multisite
studies), and in response to comments to the December 2010 ANPRM
requesting a clear description of the relationship between the QAU and
testing facility management.
    We propose in Sec.  58.35(a)(2)(ii) that, for multisite studies,
testing facility management with executive responsibility must
designate a lead QAU. The concept of a lead QAU is consistent with the
discussion in the preamble of the original GLP final rule stating that
when portions of a study must be contracted to a site that lacks a QAU
``the person letting the contract, and not the contract facility, is
responsible for the performance of the quality assurance functions''
(43 FR 59986 at 59997) (Ref. 12). This change also is consistent with
the OECD consensus document, Quality Assurance and GLP (Ref. 7).
Several comments to the December 2010 ANPRM specifically note the need
for a lead QAU in multisite studies.
    We propose several modifications to current Sec.  58.35(b). We
propose changing the present QAU requirement to maintain a copy of the
master schedule and all protocols to require that the QAU maintain
``access'' to them. For example, if the QAU is a contracted person,
then the QAU might not have overall knowledge about the person (i.e.,
testing facility) to which they are providing QA services. However, the
QAU requires ``access'' to the master schedule and protocols to ensure
GLP compliance.
    We recognize that many sites have a central computerized system for
maintenance of essential documents. Our proposed change about QAU
access to the master schedule responds to stakeholder requests to
modernize part 58 and also to comments to the December 2010 ANPRM. This
change also is consistent with our proposal in Sec.  58.195(d) that
management with executive responsibility must ensure ``maintenance'' of
the master schedule and copies of study protocols.
    Because the lead QAU is responsible for ensuring GLP compliance of
all phases of a multisite study, we propose that the lead QAU must
maintain access to the master schedule of any person that lacks a QAU.
We consider the master schedule an important tool for determining
whether a person is capable of conducting a GLP compliant study. For
example, a person with numerous scheduled studies still in progress may
lack sufficient resources to begin the conduct of a GLP compliant
study.
    Also, as many comments to the December 2010 ANPRM suggest, we
propose removing the word ``sheet'' from the term ``master schedule
sheet''. We propose removing ``sheet'' because we do not want to imply
that a paper copy is required for electronic systems.
    In new Sec.  58.35(b)(3), we propose requiring the QAU to review
the study protocol before initiating the study and all protocol
amendments before implementing them, along with documenting this
review. In new

Sec.  58.35(b)(4), we propose requiring the QAU to review all SOPs
applicable to a given nonclinical laboratory study along with
documenting this review. Current regulations state the QAU is
``responsible for monitoring each study to assure management that the
facilities, equipment, personnel, methods, practices, records, and
controls are in conformance'' with GLPs (current Sec.  58.35(a)).
    Our proposed initial review by the QAU of the study protocol and
applicable facility SOPs will help ensure compliance with part 58 from
the start of the study. Otherwise, when the study is underway,
amendments to the study protocol and SOPs might be needed if QAU
inspections reveal compliance deficiencies.
    We propose in Sec.  58.35(b)(5) expanding the types of QAU
inspections recognized by FDA by adding process-based and facility-
based inspections.\7\ Many comments to the December 2010 ANPRM request
this change consistent with QAU inspections described in the OECD
consensus document, Quality Assurance and GLP (Ref. 7), specifically
supporting an appropriate mix of study-specific and process-based
inspections.
---------------------------------------------------------------------------

    \7\ The term ``study-based inspection'' is not used in current
FDA regulations; however, this type of inspection is equivalent to
the QAU inspection currently required in part 58.
---------------------------------------------------------------------------

    However, many comments to the December 2010 ANPRM express concern
about how process-based inspection results will be appropriately
considered for all relevant studies, particularly when an inspection
reveals problems. This concern is especially relevant to any phase
involving a short-term study, as we propose to define this term.
Process-based inspections are conducted on a prearranged schedule,
which is not connected to the timing of any particular nonclinical
laboratory study. Therefore, a facility utilizing process-based
inspections might conduct a short-term study that is not inspected
during its in-life period (that is, during the time data are
collected). This concern also is addressed in the OECD consensus
document, The Application of the GLP Principles to Short Term Studies
(Ref. 15).
    To ensure that any problem revealed during a process-based
inspection is properly captured in the reports of all relevant studies,
we propose adding Sec.  58.35(e). This provision requires preparation
of a written certification, by the person conducting a phase of the
study, whenever a process-based inspection reveals problems. As
proposed, this certification requires documenting actions taken to
properly inform, and modify (when applicable), reports for all studies
impacted by the results of that process or procedure. While a
management responsibility, we propose adding this requirement in Sec.
58.35 because of its similarity to the existing requirement in current
Sec.  58.35(d) for management to provide an FDA representative, upon
request, a certification regarding the implementation of required QAU
inspections.
    In Sec.  58.35(b)(7) (a redesignation and revision of current Sec.
58.35(b)(4)), we propose expanding the requirement that the QAU must
submit to management with executive responsibility and the study
director a periodic written status report on each study. We propose
that these periodic reports ``discuss the overall progress and
compliance status of the study and include any problems observed and
the corrective actions taken.'' In conjunction with this requirement,
we propose that the content and frequency of these reports be specified
in SOPs as required in proposed Sec.  58.81(b)(21).
    We propose this revision in Sec.  58.35(b)(7) because feedback to
management with executive responsibility and the study director about
the overall progress and compliance status of the study is essential to
ensure study compliance. We intend these periodic reports to give a
general overview of the study. We expect these periodic reports to
complement any inspection reports for the study, which only provide a
snapshot in time.
    We are interested in receiving feedback about the use and relevance
of periodic status reports. Specifically, we are seeking comment about
whether QAUs regularly provide such reports and whether they are useful
to the study director and management when provided.
    Consistent with our proposals addressing multisite studies, we
propose adding in new Sec.  58.35(b)(8) (revision of current Sec.
58.35(b)(5)) that the lead QAU must identify all deviations occurring
in the entire study, including deviations identified by any other
existing QAUs participating in the study. We expect this requirement
may be facilitated by principal investigator reports to the study
director, documentation by other existing QAUs, and direct oversight by
the lead QAU of independent contributing scientists and any persons
conducting a phase of the study lacking either a principal investigator
or a QAU or both. We propose this requirement to ensure the lead QAU is
made aware of protocol deviations in a timely manner. This awareness
will help alert the lead QAU to the need to correct or modify relevant
SOPs and the study protocol when necessary to maintain data integrity.
    The remaining additions we propose in Sec.  58.35 relate to QAU
oversight of the integrity of data in the final study report. Current
responsibilities in Sec.  58.35(b)(6) (revised and redesignated as
Sec.  58.35(b)(10)) are to ensure the quality and integrity of the
final study report. Therefore, we propose in Sec.  58.35(b)(9)that the
QAU must audit the reports of all contributing scientists and all
existing principal investigators.
    Currently Sec.  58.35(b)(6) requires the QAU to assure that the
``reported results accurately reflect the raw data of the nonclinical
laboratory study.'' However, QAU members might not have the scientific
judgment needed for evaluating the scientific merits of the final
report and determining whether the results accurately reflect the data.
In the preamble to the original GLP final rule (43 FR 59986 at 59998,
comment 90) (Ref. 12), we agreed that ``the QAU should not attempt to
evaluate the scientific merits of the final report.'' Therefore, in
Sec.  58.35(b)(9) and (10), we propose clarifying our intent.
    Specifically, we propose that the QAU must audit all contributing
scientists' reports and any report amendments to ensure they include a
report of all data and reflect the protocol, and amendments, and
applicable SOPs. This requires that all data generated during the study
are included and discussed, which is essential for the full
transparency necessary for reconstruction of the study.
    For multisite studies, we propose that other QAUs participating in
the study must audit the reports and report amendments of any principal
investigators and all contributing scientists for whom they are
responsible. We also propose in Sec.  58.35(b)(9), for any person that
lacks a QAU, that the lead QAU audits the reports and amendments of all
contributing scientists and any principal investigators. This includes
audits of any independent contributing scientist. This proposed
requirement will ensure all data from a nonclinical laboratory study
will receive QAU review, thus improving the quality and integrity of
the final study report.
    In Sec.  58.35(b)(10), we propose that the QAU must verify that all
original and amended signed and dated reports from contributing
scientists are appended to the final study report. For multisite
studies, we propose that the lead QAU is responsible for this
requirement. Under existing regulations that require providing the
final study report and any

amendments, we expect that both original and amended versions of
reports from all contributing scientists be appended to the final study
report. The proposed changes make this expectation a specific
requirement. This requirement will allow the study sponsor and FDA
reviewers to have access to the original conclusions for each phase and
any modifications made as a result of interactions among those involved
with the study. We propose this requirement to address the potential
inadvertent or intentional introduction of bias that may result when
only the final amended version of contributing scientists' reports are
included.
6. Contributing Scientist (Sec.  58.37)
    As discussed in section III.B.2., we propose adding a definition
for a contributing scientist. In that definition, we include an
independent contributing scientist as an individual expert or
specialist who is an independently employed contracted person. We
propose adding responsibilities for contributing and independent
contributing scientists to help facilitate the development of a GLP
Quality System. To describe the responsibilities of these positions, we
propose adding Sec.  58.37(a) and (b), respectively.
    When a contributing scientist is responsible for a phase, we
propose in Sec.  58.37(a) that the contributing scientist must comply
with part 58; provide a signed and dated report for inclusion in the
final study report; and permit oversight by the designated QAU. (See
proposed Sec.  58.37(a)(1) through (3)).
    In Sec.  58.37(b), we propose requirements for an independent
contributing scientist in addition to those requirements in Sec.
58.37(a). The proposed requirements in Sec.  58.37(b) include, among
others, that independent contributing scientists must document,
maintain, and update information about their education, training, and
experience related to their responsibilities for a particular phase.
Also, we propose they must archive all materials as required by the
protocol and by proposed Sec.  58.195.
    Our proposal for adding Sec.  58.37 is consistent with the
expectations in the present regulations for individual scientists and
professionals. We propose these requirements in part to help clarify
the regulations.
7. Principal Investigator (Sec.  58.39)
    We propose adding Sec.  58.39 to include principal investigator
requirements related to a principal investigator's responsibilities for
a phase of a nonclinical laboratory study. We propose that designating
a principal investigator is optional.
    The OECD Principles on Good Laboratory Practice (Ref. 8) includes
the term principal investigator solely in reference to multisite
studies. We recognize, however, the possibility of a testing facility
employing a principal investigator for a single-site study. For
example, a single-site study conducted in a facility situated on a
large campus with multiple buildings might have one or more principal
investigators.
    We also recognize that a testing facility may conduct a multisite
study where, at all sites, only the study director oversees the study.
Several comments to the December 2010 ANPRM note these various
practices. We therefore propose in Sec.  58.39 principal investigator
requirements for specific responsibilities in one or more phases as
delegated to the principal investigator by the study director.
    We propose principal investigator responsibilities consistent with
a principal investigator's role of ensuring compliance with part 58 for
a specific phase. For example, we propose the principal investigator
must document and report to the study director all deviations the
principal investigator observes during the conduct of the study. These
requirements also are consistent with the responsibilities of a
principal investigator in The Application of the OECD Principles of GLP
to the Organisation and Management of Multi-Site Studies (Ref. 6), and
with a GLP Quality System.

D. Part 58, Subpart C--Facilities

1. General (Sec.  58.41)
    In Sec.  58.41, we propose changing ``Each testing facility shall
be'' to ``Any person conducting a phase of a nonclinical laboratory
study must have facilities'' of suitable size and construction to
facilitate the proper conduct of nonclinical laboratory studies. We
propose this change to include multisite studies.
2. Animal Care Facilities (Sec.  58.43)
    In Sec.  58.43, we propose changes to include multisite studies and
to cover any phase involving the use of animals. We propose these
changes consistent with our proposal revising the testing facility
definition and our goal of applying the GLP regulations to all
nonclinical laboratory studies, including multisite studies.
3. Facilities for Handling Test, Control, and Reference Articles (Sec.
58.47)
    In Sec.  58.47 we propose adding ``reference'' to refer to
``reference articles'' for consistency with our other proposals.

E. Part 58, Subpart D--Equipment

1. Equipment Design (Sec.  58.61)
    In Sec.  58.61, we propose adding that equipment includes
computerized systems. We also propose adding in Sec.  58.61, equipment
used for maintenance, archiving, and retrieval of data. We propose
these additions to update and clarify the regulations.
2. Maintenance and Calibration of Equipment (Sec.  58.63)
    In Sec.  58.63, we propose adding to paragraph (a) maintenance,
archiving, and retrieval of data. In paragraph (b), we propose changing
the citation reference from Sec.  58.81(b)(11) to (14) and adding a
reference to the written SOP requirement in Sec.  58.81(b)(15). Also,
in paragraph (b), we propose adding ``as applicable'' to address the
possibility of a multisite study. We propose these changes for
consistency with our other proposed changes in part 58 and to update
the regulations to address multisite studies.

F. Part 58, Subpart E--Nonclinical Laboratory Study Operations

    Consistent with our proposals in part 58 to address multisite
studies, we propose revising the heading of subpart E from ``Testing
Facilities Operation'' to ``Nonclinical Laboratory Study Operations''.
Also, accordingly, we propose modifying the sections in subpart E.
1. Standard Operating Procedures (SOPs) (Sec.  58.81)
    We propose modifying Sec.  58.81 Standard operating procedures
(SOPs), consistent with our proposals for a GLP Quality System and to
address multisite studies. In Sec.  58.81(a), we propose adding to the
current requirement that a testing facility must have written SOPs,
that all test sites, too, must have written SOPs. Also, in Sec.
58.81(a), we propose changing ``management'' to ``management with
executive responsibility''.
    In Sec.  58.81(b), consistent with our proposal in Sec.  58.81(a),
we propose adding that the testing facility and all test sites must
establish SOPs for an applicable phase of a nonclinical laboratory
study. As discussed in section III.B.1., we use the terms ``applicable
phases'' and ``where appropriate'' because in a multisite study no one
person will conduct all phases of the study. Therefore, each person
requires SOPs only for those phases which that person conducts.

    We propose adding to the current list of SOPs in Sec.  58.81(b)
numerous topics that require SOPs. For example, we propose adding that
SOPs must include an SOP for preparing, modifying, and administering
all SOPs. We propose these additional SOP requirements because they are
essential components of a complete quality system approach (i.e., the
proposed GLP Quality System) and also address the current prevalence of
multisite studies.
    Our proposal in Sec.  58.81 will require initial efforts by testing
facilities and test sites to modify or add SOPs as needed for a GLP
Quality System. However, once established, the GLP Quality System will
facilitate greater flexibility and efficiency for the conduct of
nonclinical laboratory studies and, over time, will help reduce costs.
2. Animal Care (Sec.  58.90)
    In Sec.  58.90, we propose modifying paragraph (b) to require,
throughout the study, evaluation of the health status of test animals
according to acceptable veterinary medical practices for the care of
test animals. We propose this change because proper animal care is
essential during the entire study to ensure the welfare of test animals
and the integrity of test results. However, test animal evaluations can
be performed by the attending veterinarian or appropriately-trained
personnel who are delegated this responsibility by the attending
veterinarian.
    In Sec.  58.90(c), we propose removing from the third sentence the
phrase ``provided that such treatment does not interfere with the
study'', and replacing this phrase with ``as deemed necessary by the
study's attending veterinarian.'' We propose few changes in Sec.
58.90(d) and (e). In the first sentence of current Sec.  58.90(d), we
propose replacing ``excluding suckling rodents'' with ``except nursing
neonates'' to update the regulation to be more inclusive and
appropriate. In Sec.  58.90(e), we propose adding the word
``reference'' to conform to changes proposed elsewhere in this
document.
    We propose these changes in Sec.  58.90 to update and clarify the
regulations, and because test animal welfare concerns are an essential
part of a GLP Quality System.

G. Part 58, Subpart F--Test, Control, and Reference Articles

    We propose adding the term ``Reference'' to the heading in subpart
F, and in certain applicable provisions in subpart F. We also propose
adding in subpart F specifics concerning tobacco products, and a
reference to method validation.\8\
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    \8\ There is a draft guidance document regarding bioanalytical
method validation, ``Bioanalytical Method Validation Draft
Guidance'' (Ref. 16). When final, this guidance will provide FDA's
current thinking. We consider many of the general principles in this
draft guidance document applicable to method validation in
nonclinical laboratory studies.
---------------------------------------------------------------------------

1. Test, Control, and Reference Article Characterization (Sec.  58.105)
    We propose modifying Sec.  58.105 to require that all information
about test, control, and reference article characterization be provided
to the study director as soon as available. This information is
necessary for determining appropriate dosing and drafting conclusions
in the final study report. The lack of this information limits the
important test result discussion in the final study report.
    Reports submitted to FDA must provide study information based on
the characteristics of the product (test article) studied. We expect a
test article to be characterized to the extent required to interpret
the study properly. For nonclinical laboratory studies conducted in
support of initiating clinical ``first-in-human'' studies, this
characterization information is particularly important for human
subject protection.
    We propose modification of Sec.  58.105(a) to exclude the use of a
marketed tobacco product's labeling to characterize such a product if
it is used as a control or reference article in a nonclinical
laboratory study. The labeling of currently marketed tobacco products
does not provide the information required for full product
characterization. That is, the chemical composition (including
mainstream smoke composition), microbiological composition, and design
parameters of the product are not fully described in tobacco product
labels. Thus, the composition and toxicant deliveries of currently
marketed tobacco products are less well defined in tobacco product
labeling than the safety and efficacy information described in the
labels of marketed drug products. Therefore, FDA notes that when using
a marketed tobacco product as a control or reference article, the
marketed tobacco product's characteristics must be determined and
documented as required in this part.
    We propose revising and redesignating the current provisions in
Sec.  58.105(b), (c), and (d). These proposed changes are necessary for
consistency with our other proposals in part 58, such as the addition
of reference articles.
    The current regulations imply that empty containers from test
articles must be retained. Comments to the December 2010 ANPRM did not
see the need to retain the empty containers provided appropriate
product information is maintained and test article accountability is
fully documented. We agree with those comments and propose to remove
this implied requirement. To provide for adequate test article
accountability, in lieu of retaining empty test article containers, we
propose requiring in Sec.  58.105(d) that the study director verify and
document by dated signature the distribution and final disposition of
the test article.
2. Test, Control, and Reference Article Handling (Sec.  58.107)
    We propose minimal conforming changes in Sec.  58.107, such as
adding ``reference'' to the section heading and first sentence.
3. Mixtures of Articles with Carriers (Sec.  58.113)
    We propose modifying Sec.  58.113 by adding ``reference'' to the
provisions proposed in Sec.  58.113(a), (a)(1), (a)(2), (b)(2), and
(d). Also, we propose requiring that the results from the determination
of the uniformity, concentration, and stability of mixtures of test
articles with carriers are provided to the study director as soon as
available. We propose these changes in Sec.  58.113 for the same
reasons we propose changes in Sec.  58.105.

H. Part 58, Subpart G--Protocol for and Conduct of a Nonclinical
Laboratory Study

1. Protocol (Sec.  58.120)
    We propose modifying Sec.  58.120 to address multisite studies more
specifically, and to provide consistency with our other proposed
changes discussed elsewhere.
    Many comments to the December 2010 ANPRM suggest that the study
protocol identify all sites participating in a multisite study. We
agree, and propose adding in Sec.  58.120(a)(3) that the protocol
contain contact information for all persons conducting a phase of the
nonclinical laboratory study.
    Current Sec.  58.120(a)(6) includes in the protocol the methods for
controlling bias. We propose adding to this provision the analysis and
reporting of study test results and procedures to be followed if a
study includes a peer review of any phase. Also, for multisite studies,
we propose adding a requirement that the protocol identify the
person(s) conducting the phases of the nonclinical laboratory study.

    We propose expanding current Sec.  58.120(a)(10) to clarify that
the protocol must include a listing of the study-specific records that
are required to be maintained. We think this clarification will help
assure that study-specific records are maintained.
    Current Sec.  58.120(a)(11) requires the date of protocol approval
by the sponsor, and the dated signature of the study director. We
propose expanding this provision to indicate study protocol approval by
the dated signature of the study sponsor, the study director,
independent contributing scientists, principal investigators, and any
other person conducting a phase of the nonclinical laboratory study, as
applicable.
    We propose redesignating and modifying Sec.  58.120(b) as Sec.
58.120(d). In Sec.  58.120(d), we propose requiring, before
implementing any change or revision to an approved protocol, that the
study sponsor and the study director document their approval of the
change or revision. For a multisite study, any person affected by the
proposed changes (for example, the principal investigator or
independent contributing scientist) also must document approval. We
consider a person's dated signature on the protocol revision to be
acceptable documentation indicating approval. We propose that these
signed and dated protocol amendments must be maintained with the
protocol.
    Before initiating any study using animals, we propose requiring in
new Sec.  58.120(b) protocol review and approval by ``a committee whose
function is to ensure that the care and use of animals in studies is
appropriate and humane''. In new Sec.  58.120(e), we propose the same
review and approval by this committee before implementing any protocol
changes that affect animal welfare. These additions are consistent with
the proposal in Sec.  58.33(b)(5) that the study director must ensure
that all studies that include the use of animals are approved by such a
committee.
    In new Sec.  58.120(c), we propose requiring that the study sponsor
and testing facility management with executive responsibility sign and
date a statement that the study will be conducted in compliance with
part 58. We propose appending this statement to the protocol. This
proposal is consistent with the requirement in Sec.  58.10(b) that a
sponsor must inform a contracted person that the study must be
conducted in compliance with chapter I. This proposal also is
consistent with the requirements discussed elsewhere in this document
that the study director documents applicable GLP regulations are
followed (section III.C.4.), and that the QAU ensures studies conform
to the regulations in part 58 (section III.C.5.).
2. Conduct of a Nonclinical Laboratory Study (Sec.  58.130)
    We propose redesignating current Sec.  58.130(a) through (c), as
(d), (f), and (g) respectively. In new proposed Sec.  58.130(a), we
require demonstration that all analytical methods are accurate,
sufficiently precise, and sensitive enough to result in accurate and
reproducible data. We expect this requirement will help ensure data
quality and integrity as its intent is to produce accurate and
reproducible data. This requirement also is consistent with
requirements in part 320 (21 CFR part 320), ``Bioavailability and
Bioequivalence Requirements'' (see Sec.  320.29(a)).
    In new Sec.  58.130(b), we propose conducting test, control, and
reference article characterization as specified in part 58, subpart F.
We propose this requirement to clarify our current and future
expectations regarding test, control, and reference article
characterization.
    In new Sec.  58.130(c), we propose that ``humane care and ethical
treatment of test animals must be considered in advance and upheld in
conjunction with achieving study objectives.'' We propose this
provision is consistent with our other proposals addressing animal
welfare discussed elsewhere in section III.A.3.
    In new Sec.  58.130(e), we propose that any change to the protocol
must be approved as an amendment. We propose this requirement
consistent with the proposed requirement in Sec.  58.120(d) for
approval of protocol amendments. However, we understand the importance
of test animal welfare along with maintaining the integrity of the
study. Therefore, FDA intends to evaluate on a case-by-case basis
certain circumstances when a protocol deviation is necessary to prevent
a potential hazard to animal welfare or study integrity.
    In proposed Sec.  58.130(h) (revised and redesignated current Sec.
58.130(d)), postmortem observations must be available to the
pathologist unless specified otherwise in the study protocol. We
understand that some study protocols might blind the pathologist to
postmortem observations. We expect, however, in most cases the
pathologist will not need to be blinded to postmortem observations.

I. Part 58, Subpart J--Records and Reports

1. Data Quality and Integrity (Sec.  58.180)
    We propose adding a new Sec.  58.180 for data quality and
integrity. Ensuring data quality and integrity in a nonclinical
laboratory study is one of our critical goals in this part 58 proposal.
Therefore, we propose adding this separate Sec.  58.180 to clearly
identify requirements for data quality and integrity. We propose this
new section in subpart J because data are part of study records and
reports.
    We propose moving to this new section, and revising, the
requirements in current Sec.  58.130(e). In Sec.  58.180(a), we propose
creating the acronym ``ALCOA''. This is a mnemonic that signifies
quality data to stakeholders that conduct clinical and nonclinical
studies. We propose therefore that all nonclinical laboratory study
data are ``accurate, legible, contemporaneous, original, and
attributable''.
    In Sec.  58.180(b), we propose modifying and updating the
provisions currently in Sec.  58.130(e) to address electronic data
capture and maintenance. Numerous comments to the December 2010 ANPRM
note that part 11 (21 CFR part 11, ``Electronic Records; Electronic
Signatures'') is applicable to part 58 and therefore parts 11 and 58
should be consistent. We agree, and do not intend to duplicate in part
58 the requirements in part 11. As a result, we propose that electronic
records systems need to be compliant with applicable regulations.
    In Sec.  58.180(c), we propose adding that the final study report
must contain all data accrued during the study. This proposed
requirement is consistent with our proposal in Sec.  58.120(b)(6)
requiring that the protocol describe methods for controlling bias. We
propose this requirement because selective data inclusion in the study
analysis could introduce bias into the final study report.
2. Reporting of Nonclinical Laboratory Study Results (Sec.  58.185)
    Study data must be maintained in a manner that allows for
``reconstruction of the study for the purpose of assessing the quality