[Federal Register Volume 81, Number 164 (Wednesday, August 24, 2016)]
[Proposed Rules]
[Pages 58342-58380]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-19875]



[[Page 58341]]

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  

[[Page 58342]]


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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: 202-395-7285, or email to 
[email protected]. 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

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    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
                                                                                         ------------------------------------------------
                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.
                                         ---------------------------------------------------------------------------------------------------------------
Costs:

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    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.

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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

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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.

[[Page 58347]]

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

[[Page 58348]]

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

[[Page 58349]]

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

[[Page 58350]]

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

[[Page 58351]]

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,

[[Page 58352]]

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.

[[Page 58353]]

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

[[Page 58354]]

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

[[Page 58355]]

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

[[Page 58356]]

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.

[[Page 58357]]

    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\
---------------------------------------------------------------------------

    \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.

[[Page 58358]]

    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 
and integrity of the results or the reinterpretation of the data in the 
light of later findings'' (41 FR 51206 at 51215) (Ref. 4). Study 
records and reports required in part 58, subpart J, are acceptable in 
electronic or paper medium, or a combination of both. In Sec.  58.185, 
we propose eliminating any current requirements that might impede a 
fully computerized facility.
    Many comments to the December 2010 ANPRM suggest we allow testing

[[Page 58359]]

facilities to develop an integrated final study report. This integrated 
final study report would be in lieu of individual scientists' reports, 
which the study director must then compile and discuss in an integrated 
final study report. The preamble to the original GLP final rule states 
that individual reports are required as part of the final report to 
ensure the findings of the individual scientists are accurately 
reflected (43 FR 59986 at 60009) (Ref. 12). Also, in the preamble to 
the 1987 final rule amending part 58, FDA thought that reports 
combining data, information, and views from scientists of different 
disciplines would obscure the individual scientist's accountability for 
accurate reporting (see 52 FR 33768 at 33778).
    We continue to affirm these statements. However, we support 
processes used for the efficient review of the draft study report to 
facilitate completion of the final study report.
    In Sec.  58.185, we propose adding general statements for 
consistency with our other part 58 proposals. We propose adding two 
provisions specific to animal welfare. In Sec.  58.185(a)(2), we 
propose requiring that final study reports contain the names of all 
study attending veterinarians. We propose redesignating and modifying 
Sec.  58.185(a)(9) as (a)(10) to add the example of ``all health-
related issues reported by an attending veterinarian or appropriately 
designated personnel during the course of the study''. This provision 
recognizes that circumstances affecting the quality and integrity of 
the data could include health-related issues noted and reported by the 
attending veterinarian or appropriately designated personnel. We 
propose this addition to help ensure that all untoward health-related 
observations of test animals are captured and reported so that FDA 
reviewers can consider their possible effect on study results.
    We propose redesignating and modifying Sec.  58.185(a)(12) as 
(a)(13) to be consistent with the EPA's GLP regulations (see 40 CFR 
160.185(a)(12) and 792.185(a)(12)). That is, we propose requiring a 
signed and dated report from each person conducting an analysis or 
evaluation of study data or specimens after data generation was 
completed. We propose this addition to provide transparency regarding 
the review of study findings and the development of conclusions 
submitted in the final study report.
    In new Sec.  58.185(a)(16), we propose that the study director 
provide with the final study report a statement about the study's 
extent of compliance with part 58, including any study deviations. This 
requirement is consistent with OECD's consensus document The Role and 
Responsibilities of the Study Director in GLP Studies (Ref. 14) and 
addresses a recommendation from stakeholders who requested that FDA 
modernize part 58.
    Many testing facilities provide services internationally and 
therefore, this statement is commonly seen in final study reports 
submitted to FDA. Such a statement also is included in EPA's study 
profile templates, which outline the necessary documents for submission 
of supporting data.\9\ FDA presently requires such a compliance 
statement from the applicant for applications and submissions for 
research and marketing and frequently receives the study director's 
statement in fulfillment of, or at least as the primary basis for, the 
required statement.
---------------------------------------------------------------------------

    \9\ A link to those templates is provided in the Pesticide 
Registration Notice 2011-3 ``Standard Format for Data Submitted 
Under the Federal Insecticide, Fungicide, and Rodenticide Act and 
Certain Provisions of the Federal Food, Drug, and Cosmetic Act'' 
(Ref.17).
---------------------------------------------------------------------------

    Several comments to the December 2010 ANPRM suggest modifying part 
58 to include requirements for studies discontinued before completion. 
In response to this suggestion, we propose new Sec.  58.185(d) 
requiring the study director to write, sign, and date a short written 
summary report closing the study and discussing why the study was 
discontinued. This report and study material must be archived as 
required in Sec.  58.190 in case of future study review or study 
completion.
3. Storage and Retrieval of Records and Data (Sec.  58.190)
    We propose modifying Sec.  58.190(a) to add reserve samples to 
those items generated as a result of a nonclinical laboratory study 
that must be retained. We also propose adding a requirement for 
retention of ``Correspondence and other documents relating to 
interpretation and evaluation of data, other than those documents 
contained in the final study report.'' We propose this addition to 
harmonize with the EPA GLP regulations (see 40 CFR 160.190(a) and 
792.190(a)) and to clarify our requirement for retaining these 
documents.
    Our other proposed modifications in Sec.  58.190 provide timeframes 
for archiving required study material and requirements for the SOPs 
about archiving to include procedures specific to removing study 
material from the archives. Stakeholders who asked that we modernize 
part 58 requested a reasonable timeframe after the study completion 
date to complete study archiving. Comments to the December 2010 ANPRM 
also made this request. The SOP requirement for procedures specific to 
removing study material from the archives is to address concerns that 
material in the archives could be lost or destroyed if removed without 
having in place adequate and specific procedures.
    We propose that archiving occur no later than 2 weeks after the 
study completion date (see study completion date defined in Sec.  
58.3). We propose this 2-week timeframe to prevent required material 
from being inadvertently misplaced, lost, or destroyed over the long 
term. We understand that certain situations may prevent archiving study 
material during, or at the completion of, a nonclinical laboratory 
study as currently required of the study director in Sec.  58.33(f).
    We also propose, when the study sponsor delays finalizing the final 
study report, that the study director must complete, sign, and date the 
final study report and archive all study material no later than 6 
months after completion of the last draft of the final study report. 
Additionally, if the study sponsor stops a nonclinical laboratory study 
before all protocol requirements are complete, a decision about 
discontinuing the study must be made no later than 6 months after 
stopping the study. For discontinued studies, a summary report and 
study material must be archived within 2 weeks of the study director 
signing the summary report. We propose these timeframes to provide the 
requested flexibility without compromising the integrity of study 
material.
4. Retention of Records (Sec.  58.195)
    We propose modifying Sec.  58.195(b) to conform withSec.  58.190(a) 
for the listing arrangement. We also propose modifying Sec.  
58.195(b)(1) to address those applications and submissions to FDA that 
might not result in an approval, clearance, or a premarket 
authorization. We therefore propose adding an additional required 
retention period from the date an application or submission is 
administratively closed by FDA. ``Administratively closed'' includes 
those applications and submissions closed administratively with or 
without a decision.
    In Sec.  58.195(h), we propose adding a statement recognizing that 
a change of archive location may be due to reasons other than closure 
of a testing facility. For example, changes in ownership as well as 
changes in physical location would change the archive location. We also 
propose including a timeframe of ``no later than 10 working days after 
the transfer occurs'' for reporting to FDA

[[Page 58360]]

and the study sponsor a change in archive location.
    We propose this timeframe to ensure that FDA is informed of the 
location of study materials if a GLP BIMO inspection of the study is 
warranted. This requirement is necessary to prevent waste of 
inspectional resources and delay in receiving FDA inspectional 
findings, which provide FDA reviewers information about data quality 
and integrity.
    Other proposed changes to Sec.  58.195 are for consistency with our 
proposals throughout this document and to update the regulations 
consistent with current practices.

J. Part 58, Subpart K--Disqualification of Any Person Conducting a 
Phase of a Nonclinical Laboratory Study

    We propose modifying subpart K to extend the authority of the 
Commissioner of Food and Drugs to disqualify any person conducting a 
phase of a nonclinical laboratory study upon finding either or both of 
the conditions for disqualification in the proposed revisions in Sec.  
58.202. We propose adding any person conducting a phase of a 
nonclinical laboratory study for consistency with other modifications 
throughout this proposal.
    We propose modifying Sec.  58.202 to clarify the conditions for 
disqualification. To help provide uniformity in FDA regulations, we 
propose adding as a basis for initiating disqualification proceedings 
the repeated or deliberate submission of false information in any 
required report. FDA intends to reserve disqualification for the rare 
case when the rejection of a particular study is an inadequate 
regulatory response (see 43 FR 59986 at 60011) (Ref. 12).
    In addition, we propose to amend the current provision in Sec.  
58.206(a) so that a person disqualified under part 58 would no longer 
be eligible to receive a test article under part 511, New Animal Drugs 
For Investigational Use. A clinical investigator who is ineligible to 
receive a test article under part 511 also would be ineligible to 
conduct any nonclinical laboratory study that is intended to support an 
application for a research or marketing permit.
    For certain FDA-regulated products, such as new animal drugs, the 
study subjects are animals in both ``nonclinical laboratory studies'' 
and ``clinical investigations.'' In the new animal drug approval 
process, nonclinical laboratory studies, such as those that target 
animal safety and human food safety, may be essential in determining 
whether to approve an application for a research or marketing permit 
for a new animal drug. For new animal drugs, the same clinical 
investigator could conduct both nonclinical laboratory studies and 
clinical investigations. Therefore, we propose this action to help 
protect the safety and welfare of animal research subjects involved in 
FDA-regulated nonclinical laboratory studies and clinical 
investigations, and to help ensure the reliability and integrity of the 
data submitted to FDA to support FDA decisions concerning new animal 
drugs.
    Concurrent with this proposal, FDA is publishing elsewhere in this 
issue of the Federal Register a proposal to amend Sec.  511.1(c), to 
expand the scope of clinical investigator disqualification under part 
511. Under the current regulations, a clinical investigator 
disqualified by the Commissioner is ineligible to receive the 
particular type of test article regulated under that part (e.g. new 
animal drugs in Sec.  511.1(c)) and is ineligible to conduct any 
clinical investigation that supports an application for a research or 
marketing permit for products regulated by FDA. Under the proposed 
amendment to part 511, a clinical investigator disqualified under part 
511 also would be ineligible to conduct any nonclinical laboratory 
study intended to support an application for a research or marketing 
permit for a new animal drug.
    When a clinical investigator is disqualified pursuant to part 511, 
the basis for that disqualification typically is the repeated or 
deliberate submission of false information to FDA or a sponsor in any 
required report. For new animal drugs, the same investigator could 
conduct both nonclinical laboratory studies and clinical 
investigations. The proposed amendment to part 511 would make a 
clinical investigator disqualified under part 511 ineligible to conduct 
any nonclinical laboratory study intended to support an application for 
a research or marketing permit for a new animal drug. In addition, the 
proposed amendment to part 511 would help to provide consistency for 
disqualification proceedings in parts 58 and 511.8.
    Other proposed provisions in Sec. Sec.  58.200, 58.202, 58.204, 
58.206, 58.210, 58.213, 58.215, and 58.217 are for clarity and 
consistency with our proposals throughout this document. In Sec.  
58.210, when a study is determined to be unacceptable, we propose to 
eliminate from consideration data in support of the application or 
submission to FDA, as defined in proposed Sec.  58.3. We also propose 
to add that such elimination may serve as new information justifying 
appropriate regulatory action not limited to termination or withdrawal 
of approval.
    We propose modifying Sec.  58.219 to reference Sec.  58.210(b) and 
to require an FDA inspection of a disqualified person before 
reinstatement can be considered. Presently, Sec.  58.219 states that 
the Commissioner ``may'' require such an inspection. Before a request 
for reinstatement can be appropriately considered by FDA, we propose 
requiring an inspection. This inspection would help provide additional 
information about the disqualified person that may be relevant to the 
consideration for reinstatement.

IV. Regulatory Hearing Before FDA

    We propose to add to 21 CFR 16.1(b)(2) a new provision for 21 CFR 
part 58, subpart K relating to disqualifying any person that conducts a 
phase of nonclinical laboratory studies of FDA-regulated products.

V. Analysis of Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Legal Authority

    Legal authority to issue good laboratory practice regulations 
exists under section 701(a) of the FD&C Act, 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; and, sections 351 and 354-360F of 
the PHS Act.

VII. Proposed Implementation Plan

    FDA proposes that any final rule that may issue based on this 
proposal become effective 1 year after the date of publication of the 
final rule in the Federal Register.

VIII. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive

[[Page 58361]]

impacts; and equity). We have developed a comprehensive Economic 
Analysis of Impacts that assesses the impacts of the proposed rule. We 
believe that this proposed rule is not a significant regulatory action 
as defined by Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because the proposed requirements are likely to 
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), we find that the proposed rule would 
have a significant economic impact on a substantial number of small 
entities, but the impacts are uncertain.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $146 million, using the most current (2015) Implicit 
Price Deflator for the Gross Domestic Product. This proposed rule would 
not result in an expenditure in any year that meets or exceeds this 
amount.

B. Summary

    This proposed rule would amend the regulations regarding GLPs and 
would require that nonclinical laboratory studies (sometimes referred 
to as preclinical studies) follow a complete quality system approach, 
referred to as a GLP Quality System, when safety and toxicity studies 
support or are intended to support applications and submissions to FDA. 
The proposed rule would expand the scope to include all products for 
which nonclinical laboratory studies are currently conducted that are 
not explicitly discussed in the current regulations, specifically 
tobacco products. The proposed expanded scope also includes all 
applications and submissions under the FD&C Act that can be supported 
by the results of nonclinical laboratory studies. In addition, the 
proposed rule would introduce and modify definitions, terms, and 
organizational and personnel roles and responsibilities consistent with 
the implementation of the proposed GLP Quality System and the 
prevalence of multisite studies. Finally, the proposed rule would 
incorporate wording consistent with some of the existing domestic and 
international guidelines, rules or regulations covering good laboratory 
practices such as those established by the OECD.
    Costs of the rule, when final, would include annual and one-time 
costs. Annual costs would include 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. Combined, all 
costs annualized over a ten-year period at a 7-percent discount rate 
are estimated to range between $34.4 million and $69.3 million, with an 
average annualized cost of $51.9 million. By contrast, with a 3 percent 
discount rate, annualized cost would range from $34.2 million to $68.9 
million, with an average annualized cost of $51.5 million.
    Conducting nonclinical laboratory studies under the proposed GLP 
Quality System is expected to improve the reliability and quality of 
the data that support applications and submissions to us, including 
those applications and submissions that lead to the use of new medical 
products in first-in-human clinical studies. In addition, the proposed 
system is conducive to improving compliance and accountability by all 
involved in the conduct of nonclinical laboratory studies.
    As described, we understand the potential effects on small 
entities. We therefore seek comment, particularly from small entities, 
about the proposed effective date of 1 year after the date of 
publication of any final rule that may issue (see section VII. Proposed 
Implementation Plan).
    The full discussion of economic impacts is available in docket FDA-
2010-N-0548 at http://www.regulations.gov and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref. 
18).
    Table 1 summarizes the costs and benefits.

                                   Table 1--Summary of Benefits, Costs and Distributional Effects of Proposed Rule \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                               Units
                                                                                         ------------------------------------------------
                Category                      Primary      Low estimate    High estimate                                      Period           Notes
                                             estimate                                      Year dollars    Discount rate      covered
                                                                                                                (%)           (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized..........................  ..............  ..............  ..............            2014               7              10
    Monetized $millions/year............  ..............  ..............  ..............            2014               3              10
    Annualized..........................  ..............  ..............  ..............            2014               7              10
     Quantified.........................  ..............  ..............  ..............            2014               3              10
                                         ---------------------------------------------------------------------------------------------------------------
    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.
                                         ---------------------------------------------------------------------------------------------------------------
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

[[Page 58362]]

 
    Quantified..........................  ..............  ..............  ..............            2014               3              10
Qualitative
Transfers:
    Federal.............................  ..............  ..............  ..............            2014               7              10
    Annualized..........................  ..............  ..............  ..............            2014               3              10
                                         ---------------------------------------------------------------------------------------------------------------
    Monetized $millions/year............  From:
                                          To:
                                         ---------------------------------------------------------------------------------------------------------------
    Other...............................  ..............  ..............  ..............            2014               7              10
    Annualized..........................  ..............  ..............  ..............            2014               3              10
                                         ---------------------------------------------------------------------------------------------------------------
    Monetized $millions/year............  From:
                                          To:
                                         ---------------------------------------------------------------------------------------------------------------
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.
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Full Disclosure Preliminary Impact Analysis of the proposed rule ``Good Laboratory Practice for Nonclinical Laboratory Studies,'' Docket No. FDA-
  2010-N-0548. (Available at: http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.)

IX. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A 
description of these provisions is given in the Description section of 
this document with an estimate of the annual reporting and 
recordkeeping burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for the proper performance of FDA's functions, 
including whether the information will have practical utility; (2) the 
accuracy of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Reporting and Recordkeeping Requirements for Good Laboratory 
Practice for Nonclinical Laboratory Studies--OMB Control Number 0910-
0119--Revision
    Description: This proposed rule would revise the existing 
information collection requirements in the GLP regulations to provide 
for the development and implementation of a GLP Quality System and to 
reflect current procedures for the conduct of nonclinical laboratory 
studies, particularly multisite studies.
    Description of respondents: Respondents to the information 
collection are persons conducting a phase of a nonclinical laboratory 
study that is within the proposed expanded scope of part 58, including 
their personnel, independent contributing scientists, and study 
sponsors as the latter two terms are defined in this proposed rule; 
universities; or government agencies.
    Reporting: Currently, the GLP regulations include requirements to: 
(1) Report the results of QAU inspections; (2) submit periodic QAU 
study reports; (3) provide a QAU statement as part of the final study 
report; (4) provide the results of test and control article 
characterization and the testing of mixtures of test and control 
articles with carriers; (5) report a change in archive location; and 
(6) prepare in writing a final study report containing an overall 
interpretation of nonclinical laboratory studies.
    The proposed rule will revise these requirements to include: (1) A 
final study report incorporating additional information about all 
persons conducting one or more nonclinical laboratory study phases and 
a study director's compliance statement; (2) QAU reports on facility-
based inspections and process-based inspections, where conducted; (3) 
written certification whenever a process-based QAU inspection reveals 
problems, with documentation that records the actions taken; (4) 
summaries of the closeout of discontinued studies; (5) notification of 
the change of archival site within a specified timeframe; (6) reports 
by the study sponsor to the study director of known risks of the test 
article and necessary measures to protect study personnel; and (7) 
reports by the study sponsor to the study director of the results of 
characterization of any reference articles that may be employed in a 
study as well of mixtures of such reference articles with carriers. 
Finally, for sponsors who submit the results of nonclinical laboratory 
studies in support of applications or submissions to FDA that are 
proposed additions to the scope of part 58 and that lack enacting 
regulations, (8) submission of the final study report and a GLP 
compliance statement.
    QAU inspection reports provide the study director and management 
with executive responsibility information about the progress of a study 
and its

[[Page 58363]]

compliance with GLP regulations so they can take any corrective actions 
required to ensure the quality and integrity of the data. Test, 
control, and reference article information helps ensure proper dosing 
of the test system(s) and allows interpretation of study results in the 
final study report. The study sponsor receives the final study report 
and commonly submits the report in support of an application or 
submission to FDA. The information in the final study report gives 
FDA's scientific review experts the information needed to help 
determine the safety or toxicity of the test article or both. FDA needs 
such safety and toxicity information to make regulatory decisions 
regarding the test article, including permitting the conduct of 
clinical studies on human subjects, determining safe levels of residual 
drug for drugs administered to animals whose products will be consumed 
by humans, and marketing new products for both human and non-human 
animal use. Since a number of the additional applications and 
submissions proposed for the scope expansion do not have enacting 
regulations, inclusion in part 58 is necessary.
    We estimate the reporting burden of this collection of information 
as follows:

                                Table 2--Estimated One-Time Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                        Average
            Activity                 Number of     responses per   Total annual     burden per      Total hours
                                    respondents     respondent       responses       response
----------------------------------------------------------------------------------------------------------------
Read and Understand the Proposed           2,193               1           2,193             7.2          15,790
 Rule: Sponsors of Nonclinical
 Laboratory Studies.............
Read and Understand the Proposed             300               1             300              18           5,400
 Rule: Testing Facilities of
 Nonclinical Laboratory Studies.
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............           2,493  ..............          21,190
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    Table 2 shows the estimated one-time burden associated with the new 
reporting provisions of the proposed rule. We expect that persons 
conducting a phase of a nonclinical laboratory study that is within the 
proposed expanded scope of part 58 will need to read and understand the 
proposed rule. We expect that some entities would face lower complexity 
from reading the proposed rule and some entities would face higher 
complexity. In the Preliminary Regulatory Impact Analysis (PRIA), we 
calculated lower and upper estimates of time to read and understand the 
proposed rule under a low-complexity scenario for sponsors of 
nonclinical laboratory studies who would face fewer provisions. Our 
estimates under a high-complexity scenario apply to testing facilities 
of nonclinical laboratory studies that would have to read and 
understand more provisions in the rule. As stated in the PRIA, we 
estimate that there are 2193 sponsors of nonclinical laboratory studies 
and 300 testing facilities of nonclinical laboratory studies. We 
estimate that the 2193 sponsors of nonclinical laboratory studies will 
take from 4.8 to 9.6 hours, for an average of 7.2 hours, to read and 
understand the proposed rule. We expect that the 300 testing facilities 
of nonclinical laboratory studies will take from 12 to 24 hours, for an 
average of 18 hours, to read and understand the proposed rule.

                                Table 3--Estimated Recurring Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                        Average
          21 CFR Section              Number of    responses per   Total annual     burden per      Total hours
                                     respondents     respondent      responses       response
----------------------------------------------------------------------------------------------------------------
Sponsor provides test, control,             1,316           5              6,580               1           6,580
 and reference article
 characterization and risk
 information (Sec.   58.5(g) &
 (h))............................
Sponsor provides nonclinical                   10           1                 10              15             150
 laboratory study report in
 support of applications and
 submissions (Sec.   58.5(k))....
Expanded content of QAU statement             300          60.25          18,075             .25        4,518.75
 in final study report (Sec.                                                        (15 minutes)
 58.35(b)(11))...................
Management report of actions                   10           2                 20               5             100
 taken when a process-based
 inspection reveals problems
 (Sec.   58.35(e))...............
Expanded contents of final study              300          60.25          18,075               2          36,150
 report (Sec.   58.185(a)).......
Compliance statement by study                 300          60.25          18,075              .5         9,037.5
 director appended to final study                                                   (30 minutes)
 report (Sec.   58.185(a)(16))...
Summary report of close-out for               300           2                600               2           1,200
 discontinued studies (Sec.
 58.185(d))......................
Reports by independent                         30           1                 30               5             150
 contributing scientists (Sec.
 58.37(a)(2))....................
Principal Investigator (PI)                   200          10              2,000               1           2,000
 reports of deviations (Sec.
 58.39(c)).......................
PI study report & compliance                  200           5              1,000               8           8,000
 statement (Sec.   58.39 (d))....
Management report of personnel                300          10              3,000              .5           1,500
 deviations from protocol (Sec.                                                     (30 minutes)
 58.29(b)).......................
                                  ------------------------------------------------------------------------------
    Total........................  ..............  .............          67,465  ..............       69,386.25
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


[[Page 58364]]

    Table 3 shows the estimated recurring reporting burden associated 
with the proposed rule. Together, this results in a total of 90,576.25 
hours and 69,958 responses.
    Recordkeeping: Currently, the GLP regulations include requirements 
that respondents must record: (1) Personnel job descriptions and 
summaries of training and experience; (2) master schedules, protocols, 
and protocol amendments; (3) equipment inspection, maintenance, 
calibration, and testing records; (4) SOPs; (5) documentation of feed 
and water analyses and animal treatments; (6) test article 
accountability records; and (7) study documentation, including raw 
data.
    This proposed rule will add to the existing requirements with 
regard to initial changes and additions to SOPs for both testing 
facilities and test sites to develop, implement, and maintain a GLP 
Quality System and to expand many SOPs to specifically include 
multisite studies.
    This proposed rule would also expand personnel record maintenance 
to require records of training and experience on GLP requirements and 
species-specific animal care. In addition, this proposed rule includes 
revisions to the required content of study protocols as part of a GLP 
Quality System and for multisite study specifics.
    The additional documentation by management with executive 
responsibility and study directors is for the implementation of a GLP 
Quality System and the resulting additional burden is nominal. 
Documentation by independent contributing scientists, as defined in 
this proposed rule, includes records these individuals would usually 
retain, so a nominal added burden is predicted.
    To implement the proposed checks and balances discussed previously 
in the preamble, proposed revisions will require that added 
documentation be made by the study director and the QAU to ensure the 
viability of the proposed GLP Quality System (see Table 5).
    This proposed rule also adds requirements for the study sponsor to 
maintain records of: (1) Protocol and protocol amendment approval; (2) 
the accreditation status of a contracted person (as defined in this 
proposed rule) that conducts a phase of the study that involves the use 
of animals; (3) test, control, and reference article characterization; 
and (4) the qualifications of all contracted persons.
    In addition, the proposed rule includes recordkeeping requirements 
for nonclinical laboratory studies that choose to utilize the option of 
having a principal investigator, particularly for multisite studies. 
These individuals will have recordkeeping responsibilities comparable 
to those of the study director for the nonclinical laboratory study 
phases for which they are responsible.
    The persons potentially retaining nonclinical laboratory study 
documents are persons conducting a phase of a nonclinical laboratory 
study that is within the proposed expanded scope of part 58, including 
independent contributing scientists, and study sponsors as defined in 
this proposed rule. Results of nonclinical laboratory studies may be 
used by firms in support of applications and submissions to FDA, 
including applications and submissions for research and marketing of 
new products. The additional documentation of the conduct and data 
collection of nonclinical laboratory studies of FDA-regulated products 
will help ensure the quality and integrity of final study reports. FDA 
conducts on-site reviews of records and study reports during 
inspections of persons conducting one or more nonclinical laboratory 
study phases to verify the reliability of results submitted in support 
of applications and submissions to FDA.
    We estimate the recordkeeping burden of this collection of 
information as follows:

                              Table 4--Estimated One-Time Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                        Average
            Activity                 Number of      records per    Total annual     burden per      Total hours
                                   recordkeepers   recordkeeper       records      recordkeeping
----------------------------------------------------------------------------------------------------------------
Update Existing SOPs............             300              12           3,600             7.5          27,000
Write New SOPs..................             300              10           3,000              24          72,000
Training........................             300               2             600              14           8,400
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............           7,200  ..............         107,400
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    Table 4 shows the estimated one-time burden associated with the 
revised recordkeeping provisions of the proposed rule. We expect that 
the 300 testing facilities of nonclinical laboratory studies will need 
to update existing SOPs and to write new SOPs. In the PRIA, we 
estimated that each facility would need to update 12 existing SOPs and 
write 10 new SOPs. We calculated lower and upper estimates of time to 
update existing SOPs and to write new SOPs. We estimate that it will 
take from 4 to 11 hours, for an average of 7.5 hours, to update 12 
existing SOPs. We estimate that it will take from 15 to 33 hours, for 
an average of 24 hours, to write 10 new SOPs. We also expect that the 
300 testing facilities of nonclinical laboratory studies will need to 
conduct training. In the PRIA, we estimated that for the low estimate 
one person would be doing the training and one person would be trained. 
By contrast, for the high estimate, we estimated that also one person 
would be doing the training and potentially three people would receive 
such training, for an average of two employees for each facility. We 
calculated lower and upper estimates of time to train, estimating that 
it will take from 5 to 23 hours, for an average of 14 hours, to train.

                                                  Table 5--Estimated Recurring Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                      Number of                        Average  burden
                                                                    Number of        records per      Total annual           per           Total hours
                                                                  recordkeepers     recordkeeper         records        recordkeeping
--------------------------------------------------------------------------------------------------------------------------------------------------------
Sponsor documentation (Sec.   58.5):

[[Page 58365]]

 
    --(c) protocol approval and (i) all amendments............             2,193               100           219,300                 1           219,300
    --(b) animal welfare......................................             1,316                 5             6,580                 2            13,160
    --(d) accreditation status of testing facility............             1,316                 5             6,580                .5             3,290
                                                                                                                          (30 minutes)
    --(g) test, control, and reference article parameters.....             1,316                 5             6,580                .5             3,290
                                                                                                                          (30 minutes)
    --(j) archival locations..................................             2,193             62.25           136,514               .25          34,128.5
                                                                                                                          (15 minutes)
    --(e) qualifications of contracted persons................             1,316                 5             6,580                 2            13,160
Documentation by management with executive responsibility:
    --GLP training and experience (Sec.   58.29(a) & (d)).....               300               500           150,000               .25            37,500
                                                                                                                          (15 minutes)
    --Animal care training and experience (Sec.   58.29(a) &                 300                 5             1,500               .25               375
     (d)).....................................................                                                            (15 minutes)
    --all persons are qualified for multisite studies (Sec.                  300               500           150,000               .25            37,500
     58.31(i))................................................                                                            (15 minutes)
    --Periodic review of GLP Quality System (Sec.   58.31(b)).               300               .25                75                .5              37.5
                                                                                                                          (30 minutes)
    --Periodic review of QAU (Sec.   58.31(r))................               300                 1               300                .5               150
                                                                                                                          (30 minutes)
    --Appointment of management representative (Sec.                         300                .1                30               .25               7.5
     58.31(e))................................................                                                            (15 minutes)
    --all test sites have master schedule (Sec.   58.31(j))...               300                15             4,500               .25             1,125
                                                                                                                          (15 minutes)
    --appointment of person to manage master schedule (Sec.                  300               0.1                30               .25               7.5
     58.31(k))................................................                                                            (15 minutes)
--selection of lead QAU for multisite studies (Sec.                          300                 5             1,500               .25               375
 58.31(p))....................................................                                                            (15 minutes)
--QAU review of protocols, SOPs, & their amendments (Sec.                    300                 5             1,500               .25               375
 58.31(q))....................................................                                                            (15 minutes)
QAU:
    --review of study protocols + amendments (Sec.                           300                17             5,100               1.5             7,650
     58.35(b)3))..............................................
    --SOPs review + amendments (Sec.   58.35(b)(4))...........               300                17             5,100               1.5             7,650
    --facility and process-based inspections (Sec.                           150                 5               750               .25             187.5
     58.35(b)(5)).............................................                                                            (15 minutes)
    --audits of final reports of contributing scientists (Sec.               300               600           180,000                .5            90,000
       58.35(b)(9))...........................................                                                            (30 minutes)
    --audits of principal investigator (reports (Sec.                        300               120            36,000                .5            18,000
     58.35(b)(9)).............................................                                                            (30 minutes)
    --audits of final study reports for multisite studies                    300                60            18,000                .5             9,000
     (Sec.   58.35(b)(10))....................................                                                            (30 minutes)
Study Director
    --Multisite study need for PIs (Sec.   58.33(b)(7)(ii))...               300               180            54,000                 1            54,000
    --communications (Sec.   58.33(b)(12))....................               300               180            54,000               .25            13,500
                                                                                                                          (15 minutes)
    --protocol followed (Sec.   58.33(b)(1))..................               300                60            18,000                 1            18,000
    --QAU review of protocol & SOPs (Sec.   58.33(b)(2))......               300                17             5,100               .25             1,275
                                                                                                                          (15 minutes)

[[Page 58366]]

 
    --management provided adequate resources (Sec.                           300                 5             1,500                .5               750
     58.33(b)(3)).............................................                                                            (30 minutes)
    --computerized systems validated (Sec.   58.33(b)(4)).....               300                 5             1,500               .25               375
                                                                                                                          (15 minutes)
    --Committee review 58.33(b)(5)............................               300                17             5,100               .25             1,275
                                                                                                                          (15 minutes)
    --multisite study personnel qualified (Sec.                              300                15             4,500                 1             4,500
     58.33(b)(7)(i))..........................................
    --test system as required (Sec.   58.33(b)(10))...........               300                 5             1,500               .25               375
                                                                                                                          (15 minutes)
    --GLP compliance (Sec.   58.33(b)(11))....................               300                60            18,000                 1            18,000
    --test article accountability when containers disposed of                300                 6             1,800               .25               450
     (Sec.   58.105(d)).......................................                                                            (15 minutes)
Independent contributing scientists:
    --Education, training, and experience (Sec.   58.37(b)(2))                30                 1                30               .25               7.5
                                                                                                                          (15 minutes)
    --Archive location (Sec.   58.37(b)(4))...................                30                 1                30               .25               7.5
                                                                                                                          (15 minutes)
    --Appropriate animal care (Sec.   58.37(b)(3))............                 2                 1                 2                .5                 1
                                                                                                                          (30 minutes)
PIs:
    --Protocol + amendment acceptance (Sec.   58.39(a)).......               200                 5             1,000               .25               250
                                                                                                                          (15 minutes)
    --Study deviations (Sec.   58.39(c))......................               200                10             2,000                .5             1,000
                                                                                                                          (30 minutes)
    --Archive location (Sec.   58.39((e)).....................               200                40             8,000               .25             2,000
                                                                                                                          (15 minutes)
    Recordkeeping (Sec.   58.195).............................               300             251.5            75,450               3.9           294,255
                                                               -----------------------------------------------------------------------------------------
        Total.................................................  ................  ................         1,188,031  ................         906,289.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    Table 5 shows the estimated recurring recordkeeping burden 
associated with the proposed rule. Together, this results in a total of 
1,013,689.5 hours and 1,195,231 records.
    To ensure that comments on information collection are received, OMB 
recommends that written comments be faxed to the Office of Information 
and Regulatory Affairs, OMB (see ADDRESSES). All comments should be 
identified with the title of the information collection.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3407(d)), the Agency has submitted the information collection 
provisions of this proposed rule to OMB for review. These requirements 
will not be effective until FDA obtains OMB approval. FDA will publish 
a notice concerning OMB approval of these requirements in the Federal 
Register.

X. Federalism

    FDA has analyzed this proposed rule according to the principles set 
forth in Executive Order 13132. FDA has determined that the proposed 
rule, if finalized, would not contain policies that would have 
substantial direct effects on the States, on the relationship between 
the National Government and the States, or on the distribution of power 
and responsibilities among the various levels of government. 
Accordingly, the Agency tentatively concludes that the proposed rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

XI. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at http://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

    1. ``OECD Series on Principles of Good Laboratory Practice (GLP) 
and Compliance Monitoring,'' (the link provided is to an index of 
all OECD documents related to GLPs, with links to each of the 
individual documents) (http://www.oecd.org/chemicalsafety/testingofchemicals/oecdseriesonprinciplesofgoodlaboratorypracticeglpandcompliancemonitoring.htm).
    2. ``Mutual Acceptance of Data (MAD),'' (http://www.oecd.org/env/ehs/mutualacceptanceofdatamad.htm).
    3. FDA, ``FDA Announces New Initiative to Modernize the 
Regulation of Clinical Trials and Bioresearch Monitoring,'' FDA News 
Release, June 26, 2006 (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108677.htm).
    4. FDA, ``Nonclinical Laboratory Studies; Proposed Regulations 
for Good Laboratory Practice Regulations'' 41 FR 51206 (November 19, 
1976).
    5. MOU 225-06-4000. ``Memorandum of Understanding Among the 
Animal and Plant Health Inspection Service, U.S. Department of 
Agriculture, and the Food and Drug Administration, U.S. Department 
of Health and Human Services, and the National Institutes of Health, 
U.S. Department of

[[Page 58367]]

Health and Human Services, Concerning Laboratory Animal Welfare,'' 
(http://www.fda.gov/AboutFDA/PartnershipsCollaborations/MemorandaofUnderstandingMOUs/DomesticMOUs/ucm247294.htm).
    6. ``OECD Series on Principles of Good Laboratory Practice and 
Compliance Monitoring Number 13,'' The Application of the OECD 
Principles of GLP to the Organisation and Management of Multi-Site 
Studies; Consensus Document of the Working Group on Good Laboratory 
Practice (http://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(2002)9).
    7. ``OECD Series on Principles of Good Laboratory Practice and 
Compliance Monitoring Number 4 (Revised),'' Consensus Document; 
Quality Assurance and GLP (http://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(99)20).
    8. ``OECD Series on Principles of Good Laboratory Practice and 
Compliance Monitoring Number 1,'' The OECD Principles on Good 
Laboratory Practice (http://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/mc/chem(98)17).
    9. ``OECD Series on Principles of Good Laboratory Practice and 
Compliance Monitoring Number 11,'' Advisory Document of the Panel on 
Good Laboratory Practices, The Role and Responsibilities of the 
Sponsor in the Application of the Principles of GLP (http://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/mc/chem(98)16).
    10. Council for International Organization of Medical Sciences 
and The International Council for Laboratory Animal Science, 
International Guiding Principles for Biomedical Research Involving 
Animals, December 2012 (revised) (http://www.cioms.ch/images/stories/CIOMS/IGP2012.pdf).
    11. Institute for Laboratory Animal Research, Guide for the Care 
and Use of Laboratory Animals, Eighth Edition, 2011 (http://grants.nih.gov/grants/olaw/Guide-for-the-Care-and-Use-of-Laboratory-Animals.pdf).
    12. FDA, ``Nonclinical Laboratory Studies, Good Laboratory 
Practice Regulations,'' Final Rule, 43 FR 59986 (December 22, 1978).
    13. Compliance Policy Guide (CPG 7151.02), Sec. 130.300--FDA 
Access to Results of Quality Assurance Program Audits and 
Inspections (http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm073841.htm).
    14. ``OECD Series on Principles of Good Laboratory Practice and 
Compliance Monitoring Number 8 (Revised),'' Consensus Document, The 
Role and Responsibilities of the Study Director in GLP Studies 
(http://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(99)24).
    15. ``OECD Series on Principles of Good Laboratory Practice and 
Compliance Monitoring Number 7 (Revised),'' Consensus Document, The 
Application of the GLP Principles to Short Term Studies (http://search.oecd.org/officialdocuments/displaydocumentpdf/?doclanguage=en&cote=env/jm/mono(99)23).
    16. Bioanalytical Method Validation Draft Guidance for Industry 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM368107.pdf).
    17. Pesticide Registration Notice 2011-3 ``Standard Format for 
Data Submitted Under the Federal Insecticide, Fungicide, and 
Rodenticide Act and Certain Provisions of the Federal Food, Drug, 
and Cosmetic Act'' (https://www.epa.gov/sites/production/files/2014-04/documents/pr2011-3.pdf) (Study profile templates available at 
https://www.epa.gov/pesticide-registration/study-profile-templates).
    18. Full Analysis of Economic Impacts (Docket Number FDA-2010-N-
0548). Preliminary Regulatory Impact Analysis, Initial Regulatory 
Flexibility Analysis, and Unfunded Mandates Reform Act Analysis for 
Good Laboratory Practice for Nonclinical Laboratory Studies; 
Proposed Rule, available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

List of Subjects

21 CFR Part 16

    Administrative practice and procedure.

21 CFR Part 58

    Laboratories, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 16 and 58 be amended as follows:

PART 16--REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION

0
1. The authority citation for part 16 continues to read as follows:

    Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394, 
467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.

0
2. In Sec.  16.1, amend paragraph (b)(2) by removing the entry for 
Sec.  58.204(b) and adding an entry for Sec. Sec.  58.200 through 
58.219 to read as follows:


Sec.  16.1  Scope.

* * * * *
    (b) * * *
    (2) * * *
    Sec. Sec.  58.200 through 58.219 (see part 58, subpart K of this 
chapter), relating to disqualifying any person conducting a phase of a 
nonclinical laboratory study of FDA-regulated products.
* * * * *

PART 58--GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY 
STUDIES

0
3. The authority citation for part 58 is revised to read as follows:

    Authority:  21 U.S.C. 342, 346, 346a, 348, 351, 352, 353, 355, 
360, 360b-360f, 360h-360j, 360ccc, 371, 379e, 381, 387e, 387j, 387k; 
42 U.S.C. 216, 262, 263b-263n.

0
4. In Sec.  58.1, revise paragraph (a) and add paragraph (c) to read as 
follows:


Sec.  58.1  Scope.

    (a) This part prescribes good laboratory practices (GLPs) for 
conducting nonclinical laboratory studies of safety or toxicity or both 
that support or are intended to support an application or submission 
for products regulated by the Food and Drug Administration (FDA), 
including food and color additives, animal food additives, human and 
animal drugs, devices, biological products, electronic products, and 
tobacco products. Applications and submissions to FDA affected by these 
regulations include those listed in Sec.  58.3. Compliance with this 
part is intended to assure the quality and integrity of data from 
nonclinical laboratory studies filed or submitted pursuant to sections 
402, 406, 408, 409, 501, 502, 503, 505, 510, 512-516, 518-520, 571, 
701, 721, 801, 905, 910, and 911 of the Federal Food, Drug, and 
Cosmetic Act and sections 351 and 354-360F of the Public Health Service 
Act.
* * * * *
    (c) In this part the term ``where appropriate'' is used several 
times. When a requirement is qualified by ``where appropriate,'' it is 
deemed to be ``appropriate'' unless justification can be otherwise 
documented. A requirement is ``appropriate'' if non-implementation 
could reasonably be expected to result in a nonclinical laboratory 
study whose results lack the required reliability.
0
5. Revise Sec.  58.3 to read as follows:


Sec.  58.3  Definitions.

    As used in this part, the following terms have the meanings 
specified:
    Applications and Submissions to FDA include:
    (1) A color additive petition, described in section 721 of the 
Federal Food, Drug, and Cosmetic Act, and as described in part 71 of 
this chapter.
    (2) A food additive petition, described in section 409 of the 
Federal Food, Drug and Cosmetic Act, and as described in parts 171 and 
571 of this chapter.
    (3) Data and information regarding a substance submitted as part of 
the procedures for establishing that a substance is generally 
recognized as safe for use, which use results or may reasonably be 
expected to result, directly or indirectly, in its becoming a component 
or otherwise affecting the characteristics of any food, described in 
Sec. Sec.  170.35 and 570.25 of this chapter.

[[Page 58368]]

    (4) Data and information regarding a food additive submitted as 
part of the procedures regarding food additives permitted to be used on 
an interim basis pending additional study, described in Sec.  180.1 of 
this chapter.
    (5) A petition for a nutrient content claim, described in section 
403 of the Federal Food, Drug, and Cosmetic Act, and as described in 
subpart D of part 101 of this chapter.
    (6) A petition for a health claim, described in section 403 of the 
Federal Food, Drug, and Cosmetic Act, and as described in subpart E of 
part 101 of this chapter.
    (7) An investigational new drug application, described in section 
505(i) of the Federal Food, Drug, and Cosmetic Act, and as described in 
part 312 of this chapter.
    (8) Applications for FDA approval to market a new drug, described 
in section 505 of the Federal Food, Drug, and Cosmetic Act, and as 
described in part 314 of this chapter.
    (9) Data and information regarding an over-the-counter drug for 
human use, submitted as part of the procedures for classifying such 
drugs as generally recognized as safe and effective and not misbranded, 
described in part 330 of this chapter.
    (10) Data and information about a substance submitted as part of 
the procedures for establishing a tolerance for unavoidable 
contaminants in food and food-packaging materials, described in 
sections 406, 408, and 409 of the Federal Food, Drug, and Cosmetic Act, 
and as described in parts 109 and 509 of this chapter.
    (11) A notice of claimed investigational exemption for a new animal 
drug, section 512(j) of the Federal Food, Drug, and Cosmetic Act, and 
as described in described in part 511 of this chapter.
    (12) New animal drug applications, described in section 512 of the 
Federal Food, Drug, and Cosmetic Act, and as described in part 514 of 
this chapter.
    (13) An abbreviated application for a new animal drug, described in 
section 512(b) of the Federal Food, Drug, and Cosmetic Act.
    (14) An application for conditional approval of new animal drugs 
for minor use and minor species, described in section 571(a)(2) of the 
Federal Food, Drug, and Cosmetic Act, and as described in part 516 of 
this chapter.
    (15) Authorization to market edible products from experimental 
animals as described in parts 170 and 570 of this chapter.
    (16) A request to establish or amend an import tolerance described 
in section 512 of the Federal Food, Drug, and Cosmetic Act.
    (17) [Reserved]
    (18) An application for a biologics license, described in section 
351 of the Public Health Service Act, and as described in part 601 of 
this chapter.
    (19) An application for an investigational device exemption, 
described in section 520(g) of the Federal Food, Drug, and Cosmetic 
Act, and as described in part 812 of this chapter.
    (20) An application for premarket approval of a medical device, 
described in section 515 of the Federal Food, Drug, and Cosmetic Act, 
and as described in part 814 of this chapter.
    (21) An application for humanitarian device exemption, authorized 
under section 520(m) of the Federal Food, Drug, and Cosmetic Act, and 
as described in part 814, subpart H of this chapter.
    (22) A product development protocol for a medical device, described 
in section 515 of the Federal Food, Drug, and Cosmetic Act, and as 
described in part 814 of this chapter.
    (23) A premarket notification submission for a medical device as 
authorized under section 510(k) of the Federal Food, Drug, and Cosmetic 
Act, and as described in part 807, subpart E of this chapter.
    (24) Data and information regarding a medical device submitted as 
part of the procedures for classifying such devices described in part 
860, subpart B of this chapter, reclassification petitions described in 
part 860, subpart C of this chapter, and requests associated with the 
evaluation of automatic class III designations, authorized under 
section 513(f)(2) of the Federal Food, Drug, and Cosmetic Act.
    (25) Data and information regarding a medical device submitted as 
part of the procedures for establishing, amending, or revoking a 
performance standard for such devices, described in section 514 of the 
Federal Food, Drug, and Cosmetic Act, and as described in part 861 of 
this chapter.
    (26) Data and information regarding an electronic product submitted 
as part of the procedures for obtaining an exemption from notification 
of a radiation safety defect or failure of compliance with a radiation 
safety performance standard, described in subpart D of part 1003 of 
this chapter.
    (27) Data and information regarding an electronic product submitted 
as part of the procedures for establishing, amending, or repealing a 
standard for such product, described in section 358 of the Public 
Health Service Act.
    (28) Data and information regarding an electronic product submitted 
as part of the procedures for obtaining a variance from any electronic 
product performance standard as described in Sec.  1010.4 of this 
chapter.
    (29) Data and information regarding an electronic product submitted 
as part of the procedures for granting, amending, or extending an 
exemption from any electronic product performance standard, as 
described in Sec.  1010.5 of this chapter.
    (30) A premarket notification for a food contact substance, 
described in section 409 of the Federal Food, Drug, and Cosmetic Act, 
and as described in part 170, subpart D of this chapter.
    (31) [Reserved]
    (32) A premarket application for a new tobacco product, as 
described in section 910(b)(1) of the Federal Food, Drug, and Cosmetic 
Act.
    (33) A substantial equivalence report as described in section 
905(j) of the Federal Food, Drug, and Cosmetic Act.
    (34) A request for exemption under section 905(j)(3) of the Federal 
Food, Drug, and Cosmetic Act, and as described in part 1107 of this 
chapter.
    (35) An application or submission related to a modified risk 
tobacco product, as described in section 911of the Federal Food, Drug, 
and Cosmetic Act.
    Attending veterinarian means a veterinarian who has training or 
experience or both in the care and management of the species being 
attended and who has direct or delegated authority for activities 
involving animals.
    Batch means a specific quantity or lot of a test, control, or 
reference article that has been characterized according to Sec.  58.105 
and handled according to Sec.  58.107.
    Contracted person means a person who assumes, either directly or 
indirectly as an independent contractor, one or more responsibilities 
for the conduct of a nonclinical laboratory study.
    Contributing scientist means an individual responsible for the 
conduct, interpretation, analysis, or any other service for a phase of 
a nonclinical laboratory study. An individual expert or specialist who 
is an independently employed contracted person, as defined in this 
section, is an independent contributing scientist.
    Control article means any food additive, color additive, drug, 
biological product, electronic product, device, tobacco product, or any 
article other than a test article, reference article, feed, or water 
that is administered to the test system in the course of a nonclinical

[[Page 58369]]

laboratory study for the purpose of establishing a basis for comparison 
with the test article.
    Establish means define, document (in writing or electronically), 
and implement.
    Facility-based inspection means an inspection which is not based on 
specific studies but covers general facilities and activities, for 
example, installations, support systems, computer systems, training, 
environmental monitoring, and equipment maintenance and calibration.
    GLP Quality System means the organizational structure, 
responsibilities, procedures, processes, and resources for implementing 
quality management in the conduct of a nonclinical laboratory study.
    Lead quality assurance unit (lead QAU) means the QAU responsible 
for quality assurance (QA) in a multisite nonclinical laboratory study. 
Testing facility management with executive responsibility selects the 
lead QAU.
    Management with executive responsibility means those senior 
employees of a testing facility or test site who have the authority to 
establish or make changes to the quality policy and GLP Quality System 
at the testing facility and test site, respectively.
    Master schedule means a compilation of information used for 
assessment of workload and the tracking of nonclinical laboratory 
studies.
    Multisite study means any study that has phases conducted at more 
than one site.
    Nonclinical laboratory study means in vivo or in vitro experiments 
in which test articles are studied prospectively in test systems under 
laboratory conditions or in the applicable environment to determine 
their safety or toxicity or both. The term does not include studies 
involving human subjects, clinical studies, or clinical investigational 
use in animals. The term does not include basic exploratory studies 
carried out to determine whether a test article has any potential 
utility or basic exploratory studies to determine the physical or 
chemical characteristics of a test article.
    Person includes an individual, partnership, corporation, 
association, scientific or academic establishment, government agency, 
or organizational unit thereof, and any other legal entity.
    Phase means a defined activity or set of activities in the conduct 
of a nonclinical laboratory study.
    Principal investigator means an individual who has specific 
responsibilities for one or more phases of a nonclinical laboratory 
study as delegated by the study director.
    Process-based inspection means an inspection conducted to monitor 
procedures or processes of a repetitive nature that are very frequently 
performed. Process-based inspections are conducted on a prearranged 
schedule, which is not connected to the timing of any particular 
nonclinical laboratory study. Performance of process-based inspections 
covering processes or procedures that occur with a very high frequency 
(for example, certain mutagenicity studies) may cause some studies to 
be uninspected during the in-life period of the study, as defined in 
this section within the definition of Short-term study.
    Quality means the totality of features and characteristics that 
bear on the ability of a nonclinical laboratory study to provide data 
that can be relied upon.
    Quality assurance unit (QAU) means any person or organizational 
element designated to perform the duties relating to quality assurance 
(QA) of nonclinical laboratory studies. For any given study, the QAU 
must be entirely separate from and independent of the personnel engaged 
in the direction and conduct of the study.
    Quality policy means the overall intentions and direction of an 
organization with respect to quality, as established by management with 
executive responsibility.
    Raw data means all original 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. Raw data includes any laboratory worksheets, 
correspondence, notes, and other documentation (regardless of capture 
medium) that are the result of original observations and activities of 
a nonclinical laboratory study and are necessary for the reconstruction 
and evaluation of the report of that study. Raw data also includes the 
signed and dated pathology report.
    Reference article means any chemical substance or mixture, or 
analytical standard, or material other than a test article, control 
article, feed, or water that is administered to or used in analyzing 
the test system in the course of a study for the purposes of 
establishing the basis for comparison with the test article for known 
chemical or biological measurements.
    Short-term study means a study for which the in-life period is 
completed within several days or a week at most. The in-life period of 
a study is that period during which data are collected.
    Specimen means any material derived from a test system for 
examination, analysis, or retention.
    Sponsor means: (1) A person that initiates and supports, by 
provision of financial or other resources, a nonclinical laboratory 
study; or
    (2) A person that submits a nonclinical laboratory study in support 
of an application or submission to FDA; or
    (3) A person that initiates a nonclinical laboratory study and 
functions as, and has the same responsibilities as, a testing facility, 
test site, or contributing scientist, as those terms are defined in 
this section.
    Standard operating procedures (SOPs) means documented procedures 
which describe how to perform tests or activities normally not 
specified in detail in study protocols.
    Study-based inspection means an inspection of a critical operation 
of the study which is scheduled according to the chronology of the 
given study. Management with executive responsibility at the testing 
facility and/or test site identifies which operations are critical 
before initiation of the study.
    Study completion date means the date the final report is signed by 
the study director.
    Study director means the individual responsible for the overall 
conduct of a nonclinical laboratory study.
    Study initiation date means the date the protocol is signed by the 
study director.
    Test article means any food additive, color additive, drug, 
biological product, electronic product, device, tobacco product, or any 
other article subject to regulation under the Federal Food, Drug, and 
Cosmetic Act or under sections 351 and 354-360F of the Public Health 
Service Act.
    Test site means a person who is responsible for one or more phases 
of a multisite nonclinical laboratory study. A test site includes 
management with executive responsibility and supporting SOPs relevant 
to the conduct of nonclinical laboratory studies.
    Test system means any animal, plant, microorganism, or subparts 
thereof to which the test, control, or reference article is 
administered or added for study. Test system also includes appropriate 
groups or components of the system not treated with the test, control, 
or reference articles.
    Testing facility means the person responsible for coordinating, 
conducting, or completing a nonclinical laboratory study, or any 
combination thereof. The testing facility designates the study 
director.
    Validation means confirmation by examination and provision of 
objective evidence that the particular

[[Page 58370]]

requirements for a specific intended use can be consistently fulfilled.
    Vehicle means any agent which 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.
0
6. Add Sec.  58.5 to subpart A to read as follows:


Sec.  58.5   Sponsor responsibilities.

    For each nonclinical laboratory study, the sponsor must:
    (a) Ensure the nonclinical laboratory study protocol (the study 
protocol) meets the requirements in Sec.  58.120.
    (b) Ensure that the study protocol provides for humane care and 
ethical treatment of animals.
    (c) Sign and date the study protocol to indicate approval.
    (d) Contract with persons accredited as following appropriate 
animal welfare procedures for phases of a nonclinical laboratory study 
that include the use of animals. If these contracted persons are not 
accredited, document this fact, the reason for using a non-accredited 
person, and the qualifications of the non-accredited person. This 
information must be included in the compliance statement required in 
paragraph (k) in this section.
    (e) Document that any contracted person conducting a phase of a 
nonclinical laboratory study is qualified according to the provisions 
in this part.
    (f) Ensure that appropriate lines of communication are established 
among all persons conducting a phase of the nonclinical laboratory 
study and document all study-related communications that involve the 
sponsor.
    (g) Document that test, control, and reference articles are 
prepared, characterized, and labeled according to subpart F of this 
part, and are appropriately shipped. Obtain, and provide to the study 
director as soon as available, information regarding test, control, and 
reference article characterization as specified in Sec.  58.105.
    (h) Inform the study director of any known potential risks of the 
test article to human health or the environment and any measures 
necessary to protect study personnel and the environment.
    (i) Review, approve, sign, and date each protocol amendment before 
implementation.
    (j) Document and update as necessary the archive location of all 
raw data and records as described in Sec. Sec.  58.190 and 58.195.
    (k) Include, in any application or submission to FDA that includes 
the results of a nonclinical laboratory study, the final study report 
and all amendments. If a summary report of the nonclinical laboratory 
study is included in such applications or submissions, a copy of the 
final study report, as described in Sec.  58.185, must be appended or 
provided elsewhere within the application or submission. Also, include 
either a statement that the study was conducted in compliance with the 
requirements set forth in this part, or, if the study was not conducted 
in compliance with these regulations, a brief statement of the reason 
for the noncompliance.
0
7. Revise Sec.  58.10 to read as follows:


Sec.  58.10  Transfer of responsibilities.

    (a) Any person utilizing the services of a contracted person (as 
defined in Sec.  58.3) to perform a phase (as defined in Sec.  58.3) of 
a nonclinical laboratory study may transfer to the contracted person 
any regulatory responsibility in this chapter, unless delegation of 
such responsibility is expressly prohibited. Any such transfer must be 
described in writing. Any responsibility not covered by the written 
description is deemed not transferred.
    (b) Any person transferring to a contracted person any 
responsibility for a phase of a nonclinical laboratory study must 
inform that contracted person that the transferred responsibility must 
be performed in compliance with the provisions in this part.
    (c) A contracted person assuming any responsibility for a phase of 
a nonclinical laboratory study must comply with the regulations in this 
chapter applicable to the transferred responsibility and is subject to 
the same regulatory actions as those transferring the responsibility.
0
8. Revise Sec.  58.15 to read as follows:


Sec.  58.15  Inspection of any person conducting a phase of a 
nonclinical laboratory study.

    (a) Any person conducting a phase of a nonclinical laboratory study 
must permit, at reasonable times and in a reasonable manner, an 
authorized employee of FDA to inspect and copy all records and inspect 
all specimens required to be maintained for nonclinical laboratory 
studies within the scope of this part and, where applicable, to collect 
reserve samples for such studies. The records inspection and copying 
requirements do not routinely apply to QAU records of findings and 
problems or to actions recommended and taken. However, FDA retains the 
authority to inspect all QAU records when necessary to ensure 
compliance with this part.
    (b) FDA will not consider a nonclinical laboratory study submitted 
in support of an application or submission to FDA if any person 
conducting a phase of the nonclinical laboratory study refuses to 
permit inspection. The determination that a nonclinical laboratory 
study will not be considered in support of an application or submission 
to FDA does not, however, relieve the applicant of any obligation under 
any other applicable statute or regulation to submit the results of the 
study to FDA.
0
9. Revise Sec.  58.29 to read as follows:


Sec.  58.29  Personnel.

    (a) Each individual engaged in the conduct of, or responsible for 
the supervision of, a nonclinical laboratory study must have education, 
training, and experience, or a combination thereof, to enable that 
individual to perform the assigned functions. This must include 
training and experience with GLP requirements. Personnel who work with 
animals must have both general and species-specific training and 
experience.
    (b) All study personnel must have access to and comply with the 
protocol and all applicable protocol amendments and SOPs. Any deviation 
must be reported to the study director.
    (c) All study personnel must record raw data, as defined in Sec.  
58.3, promptly and accurately as required by Sec.  58.180.
    (d) Any person conducting a phase of a nonclinical laboratory study 
must maintain a current summary of training and experience and a job 
description for each individual in the person's employment engaged in 
or supervising the phase of the study for which the person is 
responsible.
    (e) There must be a sufficient number of personnel for the timely 
and proper conduct of the study according to the protocol.
    (f) Personnel must take necessary personal sanitation and health 
precautions designed to avoid contamination of test, control, and 
reference articles and test systems.
    (g) Personnel engaged in a nonclinical laboratory study must wear 
clothing appropriate for the duties they perform. Such clothing must be 
changed as often as necessary to prevent microbiological, radiological, 
or chemical contamination of test systems and test, control, and 
reference articles.
    (h) Any individual found at any time to have an illness that may 
adversely affect the quality and integrity of the nonclinical 
laboratory study must be excluded from direct contact with test 
systems; test, control, and reference articles; and any other operation 
or function that may adversely affect the study until the condition is 
corrected.

[[Page 58371]]

All personnel must be instructed to report to their immediate 
supervisors any health or medical conditions that may reasonably be 
considered to have an adverse effect on a nonclinical laboratory study.
0
10. Revise Sec.  58.31 to read as follows:


Sec.  58.31  Testing facility management with executive responsibility.

    Management with executive responsibility is ultimately responsible 
for the GLP Quality System and must establish policy and objectives for 
a GLP Quality System and a commitment to quality, as defined in Sec.  
58.3. Management with executive responsibility must ensure that the 
quality policy, as defined in Sec.  58.3, is implemented and maintained 
at all levels of the organization. Management with executive 
responsibility must:
    (a) Establish and update written SOPs, as required in Sec.  
58.81(b)(2) for a GLP Quality System.
    (b) Review the suitability and effectiveness of the GLP Quality 
System at defined intervals and with sufficient frequency according to 
established procedures, to be included in SOPs for the GLP Quality 
System (Sec.  58.81(b)(2)), to ensure that the GLP Quality System 
satisfies the established quality policy and objectives and the 
requirements of this part. The dates and results of these reviews must 
be documented.
    (c) Establish and maintain an adequate organizational structure 
(personnel, resources, facilities, equipment, materials, and 
methodologies) to ensure that all testing complies with the established 
GLP Quality System, according to the requirements of this part.
    (d) Establish procedures, to be included in SOPs for the GLP 
Quality System (Sec.  58.81(b)(2)), for the appropriate responsibility, 
authority, and interrelationship among all personnel who manage, 
perform, and assess work affecting quality, and provide the 
independence and authority necessary to perform these tasks.
    (e) Appoint and document the appointment of, according to 
procedures to be included in SOPs for the GLP Quality System (Sec.  
58.81(b)(2)), a management representative who is a member of the 
testing facility management with authority over and responsibility for:
    (1) Documenting that GLP Quality System requirements are 
effectively established and effectively maintained; and
    (2) Reporting on the performance of the GLP Quality System to 
management with executive responsibility for review, including all 
reports from the QAU.
    (f) Establish SOPs for equipment, as required in Sec.  
58.81(b)(14), including standards for appropriate documentation of 
equipment validation, as defined in Sec.  58.3. For multisite studies, 
document that any person conducting a phase of the nonclinical 
laboratory study follows adequate equipment-related SOPs.
    (g) Establish SOPs to ensure that computerized systems are suitable 
for their intended purposes and are appropriately validated, operated, 
and maintained as required in Sec.  58.81(b)(15).
    (h) Document that all study personnel are trained to perform their 
assigned functions.
    (i) Establish SOPs, as required in Sec.  58.81(b)(18), for ensuring 
and documenting the qualifications of any person conducting a phase of 
a nonclinical laboratory study.
    (j) Establish SOPs for the development and maintenance of the 
master schedule as required in Sec.  58.81(b)(13).
    (k) Appoint and document the appointment of a person to maintain 
the master schedule. The master schedule must be indexed by test 
article and contain the identification of the test system, the nature 
of the study, the date the study was initiated, the current status of 
each study, the identity of the sponsor, and the name of the study 
director. For multisite studies, the master schedule of each person 
conducting a phase of a nonclinical laboratory study must also include 
the specific phases that person conducts.
    (l) Establish procedures, to be included in SOPs for multisite 
studies required in Sec.  58.81(b)(18), for the transfer of data, 
specimens, and samples among all persons conducting phases of the 
nonclinical laboratory study; verification of the accuracy and 
completeness of any translations of SOPs and protocols, when 
applicable; and storage, return, or disposal of test, control, and 
reference articles, as applicable.
    (m) Review all protocols to determine that there are no 
environmental, animal welfare, or work resource issues or issues with 
scientific methodology that might affect or bias any phase of the 
conduct of the proposed study. Document the review and acceptance of 
each protocol.
    (n) Establish SOPs, as required in Sec.  58.81(b)(3), for 
designation of a study director, as described in Sec.  58.33, before 
the study is initiated and prompt replacement of the study director if 
it becomes necessary to do so during the conduct of a study.
    (o) Establish procedures, to be included in SOPs for the GLP 
Quality System (Sec.  58.81(b)(2)), to ensure a clear line of 
communication among the study director, principal investigator(s), 
QAU(s), the sponsor, and all study personnel, as applicable.
    (p) Provide for a QAU as described in Sec.  58.35. Before 
initiating a multisite study, as defined in Sec.  58.3, designate and 
document the designation of the lead QAU with overall responsibility 
for the entire study. Provide the information described in Sec.  
58.35(a) of the lead QAU to all persons involved in the conduct of the 
study and all QAUs serving those persons.
    (q) Establish procedures, to be included in SOPs for the GLP 
Quality System (Sec.  58.81(b)(2)), to ensure QAU review of SOPs and 
study protocols to verify that they meet GLP requirements. This review 
must be documented.
    (r) 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 Sec.  58.81(b)(17), to 
ensure that the QAU satisfies established quality policy and objectives 
and the requirements of this part. For multisite studies, testing 
facility management with executive responsibility must periodically 
review the suitability and effectiveness of the lead QAU. The dates and 
results of reviews of the QAU must be documented.
    (s) Establish SOPs, as required in Sec.  58.81(b)(6), for the 
receipt of information regarding the characterization of all test, 
control, and reference articles or mixtures, including data on their 
identity, strength, purity, stability, and uniformity, as applicable.
    (t) Establish SOPs, with appropriate timeframes, for the conduct of 
QAU inspections and for the receipt, review, and followup of all 
concerns, problems, and regulatory deviations reported by the QAU. 
These SOPs must include procedures for correcting reported problems 
and, as necessary, for modification of relevant SOPs to prevent a 
recurrence of any problems, as required in Sec.  58.81(b)(20) and (21).
    (u) Establish SOPs, as required in Sec.  58.81(b)(13), for the 
development and maintenance of an archive system, including the 
designation and replacement of the archivist and any supporting staff.
    (v) Establish procedures to ensure maintenance of a historical file 
of all SOPs as required in Sec.  58.81(b)(1).
0
11. Add Sec.  58.32 to subpart B to read as follows:


Sec.  58.32  Test site management with executive responsibility.

    For multisite studies, each test site participating in the study 
must have

[[Page 58372]]

management with executive responsibility for the test site who must:
    (a) Comply with responsibilities delineated for testing facility 
management with executive responsibility, as described in section Sec.  
58.31, where appropriate.
    (b) Develop and maintain SOPs as specified in Sec.  58.81, where 
appropriate.
0
12. Revise Sec.  58.33 to read as follows:


Sec.  58.33  Study director.

    (a) For each nonclinical laboratory study, a scientist or other 
professional of appropriate education, training, and experience, or 
combination thereof, must be identified as the study director. The 
study director represents the single point of study control and has 
overall responsibility, which cannot be delegated, for:
    (1) The technical conduct of the entire study;
    (2) The implementation of procedures to ensure adequate 
communication among all study personnel and with the study sponsor, as 
applicable; and
    (3) The interpretation, analysis, documentation, and reporting of 
results and study compliance.
    (b) The study director must:
    (1) Approve the protocol, including any changes, as provided by 
Sec.  58.120, and document that it is followed.
    (2) Document that the QAU has reviewed the protocol and all 
applicable SOPs, and any amendments, before study initiation and 
implementation of applicable amendments to ensure that they are 
compliant with GLP requirements.
    (3) Document that testing facility management with executive 
responsibility has committed adequate resources for the conduct of the 
specific study.
    (4) Document that computerized systems are validated and fit for 
use in the specific study.
    (5) For studies requiring the use of animals, document that the 
initial protocol and any amendments that impact the use of animals are 
reviewed and approved, as required in Sec.  58.120(b) and (e), by a 
committee whose function is to ensure that the care and use of animals 
in studies is appropriate and humane, before study initiation and the 
implementation of applicable amendments.
    (6) Consult with the attending veterinarian, as defined in Sec.  
58.3, during review of proposed study protocols to determine potential 
animal welfare concerns and appropriate responses to likely 
contingencies. Defer to the attending veterinarian when decisions 
regarding animal welfare arise, particularly when animals are in pain 
or distress.
    (7) For multisite studies:
    (i) Document the qualifications of any person conducting a phase of 
the nonclinical laboratory study.
    (ii) Determine and document the need for principal investigators.
    (8) Document that all experimental data, including observations of 
unanticipated responses of the test system, are accurately recorded and 
verified.
    (9) Document unforeseen circumstances that may affect the quality 
and integrity of the nonclinical laboratory study when they occur and 
the corrective action taken.
    (10) Document that test systems are as specified in the approved 
study protocol.
    (11) Document that all applicable GLP regulations are followed and 
include a study compliance statement in the final study report.
    (12) Document all communications with all persons conducting a 
phase of the nonclinical laboratory study and with the sponsor, as 
applicable.
    (13) Sign and date the final study report.
    (14) Archive all raw data, documentation, protocols, specimens, 
reserve samples, and final reports no later than 2 weeks after the 
study completion date.

0
13. Revise Sec.  58.35 to read as follows:


Sec.  58.35  Quality assurance unit (QAU).

    (a)(1) Function. A QAU must monitor each study to assure management 
that the facilities, equipment, personnel, methods, practices, records, 
and controls are in conformance with the regulations in this part. For 
any given study, the QAU must be entirely separate from and independent 
of the personnel engaged in the direction and conduct of the study.
    (2) Location and identity. (i) For studies conducted entirely at 
the testing facility, the QAU can consist of personnel at the facility 
itself or be a separately contracted unit.
    (ii) For multisite studies, a lead QAU must be designated by 
testing facility management with executive responsibility and must have 
responsibility for the QA of the entire study. The lead QAU can consist 
of personnel at the testing facility, be a QAU for another person 
conducting a phase of the study, or be a separately contracted unit. 
QAUs for persons conducting a phase of the study must coordinate with 
the lead QAU as specified in SOPs as described in Sec.  58.81(b)(17) 
and (20). The lead QAU has direct QA responsibility for any person 
lacking a QAU.
    (b) QAUs must: (1) Maintain access to the master schedule (defined 
in Sec.  58.3) of all nonclinical laboratory studies conducted by the 
person employing the QAU or contracting for QA services. For multisite 
studies, the lead QAU must maintain access to the master schedule of 
any person lacking a QAU.
    (2) Maintain access to copies of all protocols pertaining to all 
nonclinical laboratory studies for which the QAU is responsible.
    (3) Review all protocols before study initiation, and all protocol 
amendments before implementation, to ensure that they can be conducted 
in compliance with this part. This review must be documented.
    (4) Review all SOPs to be used for the conduct of all phases of a 
nonclinical laboratory study to assess their clarity and compliance 
with this part. This review must be documented.
    (5) Inspect each nonclinical laboratory study for which the QAU is 
responsible at intervals adequate to ensure the integrity of the 
specific study. Inspections must determine compliance with the 
protocol, applicable SOPs, and the requirements of this part. These can 
include study-based, process-based, and facility-based inspections as 
defined in Sec.  58.3 and as specified in SOPs as required in Sec.  
58.81(b)(20). For multisite studies, the lead QAU must coordinate the 
conduct of study inspections with any other existing QAUs, as specified 
in SOPs as required in Sec.  58.81(b)(20). Upon discovery, any problems 
found during an inspection which are likely to affect study integrity 
must be reported to the study director and management with executive 
responsibility for the study or studies affected.
    (6) Maintain written and properly signed records of all inspections 
that include the date of the inspection, the individual performing the 
inspection, findings and problems, action recommended and taken to 
resolve existing problems, and any scheduled date for reinspection. For 
study-specific inspections, reports must also include the identity of 
the study and the phase of the study inspected.
    (7) Periodically submit to management with executive responsibility 
and the study director written status reports on each study that 
discuss the overall progress and compliance status of the study and 
that include any problems observed and the corrective actions taken. 
The content and frequency of these reports must be specified in SOPs, 
as described in Sec.  58.81(b)(21).
    (8) Determine that no deviations from approved protocols or SOPs 
were made without proper authorization and

[[Page 58373]]

documentation. For multisite studies, the lead QAU is responsible for 
identifying all deviations that occur across the entire study, 
including deviations identified by all other QAUs participating in the 
study, as described in SOPs in Sec.  58.81(b)(17).
    (9) Audit the reports of all contributing scientists, and any 
amendments to such reports, to ensure such reports reflect the protocol 
and all amendments, accurately describe the methods and SOPs, and 
report all of the raw data of the specific phases covered by each 
report. For multisite studies, QAUs for persons conducting a phase of 
the study must audit the reports of any principal investigators and all 
contributing scientists for whom they are responsible, and any 
amendments to such reports, as specified in SOPs as described in Sec.  
58.81(b)(17). The lead QAU must audit the reports, and any amendments 
to such reports, of any principal investigators and all contributing 
scientists for any person lacking a QAU and of any independent 
contributing scientists.
    (10) Audit the final study report, and any amendments to this 
report, to ensure that such report accurately describes the methods and 
SOPs, all raw data of the nonclinical laboratory study are reported, 
and that all original and amended signed and dated reports from all 
contributing scientists are appended. For multisite studies, this is 
the responsibility of the lead QAU.
    (11) Prepare, sign, and date a statement to be included with the 
final study report that specifies:
    (i) The dates of study-specific inspections, process-based 
inspections if applicable, and facility-based inspections;
    (ii) Findings reported to management with executive responsibility 
and to the study director; and
    (iii) The dates of QAU audits of the reports of all contributing 
scientists (including any independent contributing scientists), any 
principal investigators, and of the final study report and all 
amendments to such. For multisite studies, this is the responsibility 
of the lead QAU. When other persons conducting a phase of the study 
have QAUs, those QAUs must provide to the lead QAU such statements 
regarding the audits they conducted, for appending to the final study 
report.
    (c) The responsibilities and procedures applicable to the QAU, the 
records maintained by the QAU, and the method of indexing such records 
must be in writing and must be maintained as specified in SOPs as 
required in Sec.  58.81(b)(17). For multisite studies, the lead QAU and 
all other QAUs participating in the study must maintain those documents 
relevant to their oversight. These SOPs as well as documentation of the 
dates of all QAU inspections, the study or process or procedure, or 
facility inspected as applicable, the phase or segment of the study 
inspected for study-specific inspections, and the name of the 
individual performing the inspection must be made available for 
inspection to authorized employees of FDA.
    (d) A designated representative of FDA must, upon request, be given 
access to the written SOPs established for QAU inspections. If 
requested by FDA, the person inspected must certify that inspections 
are being implemented, performed, documented, and followed up according 
to this part.
    (e) If a person conducting a phase of a nonclinical laboratory 
study chooses to conduct process-based inspections, that person must 
prepare a written certification, as specified in SOPs as required in 
Sec.  58.81(b)(21), whenever a process-based inspection reveals 
problems. This certification must document actions taken to properly 
inform and, when applicable, modify reports for all studies impacted by 
the results of the process or procedure in question.
0
14. Add Sec.  58.37 to subpart B to read as follows:


Sec.  58.37  Contributing scientist.

    (a) Each contributing scientist must:
    (1) Conduct, oversee, analyze, and provide any other service for 
the conduct of all phases of the nonclinical laboratory study for which 
the contributing scientist is responsible according to the requirements 
of this part.
    (2) Provide a signed and dated report of all phases for which the 
contributing scientist is responsible, to be included in the final 
study report. When there are amendments to the original report, provide 
a signed and dated copy of the amended report, to be included in the 
final study report along with the original report. Provide the report, 
and all amendments, to the study director or, when a multisite study 
employs principal investigators, through the principal investigator.
    (3) Permit oversight by the designated QAU.
    (b) In addition to the requirements in paragraphs (a)(1) through 
(3) of this section, an independent contributing scientist must:
    (1) Date and sign the study protocol to indicate agreement to 
comply with protocol requirements for all phases of the nonclinical 
laboratory study the independent contributing scientist will conduct 
and the applicable requirements of this part. Date and sign any 
protocol amendments applicable to the phases of the nonclinical 
laboratory study conducted by the independent contributing scientist to 
indicate agreement.
    (2) Maintain and update documentation of education, training, and 
experience pertinent to those phases of the nonclinical laboratory 
studies for which the independent contributing scientist is 
responsible.
    (3) If conducting phases of a nonclinical laboratory study that 
include the use of animals:
    (i) Document that housing, feeding, handling, and care of the 
animals as specified in Sec.  58.90 are available.
    (ii) Document that an attending veterinarian is available for 
consult and deferred to as necessary, particularly when animals are in 
pain or distress.
    (iii) Document corrective actions required to assure the humane 
care and ethical treatment of animals.
    (4) Archive all materials pertinent to all phases of the 
nonclinical laboratory the independent contributing scientist 
conducted, as required by the protocol and Sec.  58.195; document when 
and where archiving was completed.
0
15. Add Sec.  58.39 to subpart B to read as follows:


Sec.  58.39  Principal investigator.

    The study director can delegate to principal investigators 
responsibility for phases of a nonclinical laboratory study but not 
responsibility for an entire study. For all phases of the nonclinical 
laboratory study for which the principal investigator is responsible, a 
principal investigator must:
    (a) Sign and date the study protocol, and any applicable 
amendments, to document agreement to comply with the protocol 
requirements and the applicable requirements of this part.
    (b) Verify that the study is conducted according to the 
requirements of this part.
    (c) Document all deviations noted during the conduct of the study, 
report those deviations to the study director as soon as possible after 
discovery, and document that the information was forwarded to the study 
director.
    (d) Submit to the study director either:
    (1) The signed and dated reports from all contributing scientists 
for whom the principal investigator is responsible and any amendments 
to such reports, any raw data not covered by such reports, and a signed 
compliance statement indicating any areas of noncompliance; or

[[Page 58374]]

    (2) Signed and dated report of all phases for inclusion in the 
final study report. The signed report must include the original 
principal investigator's report and any amendments, reports of all 
contributing scientists for whom the principal investigator is 
responsible and any amendments to such reports, and a signed compliance 
statement indicating any areas of noncompliance.
    (e) Document that all materials and records are appropriately 
archived, as required by the protocol and Sec.  58.195.
0
16. Revise Sec.  58.41 to read as follows:


Sec.  58.41  General.

    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. Facilities must 
be designed so that there is a degree of separation that will prevent 
any function or activity from having an adverse effect on the study.
0
17. In Sec.  58.43, revise paragraphs (a), (b), and (d) to read as 
follows:


Sec.  58.43  Animal care facilities.

    (a) Any person conducting a phase of a nonclinical laboratory study 
that utilizes animals must have a sufficient number of animal rooms or 
areas, as needed, to assure proper:
    (1) Separation of species or test systems,
    (2) Isolation of individual projects,
    (3) Quarantine of animals, and
    (4) Routine or specialized housing of animals.
    (b) Any person conducting a phase of a nonclinical laboratory study 
that utilizes animals must have a number of animal rooms or areas 
separate from those described in paragraph (a) of this section to 
ensure isolation of studies being done with test systems or test, 
control, or reference articles known to be biohazardous, including 
volatile substances, aerosols, radioactive materials, and infectious 
agents.
* * * * *
    (d) When animals are housed, facilities must exist for the 
collection and disposal of all animal waste and refuse or for safe 
sanitary storage of waste before removal from any facility at which a 
phase of a nonclinical laboratory study that utilizes animals is 
conducted. Disposal facilities must be so provided and operated as to 
minimize vermin infestation, odors, disease hazards, and environmental 
contamination.
0
18. Revise Sec.  58.47 to read as follows:


Sec.  58.47  Facilities for handling test, control, and reference 
articles.

    (a) As necessary to prevent contamination or mixups, there must be 
separate areas for:
    (1) Receipt and storage of the test, control, and reference 
articles.
    (2) Mixing of the test, control, and reference articles with a 
carrier, e.g., feed.
    (3) Storage of the test, control, and reference article mixtures.
    (b) Storage areas for the test, control, and reference articles and 
test, control, and reference article mixtures must be separate from 
areas housing the test systems and must be adequate to preserve the 
characteristics of the articles and mixtures, including their identity, 
strength, purity, and stability, as applicable.
0
19. Revise Sec.  58.61 to read as follows:


Sec.  58.61  Equipment design.

    Equipment, including computerized systems, used in the generation, 
measurement, maintenance, archiving, retrieval, or assessment of data 
(or any combination thereof) and equipment used for facility 
environmental control must be of appropriate design and adequate 
capacity to function according to the protocol and must be suitably 
located for operation, inspection, cleaning, and maintenance.
0
20. In Sec.  58.63, revise paragraphs (a) and (b) to read as follows:


Sec.  58.63  Maintenance and calibration of equipment.

    (a) Equipment must be adequately inspected, cleaned, and 
maintained. Equipment used for the generation, measurement, 
maintenance, archiving, retrieval, or assessment of data (or any 
combination thereof) must be adequately tested, calibrated, and 
standardized, as applicable.
    (b) The written SOPs required under Sec.  58.81(b)(14) and (15) 
must set forth in sufficient detail the methods, materials, and 
schedules to be used in the routine inspection, cleaning, maintenance, 
testing, calibration, and standardization of equipment, as applicable, 
and must specify, when appropriate, remedial action to be taken in the 
event of failure or malfunction of equipment. The written SOPs must 
designate the person responsible for the performance of each operation.
* * * * *
0
21. Revise the heading of subpart E to read as follows:

Subpart E--Nonclinical Laboratory Study Operations

0
22. Revise Sec.  58.81 to read as follows:


Sec.  58.81  Standard operating procedures (SOPs).

    (a) The testing facility and all test sites must have SOPs in 
writing setting forth nonclinical laboratory study procedures that 
management with executive responsibility is satisfied are adequate to 
ensure the quality and integrity of the data generated in the course of 
a study. All deviations from SOPs in a study must be authorized by the 
study director and must be documented in the raw data. Significant 
changes in established SOPs must be properly authorized in writing by 
management with executive responsibility.
    (b) The testing facility and all test sites must establish SOPs for 
all applicable phases of a nonclinical laboratory study. Where 
appropriate, SOPs must include the following:
    (1) Preparation, modification, and administration of all SOPs. 
These must include procedures for developing and maintaining a 
historical file of SOPs and all revisions, including the dates of such 
revisions.
    (2) Establishment and periodic review of a GLP Quality System.
    (3) Designation and replacement of the study director.
    (4) Animal room preparation.
    (5) Animal care.
    (6) Receipt, identification, storage, handling, mixing, and method 
of sampling of the test, control, and reference articles.
    (7) Test system observations for in vivo and in vitro testing, as 
applicable.
    (8) Laboratory tests.
    (9) Handling of animals found moribund or dead during study.
    (10) Necropsy of animals or post mortem examination of animals.
    (11) Collection and identification of specimens.
    (12) Histopathology.
    (13) Data handling, storage, and retrieval, including maintenance 
of the master schedule and all study protocols, and the establishment 
and maintenance of an archive system.
    (14) Validation, maintenance, and calibration of equipment.
    (15) Ensuring computerized systems are suitable for their intended 
purpose and are appropriately validated, operated, and maintained and 
that electronic records from computerized systems are readily available 
for review and assessment.
    (16) Transfer, proper placement, and identification of animals.
    (17) QAU functions, including QA oversight for multisite studies.
    (18) Multisite studies.
    (19) Designation and replacement of a principal investigator.

[[Page 58375]]

    (20) Planning, performing, documenting, and reporting inspections 
conducted by the QAU.
    (21) Receipt, review, and followup of all concerns, problems, and 
regulatory deviations reported by the QAU, including the frequency and 
content of periodic study reports required by Sec.  58.35(b)(7), and 
for modifying relevant SOPs when necessary to prevent recurrence.
    (22) Certifying copies of study records as true copies of the 
original that maintain the original intent and meaning.
    (c) Each laboratory area must have immediately available laboratory 
manuals and SOPs relative to the laboratory procedures being performed. 
Published literature may be used as a supplement to SOPs.
0
23. In Sec.  58.90, revise paragraphs (b) through (e) to read as 
follows:


Sec.  58.90  Animal care.

* * * * *
    (b) All newly received animals from outside sources must be 
isolated and their health status must be evaluated according to 
acceptable veterinary medical practices. Also, throughout the study, 
all test animals must be evaluated for their health status according to 
acceptable veterinary medical practices.
    (c) At the initiation of a nonclinical laboratory study, animals 
must be free of any disease or condition that might interfere with the 
purpose or conduct of the study. If, during the course of the study, 
the animals contract such a disease or condition, the diseased animals 
must be isolated, if necessary. These animals may be treated for 
disease or signs of disease as deemed necessary by the study's 
attending veterinarian. The diagnosis, treatment authorizations, 
treatment description, and each treatment date must be documented and 
must be retained as part of the study raw data.
    (d) Warm-blooded animals, except nursing neonates, used in 
laboratory procedures that require manipulations and observations over 
an extended period of time or in studies that require the animals to be 
removed from and returned to their home cages for any reason (e.g., 
cage cleaning, treatment, etc.), must receive appropriate 
identification. All information needed to specifically identify each 
animal within an animal-housing unit must appear on the outside of that 
unit.
    (e) Animals of different species must be housed in separate rooms 
when necessary. Animals of the same species, but used in different 
studies, should not ordinarily be housed in the same room when 
inadvertent exposure to control, reference, or test articles or animal 
mixup could affect the outcome of either study. If such mixed housing 
is necessary, adequate differentiation by space and identification must 
be made.
* * * * *
0
24. Revise the heading of subpart F to read as follows:

Subpart F--Test, Control, and Reference Articles

0
25. Revise Sec.  58.105 to read as follows:


Sec.  58.105  Test, control, and reference article characterization.

    (a) For all test, control, and reference articles other than 
tobacco products, the identity, strength, purity, and composition or 
other characteristics which will appropriately define the test, 
control, or reference article must be determined for each batch and 
must be documented. For test, control, and reference articles for 
tobacco products, the chemical composition (including mainstream or 
aerosol smoke composition, when applicable), microbiological 
characterization (fermented tobacco products), and design parameters 
which will appropriately define the test, control, or reference article 
must be determined for each batch and must be documented. These 
analyses must be performed by the sponsor or by a contracted person 
either:
    (1) Before study initiation, or
    (2) Concomitantly according to written SOPs as required in Sec.  
58.81(b)(6). The results of such analyses must be provided to the study 
director as soon as available. In those cases where marketed products 
are used as control or reference articles, with the exception of 
tobacco products, such products can be characterized by their labeling.
    (b) Methods of synthesis, fabrication, or derivation of the test, 
control, and reference articles must be documented by the person who 
conducts the analyses.
    (c) The stability of each test, control, and reference article must 
be determined as required by the conditions of the study either:
    (1) Before study initiation, or
    (2) Concomitantly according to written SOPs, as required in Sec.  
58.81(b)(6), which provide for periodic analysis of each batch. The 
results of such testing must be provided to the study director as soon 
as available.
    (d) Each storage container for a test, control, or reference 
article must be labeled by name; Chemical Abstract Service (CAS) number 
or code number, where such identification exists; batch number; 
expiration date, if any; and, where applicable, storage conditions 
necessary to maintain the identity, strength, purity, and composition 
of the test, control, or reference article, other than tobacco 
products. For tobacco product test, control, and reference articles, 
labeling must include storage conditions necessary to maintain the 
chemical composition (including mainstream smoke composition), 
microbiological composition, and design parameters, where applicable. 
Storage containers must be assigned to a particular test article for 
the duration of the study. Empty test article containers may be 
disposed of once the study director verifies and documents the 
distribution and final disposition of the test article. Approval for 
the disposal of empty containers must be in writing and signed and 
dated by the study director.
    (e) For studies of more than 4 weeks duration, reserve samples from 
each batch of test, control, and reference article must be retained for 
the period of time provided by Sec.  58.195.
0
26. In Sec.  58.107, revise the heading and introductory text to read 
as follows:


Sec.  58.107  Test, control, and reference article handling.

    Procedures must be established, as required in Sec.  58.81(b)(6), 
for a system for the handling of the test, control, and reference 
articles to ensure that:
* * * * *
0
27. Revise Sec.  58.113 to read as follows:


Sec.  58.113  Mixtures of articles with carriers.

    (a) For each test, control, and reference article that is mixed 
with a carrier, tests by appropriate analytical methods must be 
conducted:
    (1) To determine the uniformity of the mixture and to determine, 
periodically, the concentration of the test, control, or reference 
article in the mixture; and
    (2) To determine the stability of the test, control, and reference 
articles in the mixture as required by the conditions of the study.
    (b) Determination of uniformity, concentration, and stability must 
be conducted either:
    (1) Before study initiation; or
    (2) Concomitantly according to written SOPs, as required by Sec.  
58.81(b)(6), which provide for periodic analysis of the test, control, 
or reference articles in the mixture.
    (c) The results of such testing, performed by the sponsor or by a 
contracted person, must be provided to the study director as soon as 
available.
    (d) Where any of the components of the test, control, or reference 
article carrier mixture has an expiration date,

[[Page 58376]]

that date must be clearly shown on the container. If more than one 
component has an expiration date, the earliest expiration date must be 
shown.
0
28. Revise Sec.  58.120 to read as follows:


Sec.  58.120  Protocol.

    (a) Each study must have an approved written protocol that clearly 
indicates the specific objectives and all methods for the conduct of 
the study. The protocol must contain, where appropriate, the following 
information:
    (1) A descriptive title and statement of the purpose of the study.
    (2) Identification of test, control, and reference articles by:
    (i) Name;
    (ii) Chemical Abstract Service (CAS) number or code number, where 
such identification exists;
    (iii) The name and address of the manufacturer(s); and
    (iv) The person(s) determining their characteristics, as 
applicable.
    (3) The name and contact information (including address, phone 
number, email address, and facsimile number) for the sponsor and the 
testing facility and the name and affiliation of the study director. 
Also, for multisite studies, the contact information for all persons 
conducting a phase of the nonclinical laboratory study, including all 
principal investigators and independent contributing scientists.
    (4) The number, body weight range, sex, source of supply, species, 
strain, substrain, and age of the test system.
    (5) The procedure for identification of the test system.
    (6) A description of the experimental design, including the methods 
for the control of bias in the conduct of the study and the analysis 
and reporting of study test results and procedures to be followed when 
a study includes a peer review of any phase. For multisite studies, 
identification of which phases of the nonclinical laboratory study will 
be conducted by which person or persons.
    (7) A description or identification, as applicable, of the diet 
used in the study as well as solvents, emulsifiers, and/or other 
materials used to solubilize or suspend the test, control, or reference 
articles, as applicable, before mixing with the carrier. The 
description must include specifications for acceptable levels of 
contaminants that are reasonably expected to be present in the dietary 
materials and are known to be capable of interfering with the purpose 
or conduct of the study if present at levels greater than established 
by the specifications.
    (8) Each dosage level, expressed in milligrams per kilogram of body 
weight or other appropriate units, of the test, control, or reference 
article to be administered and the method and frequency of 
administration. For each test, control, or reference article that is 
mixed with a carrier for administration, limits for the results of 
concentration, uniformity, and stability testing and the name and 
address of the person conducting the testing.
    (9) The type and frequency of tests, analyses, and measurements to 
be made.
    (10) A list or description of the records to be maintained for the 
specific study. For multisite studies, the archive location(s) of study 
materials and records from all phases of the nonclinical laboratory 
study.
    (11) 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.
    (12) A statement of the proposed statistical methods to be used.
    (b) For studies that include the use of animals, a committee whose 
function is to ensure that the care and use of animals is appropriate 
and humane must review and approve the study before initiation of the 
study and approval must be documented.
    (c) A statement that the study must be conducted in compliance with 
the provisions of this part, to be signed and dated by the study 
sponsor and testing facility management with executive responsibility, 
must be appended to the protocol.
    (d) All changes in or revisions of an approved protocol and the 
reasons for the changes must be documented. These amendments to the 
protocol must be signed and dated by the study sponsor and the study 
director. For multisite studies, these amendments must also be signed 
and dated by all independent contributing scientists, principal 
investigators, and any other person conducting a phase of the 
nonclinical laboratory study affected by the amendment. Signed and 
dated amendments must be maintained with the protocol.
    (e) A committee whose function is to ensure that the care and use 
of animals in studies is appropriate and humane must review and approve 
any protocol changes that would impact animal welfare before 
implementation and approval must be documented.
0
29. Revise Sec.  58.130 to read as follows:


Sec.  58.130  Conduct of a nonclinical laboratory study.

    (a) The analytical methods used for all phases of a nonclinical 
laboratory study must be demonstrated to be accurate and of sufficient 
sensitivity to measure, with appropriate precision, the analytes in 
question.
    (b) Test, control, and reference article characterization testing 
must be conducted as described in subpart F of this part.
    (c) Humane care and ethical treatment of test animals must be 
considered in advance and upheld in conjunction with achieving study 
objectives. The attending veterinarian must be included in 
consultations regarding the impact of a given protocol on the welfare 
of test animals, in particular the recognition and alleviation of 
species-specific pain or distress and methods of euthanasia. The 
attending veterinarian must be deferred to when decisions regarding 
animal welfare arise, particularly when animals are in pain or 
distress.
    (d) The nonclinical laboratory study must be conducted according to 
the protocol. The person responsible for a given phase of a nonclinical 
laboratory study must sign and date the protocol, as required in Sec.  
58.120(a)(11), before initiation of that phase of the study.
    (e) Any change to the protocol must be approved as an amendment, as 
required in Sec.  58.120(d), before implementation.
    (f) The test systems must be monitored in conformity with the 
protocol.
    (g) Specimens must be identified by test system, study, nature, and 
date of collection. This information must be located on the specimen 
container or must accompany the specimen in a manner that precludes 
error in the recording and storage of data.
    (h) Records of gross findings for a specimen from post mortem 
observations must be available to a pathologist when examining that 
specimen histopathologically, unless specified otherwise in the study 
protocol.
0
30. Add Sec.  58.180 to subpart J to read as follows:


Sec.  58.180  Data quality and integrity.

    (a) All data generated during the conduct of a nonclinical 
laboratory study must be accurate, legible, contemporaneous, original, 
and attributable (ALCOA). Also, data must be credible, internally 
consistent, and corroborated.
    (b) All data must be recorded indelibly, directly, and promptly to 
a permanent medium at the time of observation and must identify 
unambiguously the person entering the data. Any change to any entry 
must be made so as not to obscure the original entry, must indicate the 
reason for such

[[Page 58377]]

change, must indicate when the change was made, and must identify who 
made the change. When data are either captured or maintained, or both 
captured and maintained electronically, these requirements are 
fulfilled by the use of an electronic records system fully compliant 
with applicable regulations.
    (c) All data accrued as required in paragraphs (a) and (b) of this 
section must be included in the final study report.
0
31. Revise Sec.  58.185 to read as follows:


Sec.  58.185  Reporting of nonclinical laboratory study results.

    (a) A final study report must be prepared for each nonclinical 
laboratory study and must include the following:
    (1) Name and address of the testing facility and the dates on which 
the study was initiated and completed. For multisite studies, 
additionally the name and address of any person conducting a phase of 
the nonclinical laboratory study, including the location of all 
independent contributing scientists.
    (2) Names of the attending veterinarians for all phases of the 
nonclinical laboratory study that included the use of animals.
    (3) Objectives and procedures stated in the approved protocol, 
including any changes in the original protocol.
    (4) Statistical methods employed for analyzing the data.
    (5) Test, control, and reference articles identified by:
    (i) Name;
    (ii) Chemical Abstract Service (CAS) number or code number, where 
such identification exists;
    (iii) Strength, purity, and composition or other appropriate 
characteristics, and for tobacco products as described in Sec.  
58.105(a);
    (iv) The name and address of the manufacturer(s); and
    (v) The name and address of the person(s) conducting the testing to 
define their characteristics, as applicable.
    (6) Stability of test, control, and reference articles under the 
conditions of administration, including the name and address of the 
person(s) conducting the testing.
    (7) A description of the methods used, including methods for the 
control of bias in the conduct of the study and the analysis and 
reporting of test results.
    (8) A description of the test system used. Where applicable, the 
final study report must include the number of animals used, sex, body 
weight range, source of supply, species, strain and substrain, age, and 
procedure used for identification.
    (9) A description of the dosage, dosage regimen, route of 
administration, and duration, including the results of testing 
conducted to determine the concentration, uniformity, and stability of 
mixtures of articles with carriers, as applicable, and the name and 
address of the person conducting the testing.
    (10) A description of all circumstances that may have affected the 
quality or integrity of the data, including those documented by the 
study director as described in Sec.  58.33(b)(9) and all health-related 
issues reported by an attending veterinarian or appropriately 
designated personnel during the course of the study as described in 
Sec.  58.90(b) and (c).
    (11) The name and affiliation of the study director, the names of 
all contributing scientists, principal investigators, and other 
professionals, the sponsor, and all supervisory personnel who were 
involved in the study or in the preparation or review of the final 
study report.
    (12) A description of the transformations, calculations, or 
operations performed on the data, a summary and analysis of the data, 
and a statement of the conclusions drawn from the analysis.
    (13) The original, and any amended, signed and dated reports of 
each of the contributing scientists, principal investigators, or any 
other person involved in the study, including each person who conducted 
an analysis or evaluation of data or specimens from the study after 
data generation was completed. These reports must contain all data 
generated.
    (14) The locations where all specimens, reserve samples, raw data, 
and the final study report are to be stored.
    (15) The statement prepared and signed by the responsible QAU as 
described in Sec.  58.35(b)(11).
    (16) A statement by the study director of the study's extent of 
compliance with this part, including a discussion of any study 
deviations found to impact the integrity of the study as described in 
Sec.  58.185(a)(10).
    (b) The final report must be signed and dated by the study 
director.
    (c) Corrections or additions to a final report must be in the form 
of an amendment by the study director. The amendment must clearly 
identify that part of the final report that is being added to or 
corrected and the reasons for the correction or addition, and must be 
signed and dated by the person responsible.
    (d) If for any reason a study is discontinued before completion, 
the study director must write, sign, and date a short summary report 
closing the study. This report must discuss the reasons for closure and 
must be archived, along with all study material, as described in Sec.  
58.190.
0
32. Revise Sec.  58.190 to read as follows:


Sec.  58.190  Storage and retrieval of records and data.

    (a) All raw data, documentation, protocols, final reports, reserve 
samples, and specimens (except those specimens obtained from 
mutagenicity tests and wet specimens of blood, urine, feces, and 
biological fluids) generated as a result of a nonclinical laboratory 
study must be retained. Correspondence and other documents relating to 
interpretation and evaluation of data, other than those documents 
contained in the final study report, must also be retained.
    (b) There must be archives for orderly storage and expedient 
retrieval of all raw data, documentation, protocols, specimens, and 
interim and final reports. Conditions of storage must minimize 
deterioration of the documents or specimens in accordance with the 
requirements for the time period of their retention and the nature of 
the documents or specimens. A testing facility may contract with 
commercial archives to provide a repository for all material to be 
retained. Raw data and specimens may be retained elsewhere provided 
that the archives have specific reference to those other locations.
    (c) Material retained or referred to in the archives must be 
indexed to permit expedient retrieval.
    (d) All study material described in paragraph (a) of this section 
must be archived no later than 2 weeks after the study completion date 
(as defined in Sec.  58.3).
    (e) If a sponsor delays completion of the final study report, the 
study director must complete, sign, and date the final study report and 
archive all study material no later than 6 months after completion of 
the last draft of the final study report.
    (f) If a study sponsor halts a nonclinical laboratory study before 
all protocol-required testing is completed, a decision that the study 
is discontinued must be made no later than 6 months after the study was 
stopped. Once the study has been determined to be discontinued, the 
study director must prepare a summary report, as required by Sec.  
58.185(d). The summary report and all study material must be archived 
no later than 2 weeks after the study director signs the summary 
report.
    (g) An individual must be identified as responsible for the 
archives. Archiving specifications for multisite

[[Page 58378]]

studies must also be included in the approved study protocol.
    (h) Only authorized personnel can have access to the archives.
    (i) SOPs regarding archiving, required in Sec.  58.81(b)(13), must 
include specific procedures for removal of study materials from the 
archives, including maximum timeframes material can remain outside of 
the archives.
0
33. Revise Sec.  58.195 to read as follows:


Sec.  58.195  Retention of records.

    (a) Record retention requirements set forth in this section do not 
supersede the record retention requirements of any other regulations in 
this chapter nor do they supersede any other legal requirements 
elsewhere in applicable statutes or regulations.
    (b) Except as provided in paragraph (c) of this section, all raw 
data, documentation, protocols, final study reports, reserve samples, 
and specimens pertaining to a nonclinical laboratory study and required 
to be made by this part must be retained in the archive(s) for 
whichever of the following periods is shortest:
    (1) A period of at least 2 years following the date on which an 
application or submission to FDA, in support of which the results of 
the nonclinical laboratory study were submitted, is approved or cleared 
by FDA, a premarket authorization is issued, or the application or 
submission is administratively closed. This requirement does not apply 
to studies supporting investigational new drug applications (INDs) or 
applications for investigational device exemptions (IDEs), records of 
which are governed by the provisions of paragraph (b)(2) of this 
section.
    (2) A period of at least 5 years following the date on which the 
results of the nonclinical laboratory study are submitted to FDA in 
support of an application or submission.
    (3) In other situations (e.g., where the nonclinical laboratory 
study does not result in the submission of the study in support of an 
application or submission to FDA), a period of at least 2 years 
following the study completion date or the date on which the study is 
terminated or discontinued.
    (c) Wet specimens (except those specimens obtained from 
mutagenicity tests and wet specimens of blood, urine, feces, and 
biological fluids), samples of test, control, and reference articles, 
and specially prepared material, which are relatively fragile and 
differ markedly in stability and quality during storage, must be 
retained only as long as the quality of the preparation affords 
evaluation. In no case is retention required for longer periods than 
those set forth in paragraphs (a) and (b) of this section.
    (d) Management with executive responsibility must ensure 
maintenance of the master schedule and copies of study protocols, as 
specified in SOPs as described in Sec.  58.81(b)(13) and as specified 
in paragraphs (a) and (b) of this section. QAUs must maintain records 
of QAU inspections, as required by Sec.  58.35(c) for the period of 
time specified in paragraphs (a) and (b) of this section.
    (e) Summaries of training and experience and job descriptions 
required to be maintained by Sec.  58.29(d) may be retained along with 
all other employment records for the length of time specified in 
paragraphs (a) and (b) of this section.
    (f) Records and reports of the maintenance and calibration and 
inspection of equipment, as required by Sec.  58.63(b) and (c), must be 
retained for the length of time specified in paragraph (b) of this 
section.
    (g) Records required by this part may be retained either as 
original records or as true copies that maintain the original intent 
and meaning and are made according to the person's SOPs as described in 
Sec.  58.81(b)(22).
    (h) If a facility conducting nonclinical laboratory testing goes 
out of business or for any reason can no longer serve as the archive 
site for a particular study, all raw data, documentation, and other 
material specified in this section must be transferred to the archives 
of the sponsor of the study or to another appropriate archive facility. 
The facility must notify FDA in writing (and the study sponsor if not 
the recipient of the study material) of the transfer no later than 10 
working days after the transfer occurs.
    (i) A copy of the notification of change of archive site, as 
required by paragraph (h) of this section, can serve as the amendment 
to the final study report required in Sec.  58.185(c) when appended to 
that report.
0
34. Revise the heading of subpart K to read as follows:

Subpart K--Disqualification of Any Person Conducting a Phase of a 
Nonclinical Laboratory Study

0
35. Revise Sec.  58.200 to read as follows:


Sec.  58.200  Purpose.

    (a) The purposes of disqualification are:
    (1) To permit the exclusion from consideration of completed studies 
for which a phase was conducted by any person failing to comply with 
the requirements of the GLP regulations until it can be adequately 
demonstrated that such noncompliance did not occur during, or did not 
affect the validity or acceptability of data generated by, a particular 
study; and
    (2) To exclude from consideration all studies completed after the 
date of disqualification until the disqualified person can satisfy the 
Commissioner that it will conduct studies in compliance with such 
regulations.
    (b) The determination that a nonclinical laboratory study may not 
be considered in support of an application or submission to FDA does 
not, however, relieve the applicant of any obligation under any other 
applicable regulation to submit the results of the study to FDA.
0
36. Revise Sec.  58.202 to read as follows:


Sec.  58.202  Grounds for disqualification.

    FDA may disqualify any person conducting a phase of a nonclinical 
laboratory study upon finding that person repeatedly or deliberately 
failed to comply with one or more of the regulations set forth in this 
part (or any other regulations regarding such facilities in this 
chapter) or repeatedly or deliberately submitted false information in 
any required report.
0
37. In Sec.  58.204, revise paragraph (a) to read as follows:


Sec.  58.204  Notice of and opportunity for hearing on proposed 
disqualification.

    (a) Whenever FDA has information indicating that grounds exist 
under Sec.  58.202, which justifies disqualification of any person 
conducting a phase of a nonclinical laboratory study, FDA may issue to 
that person a written notice proposing that person be disqualified.
* * * * *
0
38. Revise Sec.  58.206 to read as follows:


Sec.  58.206  Final order on disqualification.

    (a) If the Commissioner, after the regulatory hearing, or after the 
time for requesting a hearing expires without a request being made, 
upon an evaluation of the administrative record of the disqualification 
proceeding, makes the findings required in Sec.  58.202, the 
Commissioner issues a final order disqualifying that person. Such order 
must include a statement of the basis for that determination. Upon 
issuing a final order, the Commissioner notifies (with a copy of the 
order) the disqualified person of the action. The notification also 
will explain that a person who is disqualified under this part will be 
ineligible to receive a test article under part 511 of this chapter. A 
clinical investigator ineligible to receive a test article under part 
511 of this chapter

[[Page 58379]]

will be ineligible to conduct any nonclinical laboratory study intended 
to support an application for a research or marketing permit for a new 
animal drug.
    (b) If the Commissioner, after a regulatory hearing or after the 
time for requesting a hearing expires without a request being made, 
upon an evaluation of the administrative record of the disqualification 
proceeding, does not make the findings required in Sec.  58.202, the 
Commissioner issues a final order terminating the disqualification 
proceeding. Such order must include a statement of the basis for that 
determination. Upon issuing a final order the Commissioner notifies 
that person and provides a copy of the order.
0
39. Revise Sec.  58.210 to read as follows:


Sec.  58.210  Actions upon disqualification.

    (a) Once a person has been disqualified, each application and 
submission to FDA containing or relying upon any nonclinical laboratory 
study for which a phase was conducted by the disqualified person may be 
examined to determine whether such study was or would be essential to a 
decision. If it is determined that a study was or would be essential, 
FDA must also determine whether the study is acceptable, 
notwithstanding the disqualification of that person. Any study for 
which a phase was conducted by the disqualified person before 
disqualification may be presumed to be unacceptable, and the person 
relying on the study may be required to establish that the study was 
not affected by the circumstances that led to the disqualification, 
e.g., by submitting validating information. If the study is then 
determined to be unacceptable, such data will be eliminated from 
consideration in support of the application or submission to FDA and 
such elimination may serve as new information justifying appropriate 
regulatory action.
    (b) No nonclinical laboratory study for which any phase was begun 
by a disqualified person after the date of that person's 
disqualification can be considered in support of any application or 
submission to FDA, unless the disqualified person has been reinstated 
under Sec.  58.219. The determination that a study may not be 
considered in support of an application or submission to FDA does not, 
however, relieve the applicant of any obligation under any other 
applicable regulation to submit the results of the study to FDA.
0
40. Revise Sec.  58.213 to read as follows:


Sec.  58.213  Public disclosure of information regarding 
disqualification.

    (a) Upon issuance of a final order disqualifying a person under 
Sec.  58.206(a), the Commissioner may notify all or any interested 
persons. Such notice may be given at the discretion of the Commissioner 
whenever the Commissioner believes that such disclosure would further 
the public interest or would promote compliance with the GLP 
regulations set forth in this part. Such notice, if given, must include 
a copy of the final order issued under Sec.  58.206(a) and must state 
that the disqualification constitutes a determination by FDA that 
nonclinical laboratory studies for which a phase was performed by the 
disqualified person will not be considered by FDA in support of any 
application or submission to FDA. If such notice is sent to another 
Federal Government agency, FDA will recommend that the agency also 
consider whether or not it should accept nonclinical laboratory studies 
for which a phase was performed by the disqualified person. If such 
notice is sent to any other person, it states that it is given because 
of the relationship between the disqualified person and the person 
being notified and that FDA is not advising or recommending that any 
action be taken by the person notified.
    (b) A determination that a person has been disqualified and the 
administrative record regarding such determination are disclosable to 
the public under part 20 of this chapter.
0
41. Revise Sec.  58.215 to read as follows:


Sec.  58.215  Alternative or additional actions to disqualification.

    (a) Disqualification of any person under this subpart is 
independent of, and neither in lieu of nor a precondition to, other 
proceedings or actions authorized by the Federal Food, Drug, and 
Cosmetic Act. FDA may, at any time, institute against a disqualified 
person or against the sponsor of a nonclinical laboratory study that 
has been submitted to FDA, or both, any appropriate judicial 
proceedings (civil or criminal) and any other appropriate regulatory 
action, including civil money penalties, in addition to or in lieu of, 
and before, simultaneously with, or subsequent to, disqualification. 
FDA may also refer the matter to another Federal, State, or local 
government law enforcement or regulatory agency for such action as that 
agency deems appropriate.
    (b) FDA may refuse to consider any particular nonclinical 
laboratory study in support of an application or submission to FDA, if 
it finds that the study was not conducted according to the GLP 
regulations set forth in this part, without disqualifying any person 
that conducted one or more phases of the study or undertaking other 
regulatory action.
0
42. Revise Sec.  58.217 to read as follows:


Sec.  58.217  Suspension or termination of any person conducting a 
phase of a nonclinical laboratory study by a sponsor.

    Termination of any person conducting a phase of a nonclinical 
laboratory study by a sponsor is independent of, and neither in lieu of 
nor a precondition to, proceedings or actions authorized by this 
subpart. If a sponsor terminates or suspends any person conducting a 
phase of a nonclinical laboratory study from further participation in a 
study that is being conducted as part of any application or submission 
to FDA that has been submitted to any Center of FDA (whether approved 
or cleared, premarket authorization issued, or administratively 
closed), the sponsor must notify that Center in writing within 15 
working days of the action; the notice must include a statement of the 
reasons for such action. Suspension or termination of any person 
conducting a phase of a nonclinical laboratory study by a sponsor does 
not relieve the sponsor of any obligation under any other applicable 
regulation to submit the results of the study to FDA.
0
43. Revise Sec.  58.219 to read as follows:


Sec.  58.219  Reinstatement of a disqualified person.

    Any person that has been disqualified may be reinstated as an 
acceptable source of data for a phase of a nonclinical laboratory study 
to be submitted to FDA if the Commissioner determines, upon an 
evaluation of materials submitted by that person, as well as the 
results from an FDA inspection of that person, that procedures are in 
place that would allow that person to conduct a phase of future 
nonclinical laboratory studies in compliance with the GLP regulations 
set forth in this part. As noted in Sec.  58.210(b), no nonclinical 
laboratory study for which a phase was begun by a disqualified person 
after the date of that person's disqualification is considered in 
support of any application or submission to FDA, unless that person has 
been reinstated. A disqualified person that wishes to be so reinstated 
must present in writing to the Commissioner reasons why it believes it 
should be reinstated and a detailed description of the corrective 
actions it has taken or intends to take to assure that the acts or 
omissions which led to its disqualification will not recur.

[[Page 58380]]

The disqualified person must also state its availability for 
inspection. If a disqualified person is reinstated, the Commissioner 
must so notify that person and all organizations and persons who were 
notified, under Sec.  58.213 of the disqualification of that person. A 
determination that a disqualified person has been reinstated is 
disclosable to the public under part 20 of this chapter.

    Dated: August 16, 2016.
Peter Lurie,
Associate Commissioner for Public Health Strategy and Analysis.
[FR Doc. 2016-19875 Filed 8-23-16; 8:45 am]
 BILLING CODE 4164-01-P