[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
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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
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Category Primary Low estimate High estimate Period Notes
estimate Year dollars Discount rate covered
(%) (years)
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Benefits:
Annualized.......................... .............. .............. .............. 2014 7 10
Monetized $millions/year............ .............. .............. .............. 2014 3 10
Annualized.......................... .............. .............. .............. 2014 7 10
Quantified.......................... .............. .............. .............. 2014 3 10
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Qualitative......................... The proposed rule would clarify GLP standards
to facilitate a more consistent approach and
provide greater international consistency. As
a result, we anticipate improvements in the
integrity and quality of data submitted for
FDA review decisions.
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Costs:
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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
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Qualitative:
Federal............................. .............. .............. .............. 2014 7 10
Annualized.......................... .............. .............. .............. 2014 3 10
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Monetized millions/year............. From:
To:
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Transfers:
Other............................... .............. .............. .............. 2014 7 10
Annualized.......................... .............. .............. .............. 2014 3 10
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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.
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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\
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\8\ There is a draft guidance document regarding bioanalytical
method validation, ``Bioanalytical Method Validation Draft
Guidance'' (Ref. 16). When final, this guidance will provide FDA's
current thinking. We consider many of the general principles in this
draft guidance document applicable to method validation in
nonclinical laboratory studies.
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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.
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\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).
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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