# Good Laboratory Practice for Nonclinical Laboratory Studies

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URL: https://www.frixlaw.com/law-library/documents/fr%3A2016-19875

## Record

- **Collection:** Federal Register
- **Document type:** Proposed Rule
- **Published:** August 24, 2016
- **Citation:** 81 FR 58342

## Text

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.

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
oira_submission@omb.eop.gov.
All comments should be identified with the title, “Reporting and Recordkeeping Requirements for Good Laboratory Practice for Nonclinical Laboratory Studies.”

FOR FURTHER INFORMATION CONTACT:

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

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary

A. Purpose of the Proposed Rule

B. Summary of the Major Provisions of the Proposed Rule

C. Legal Authority

D. Costs and Benefits

II. Introduction

A. What is the background for this rule?

B. Why is FDA proposing this rule?

III. Description of the Part 58 Proposal

A. What did FDA consider when drafting this rule?

B. Part 58, Subpart A—General Provisions

C. Part 58, Subpart B—Organization and Personnel

D. Part 58, Subpart C—Facilities

E. Part 58, Subpart D—Equipment

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

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

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

I. Part 58, Subpart J—Records and Reports

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

IV. Regulatory Hearing Before FDA

V. Analysis of Environmental Impact

VI. Legal Authority

VII. Proposed Implementation Plan

VIII. Economic Analysis of Impacts

A. Introduction

B. Summary

IX. Paperwork Reduction Act of 1995

X. Federalism

XI. References

I. Executive Summary

A. Purpose of the Proposed Rule

Nonclinical laboratory studies, often referred to as preclinical studies when conducted before first-in-human clinical studies, provide safety or toxicity information, or both, that is essential for the development of FDA-regulated products and help determine the safety of new food ingredients. For drugs administered to animals whose products will be consumed by humans, nonclinical laboratory studies are critical for determining safe levels of residual drug product. For tobacco products, nonclinical laboratory studies may provide evidence regarding the relative toxicities of new or modified risk tobacco products. FDA's regulation of the conduct of nonclinical laboratory studies is important to help ensure the quality and integrity of data derived from those studies, the protection of human subjects, and that marketing decisions are based on accurate and reliable data.

Therefore, FDA proposes to amend the GLP regulations to require the use of a complete quality system approach (proposed GLP Quality System) when a nonclinical laboratory study supports or is intended to support an application or submission to FDA. Part 58 (21 CFR part 58) presently includes many aspects of a quality system approach. However, certain fundamentals of a fully implemented GLP Quality System considered essential to a quality system, such as certain SOPs and adequate management roles, responsibilities, and accountability, are not presently required. We therefore propose a fully implemented GLP Quality System as the proper framework for building quality into planning, conducting, and reporting a nonclinical laboratory study to help ensure the quality and integrity of the resulting data used to support FDA regulatory decisions.

We also propose to amend the GLP regulations to reflect current practices for the conduct of nonclinical laboratory studies, particularly multisite studies, while allowing industry flexibility to meet the proposed requirements.

B. Summary of the Major Provisions of the Proposed Rule

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

C. Legal Authority

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

D. Costs and Benefits

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

Summary of Benefits, Costs and Distributional Effects of Proposed Rule

Category

Primary
estimate

Low estimate
High estimate
Units
Year dollars
Discount rate (%)

Period
covered
(years)

Notes

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

Quantified

2014
3
10

Qualitative:

Federal

2014
7
10

Annualized

2014
3
10

Monetized millions/year
From:
To:

Transfers:

Other

2014
7
10

Annualized

2014
3
10

Monetized millions/year
From:
To:

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.

II. Introduction

FDA is proposing to amend the GLP regulations in part 58 to require the use of a complete quality system approach, referred to as a GLP Quality System, for the conduct of nonclinical laboratory studies when safety or toxicity studies, or both, support or are intended to support applications or submissions to FDA. FDA proposes to define a GLP Quality System as the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management in the conduct of nonclinical laboratory studies.

While many aspects of a quality system approach are presently included in part 58, we expect that implementation of a GLP Quality System will provide an improved framework that is more flexible and will help ensure quality in planning, conducting, and reporting nonclinical laboratory studies. Consistent with the proposed requirement for a GLP Quality System, we propose additional management responsibilities, with accompanying SOPs, to ensure management's responsibility for establishing and maintaining the quality system. We also propose to revise the definition of a testing facility to reflect current practices for the conduct of nonclinical laboratory studies, particularly the conduct of multisite studies. Conforming modifications are proposed for consistency with the proposed GLP Quality System and today's prevalence of multisite studies.

FDA is proposing these changes to help ensure the quality and integrity of data from nonclinical laboratory studies conducted in support of applications and submissions to FDA. We also are modernizing the regulations to further the Agency's efforts to encourage the implementation of the principles of the “3Rs,” to reduce, refine, and replace animal use in testing. This approach seeks to minimize the use of animals in such testing and promote more humane, appropriate, and specific test methods for evaluating product safety. These proposed changes will clarify and update the regulations. In particular, we are proposing changes recognizing the current prevalence of multisite studies while adding flexibility consistent with current practices and the use of ever-changing technology.

A. What is the background for this rule?

On December 21, 2010, FDA published an advanced notice of proposed rulemaking (ANPRM), “Good Laboratory Practice for Nonclinical Laboratory Studies” (December 2010 ANPRM) (75 FR 80011), to solicit stakeholder input regarding FDA's intention to modify the GLP regulations in part 58. As stated in the December 2010 ANPRM, FDA is proposing to require that all facilities conduct nonclinical laboratory studies under a GLP Quality System when those studies support or are intended to support an application or submission to FDA.

The December 2010 ANPRM addressed nine specific areas to consider for amending part 58. Those nine areas are: (1) The GLP Quality System, (2) Multisite Studies, (3) Electronic/Computerized Systems, (4) Sponsor Responsibilities, (5) Animal Welfare, (6) Information on Quality Assurance Inspection Findings, (7) Process-Based Systems Inspections, (8) Test and Control Article Information, and (9) Sample Storage Container Retention.

FDA received about 90 comments to the December 2010 ANPRM. Most of the comments address the nine specific areas; however, a number of the comments include additional areas for FDA's consideration. All comments were reviewed and considered by a working group with representatives from all FDA Centers, along with representatives from the U.S. Environmental Protection Agency (EPA), the Animal and Plant Health Inspection Service of the U.S.

Department of Agriculture (USDA/APHIS), and the Office of Laboratory Animal Welfare at the National Institutes of Health (NIH/OLAW).

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

B. Why is FDA proposing this rule?

The proposed GLP Quality System would help to provide a flexible framework for building quality into planning, conducting, and reporting a nonclinical laboratory study, and would help ensure the integrity of data submitted to FDA to support FDA regulatory decisions. The present regulations do not require certain fundamentals considered essential to a complete quality system. For example, the present regulations do not specifically require SOPs for developing and maintaining SOPs, or SOPs for developing and periodically assessing a quality system, nor do they provide for adequate management roles, responsibilities, and accountability. We note that a major principle of a complete quality system is management's ultimate responsibility for establishing and maintaining the quality system.

This proposal also is intended to update the regulations to reflect today's conduct of nonclinical laboratory studies, particularly the conduct of multisite studies. For multisite studies that may have multiple contracts and subcontracts for various study phases, effective communication is essential, especially considering the proposed requirement for a single final study report. We agree with the numerous comments to the December 2010 ANPRM that support a clear delineation of study responsibilities and effective communication among all parties involved in multisite studies.

Some stakeholders suggest that certain provisions in part 58 are outdated and hamper efficient use of present technology (for example, requiring hard copies of records and documentation instead of allowing computerized options). Several industry organizations approached FDA after the announcement of the Bioresearch Monitoring (BIMO) Modernization Initiative in 2006 (Ref. 3), requesting that we modernize the GLP regulations. One request, among others, was to remove the requirement that the quality assurance unit (QAU) must maintain the master schedule and copies of protocols. These requests were echoed in several comments to the December 2010 ANPRM. FDA agrees with those comments and proposes to update part 58 to help address the use of present technology.

Because the number of FDA inspections is limited by competing priorities and limited resources, we look to sponsors and nonclinical laboratory management to help ensure that data submitted to FDA in support of applications and submissions are reliable. For those nonclinical laboratory studies that are the bases for allowing a new medical product into first-in-human clinical studies, the quality and integrity of the data are crucial to human subject protection.

This proposal complements the intent of the original GLP proposed rule to ensure the quality and integrity of the resulting data (41 FR 51206 at 51210, November 19, 1976) (Ref. 4). FDA expects that requiring a GLP Quality System will help ensure data quality and integrity. The proposed GLP Quality System also will allow the flexibility to develop site-specific procedures for related SOPs. Because of the great diversity in institutions, research activities, and organizational structures covered by these regulations, it is important to have sufficient flexibility in the regulations to allow the regulated parties to meet these requirements in a manner that best suits their organizational needs.

III. Description of the Part 58 Proposal

A. What did FDA consider when drafting this rule?

1. Animal Rule

Several comments to the December 2010 ANPRM requested that FDA modify part 58 to accommodate studies conducted in animals to support the effectiveness of human drugs or biological products when human efficacy studies are not ethical or feasible. Those comments refer to the “Animal Rule” (21 CFR parts 314 and 601) (67 FR 37988, May 31, 2002).

The Animal Rule provides a pathway for FDA to grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drugs or biological products are reasonably likely to produce clinical benefit in humans. Products evaluated for efficacy under the Animal Rule should be evaluated for safety under the existing requirements for establishing the safety of new drugs and biological products. The provisions in part 314, subpart I for drugs and part 601, subpart H for biological products apply only to situations when adequate and well-controlled human efficacy studies cannot ethically be conducted because they would involve deliberate exposure of healthy human volunteers to a potentially lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substance, and field trials to study the product's effectiveness after an accidental or hostile exposure have not been feasible.

In the past, FDA has said that “All studies subject to this rule must be conducted in accordance with preexisting requirements under the good laboratory practices (21 CFR part 58) regulations” (67 FR 37988 at 37989, May 31, 2002). FDA made this statement because part 58 includes requirements for a quality system structure to ensure the quality and integrity of animal study data. These studies are intended to generate data that are essential for the approval or licensure of products intended for human use. Thus, ensuring the quality and integrity of data from these studies is critical as they serve as substantial evidence of effectiveness of the product.

Part 58 was issued to ensure the quality and integrity of nonclinical laboratory studies conducted to assess the safety of FDA-regulated products. In response to comments made to the ANPRM, FDA questions whether any requirement presently in part 58 or in this proposal poses a unique or disproportionate obstacle or burden on the conduct of certain animal studies specific to product development under the Animal Rule.

FDA, however, tentatively concludes there may be justifiable limitations to applying GLP regulations when conducting Animal Rule-specific studies, especially for studies using challenge agents that require high-containment facilities (for example, biosafety level 4 (BSL-4)
1

laboratory environments). Therefore, although part 58 embodies critical elements of a quality system to ensure data quality

and integrity, FDA also recognizes that some current part 58 requirements may not be appropriate, or may require modification to address adequately data quality practices for the Animal Rule-specific studies.

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.

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 § 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 § 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

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.

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 § 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 § 58.1(a) impact entities conducting covered Animal Rule studies?

b. Would the proposed expansion of the scope in § 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

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.

2. ISO 9001 and GLP Quality System

Many comments to the December 2010 ANPRM note that the International Organization for Standardization (ISO) 9001 is very general and not all aspects outlined in ISO 9001 are applicable to GLPs. FDA acknowledges this.

However, ISO 9001 is an internationally recognized standard for quality systems. Also, FDA's Quality System Regulation (QSR) in part 820 (21 CFR part 820) for current good manufacturing practice requirements for medical devices was harmonized, to the extent possible, with the ISO 9001: 1994 “Quality Systems—Model for Quality Assurance in Design, Development, Production, Installation and Servicing.”

Some comments to the December 2010 ANPRM state that consistency with the ISO 9001 standard would be acceptable if we retained what they perceived as the present flexibility of the regulations. A number of comments state that it would be beneficial to borrow elements of a quality system from the QSR requirements in part 820 rather than reference ISO 9001:1994. Many comments also request that we define the operational areas necessary for broader adoption of a quality system approach.

In this proposal, we incorporate aspects of ISO 9001:1994 that are consistent with part 820 and our desire to propose a complete quality system approach. For example, we propose to address establishing and maintaining a GLP quality system by adding to part 58 certain definitions, relevant SOPs, and management roles and responsibilities modeled after the part 820 requirements. Our proposed additions to more fully enable a GLP quality system will help expand the present flexibility in part 58. Our proposals also are consistent with OECD guidance documents for GLP wherever possible and, at the very least, do not conflict with them.

3. Animal Welfare

Many comments to the December 2010 ANPRM note that § 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 § 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 (§ 58.1)

We propose to expand the scope of FDA-regulated nonclinical laboratory studies to specifically include toxicity studies. For purposes of this proposal, toxicity means the acute or long-term adverse effects that could result from use of the FDA-regulated product. While some nonclinical laboratory studies of FDA-regulated products evaluate a product's safety, including toxicity, most are conducted solely to determine a product's toxicity. For example, when combined with the results of clinical trials, determination of toxicity at various doses can inform an appropriate risk-to-benefit analysis when relevant to FDA's consideration of a product's marketing application or submission.

For drugs administered to animals whose products will be consumed by humans, toxicity studies are critical for determining safe levels of residual drug product. Nonclinical laboratory studies of food ingredients and food contact substances provide the basis for

establishing levels at which a substance will not, with reasonable certainty, be harmful under its intended conditions of use. In the evaluation of tobacco products, FDA could use the data derived from nonclinical laboratory studies to evaluate relative toxicity as opposed to evaluating safety.

Additional proposed modifications to the scope in § 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 § 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 § 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 (§ 58.3)

The current § 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 § 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 § 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 § 58.3(n) to reference the relevant provisions in § 58.105 (Test, control, and reference article characterization) and § 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 § 58.185 for reporting study results refers to “individual scientists or other professionals involved in the study” (see § 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 § 58.37 (Contributing scientist).

Control Article:
We propose modifying the definition of control article currently in § 58.3(c) by changing “medical device for human use” to “device” to expand the regulations to include devices used in veterinary medicine. Also, the revised definition proposes to include a “tobacco product”.

Establish:
For this part 58 proposal, the meaning of establish is to define, document (in writing or electronically), and implement. We propose adding a definition for establish to help eliminate repeating in the applicable regulatory text the words that define establish. Our proposed definition is identical to the

definition of establish in the part 820 quality system regulation in § 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 § 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 § 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 § 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 § 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 § 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 § 58.35.

Quality Policy:
We propose adding a definition for quality policy that is identical to the definition in § 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 § 58.3(k) to update the regulations to address copying requirements and computerized systems, and to specifically include the pathology report. We propose adding to the definition that raw data means “all nonclinical laboratory study records and

documentation or exact copies that maintain the original intent and meaning and are made according to the person's certified copy procedures.” This additional regulatory text eliminates the need to provide examples of what we consider a copy. We also propose adding “correspondence” and “other documentation (regardless of capture medium)” to the examples of raw data. The addition of “regardless of capture medium” eliminates the need to provide examples of possible capture media. Also, we propose including as raw data “the signed and dated pathology report” to clarify what we consider as raw data.

Reference Article:
We propose adding a definition for reference article consistent with EPA's GLP regulations in 40 CFR 160.3 and 792.3 for defining a “reference substance” to mean an article used to establish a basis for comparison of the test article for known chemical or biological measurements. We propose this addition to acknowledge the use of reference articles in certain studies.

Short-Term Study:
We propose adding a definition for short-term study to mean when the in-life period (study period during which data are collected) is completed within several days or, at most, a week. Since the pre-specified, periodic timing of process-based inspections can result in the lack of an inspection of a short-term study, this definition is necessary to address our proposed addition of process-based inspections (see also the discussion of the definition of process-based inspection in section III.B.2.).

Specimen:
We propose adding “or retention” to the end of the current definition of specimen in § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 (§ 58.5)

The present regulations in § 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 § 58.5
Sponsor responsibilities,
that provides explicit provisions for the presently implied sponsor responsibilities and adds new sponsor responsibilities. Our proposed sponsor responsibilities are consistent with the preamble to the original GLP proposed rule stating that the adequacy and validity of nonclinical laboratory tests remain the responsibility of the sponsor of the product as part of establishing the marketability of the product (41 FR

51206 at 51206) (Ref. 4). In addition, we propose adding provisions consistent with the OECD advisory document,
The Role and Responsibilities of the Sponsor in the Application of the Principles of GLP
(Ref. 9).

For each nonclinical laboratory study, we propose that the sponsor must ensure the study protocol meets the requirements specified in § 58.120 (
Protocol
(see proposed § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 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 § 58.105. (See proposed § 58.5(g).) We propose this requirement in § 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 § 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 § 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 §§ 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 § 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 § 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 § 58.5(k)). We propose this requirement,

consistent with the proposed expansion of the scope, to include all applications and submissions to FDA supported by data from nonclinical laboratory studies.

4. Transfer of Responsibilities (§ 58.10)

We propose significant changes to current § 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 § 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 § 58.10(a), we propose to require written documentation of any transfer of responsibilities to a “contracted person”, as that term is proposed in § 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 § 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 § 58.10.

In § 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 (§ 58.15)

We propose revising § 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 § 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 § 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 § 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 (§ 58.29)

We propose no changes to the intent of current § 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 § 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 § 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 § 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 § 58.29(d) (currently, § 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 § 58.29 to address the occurrence of contracting and subcontracting in multisite studies, to update the regulations, and for consistency with our proposals in part 58.

2. Testing Facility Management With Executive Responsibility (§ 58.31)

We propose significant changes in § 58.31 consistent with our proposal requiring a GLP Quality System. To clarify who is responsible for the proposed requirements in § 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 § 820.20).

The current provisions in § 58.31(c) through (g) require only assurances that certain activities are available, performed, understood, or communicated. For those responsibilities currently in § 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 § 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 § 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 § 58.31(b), according to established procedures to be included in proposed § 58.81(b)(2) (establishment and periodic review of a GLP Quality System).

In § 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 § 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 § 58.31(h), we propose this same management is responsible for documenting that all study personnel are trained to perform their assigned functions. In § 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 § 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 § 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 § 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 § 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 § 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 § 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 (§ 58.32)

We propose updating the regulations by adding § 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 § 58.31 and develop and maintain SOPs described in § 58.81, “where appropriate”, as that term is proposed in § 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 (§ 58.33)

In § 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 § 58.33(a), we propose keeping the current requirement that the study director is the single point of study control. We propose adding that the study director cannot delegate overall responsibility for a nonclinical laboratory study. This proposed addition clarifies and emphasizes that a study director cannot delegate oversight of an entire nonclinical laboratory study, even though a study director may delegate to a principal investigator certain responsibilities.

This proposed change is consistent with FDA's longstanding interpretation

of a study director's responsibilities and consistent with present FDA and EPA GLP regulations. This proposed addition also is consistent with the OECD consensus document,
The Role and Responsibilities of the Study Director in GLP Studies
(Ref. 14). Many comments to the December 2010 ANPRM stress the importance of the study director remaining the single point of study control.

We propose in § 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 § 58.33(b), we propose new requirements for the study director for documenting, consulting, signing, and archiving (see proposed §§ 58.33(b)(2) through (7) and (12) through (14)). In § 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 § 58.33(b)(14)), and we seek comment on which term is preferred by industry.

We propose adding in § 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 § 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) (§ 58.35)

In § 58.35, we propose keeping the QAU functions currently in the regulations. We propose modifying § 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 § 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 § 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 § 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 § 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

§ 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 § 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 § 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 § 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 § 58.35 because of its similarity to the existing requirement in current § 58.35(d) for management to provide an FDA representative, upon request, a certification regarding the implementation of required QAU inspections.

In § 58.35(b)(7) (a redesignation and revision of current § 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 § 58.81(b)(21).

We propose this revision in § 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 § 58.35(b)(8) (revision of current § 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 § 58.35 relate to QAU oversight of the integrity of data in the final study report. Current responsibilities in § 58.35(b)(6) (revised and redesignated as § 58.35(b)(10)) are to ensure the quality and integrity of the final study report. Therefore, we propose in § 58.35(b)(9)that the QAU must audit the reports of all contributing scientists and all existing principal investigators.

Currently § 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 § 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 § 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 § 58.35(b)(10), we propose that the QAU must verify that all original and amended signed and dated reports from contributing scientists are appended to the final study report. For multisite studies, we propose that the lead QAU is responsible for this requirement. Under existing regulations that require providing the final study report and any

amendments, we expect that both original and amended versions of reports from all contributing scientists be appended to the final study report. The proposed changes make this expectation a specific requirement. This requirement will allow the study sponsor and FDA reviewers to have access to the original conclusions for each phase and any modifications made as a result of interactions among those involved with the study. We propose this requirement to address the potential inadvertent or intentional introduction of bias that may result when only the final amended version of contributing scientists' reports are included.

6. Contributing Scientist (§ 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 § 58.37(a) and (b), respectively.

When a contributing scientist is responsible for a phase, we propose in § 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 § 58.37(a)(1) through (3)).

In § 58.37(b), we propose requirements for an independent contributing scientist in addition to those requirements in § 58.37(a). The proposed requirements in § 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 § 58.195.

Our proposal for adding § 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 (§ 58.39)

We propose adding § 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 § 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 (§ 58.41)

In § 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 (§ 58.43)

In § 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 (§ 58.47)

In § 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 (§ 58.61)

In § 58.61, we propose adding that equipment includes computerized systems. We also propose adding in § 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 (§ 58.63)

In § 58.63, we propose adding to paragraph (a) maintenance, archiving, and retrieval of data. In paragraph (b), we propose changing the citation reference from § 58.81(b)(11) to (14) and adding a reference to the written SOP requirement in § 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) (§ 58.81)

We propose modifying § 58.81 Standard operating procedures (SOPs), consistent with our proposals for a GLP Quality System and to address multisite studies. In § 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 § 58.81(a), we propose changing “management” to “management with executive responsibility”.

In § 58.81(b), consistent with our proposal in § 58.81(a), we propose adding that the testing facility and all test sites must establish SOPs for an applicable phase of a nonclinical laboratory study. As discussed in section III.B.1., we use the terms “applicable phases” and “where appropriate” because in a multisite study no one person will conduct all phases of the study. Therefore, each person requires SOPs only for those phases which that person conducts.

We propose adding to the current list of SOPs in § 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 § 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 (§ 58.90)

In § 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 § 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 § 58.90(d) and (e). In the first sentence of current § 58.90(d), we propose replacing “excluding suckling rodents” with “except nursing neonates” to update the regulation to be more inclusive and appropriate. In § 58.90(e), we propose adding the word “reference” to conform to changes proposed elsewhere in this document.

We propose these changes in § 58.90 to update and clarify the regulations, and because test animal welfare concerns are an essential part of a GLP Quality System.

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

We propose adding the term “Reference” to the heading in subpart F, and in certain applicable provisions in subpart F. We also propose adding in subpart F specifics concerning tobacco products, and a reference to method validation.
8

8
There is a draft guidance document regarding bioanalytical method validation, “Bioanalytical Method Validation Draft Guidance” (Ref. 16). When final, this guidance will provide FDA's current thinking. We consider many of the general principles in this draft guidance document applicable to method validation in nonclinical laboratory studies.

1. Test, Control, and Reference Article Characterization (§ 58.105)

We propose modifying § 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 § 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 § 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 § 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 (§ 58.107)

We propose minimal conforming changes in § 58.107, such as adding “reference” to the section heading and first sentence.

3. Mixtures of Articles with Carriers (§ 58.113)

We propose modifying § 58.113 by adding “reference” to the provisions proposed in § 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 § 58.113 for the same reasons we propose changes in § 58.105.

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

1. Protocol (§ 58.120)

We propose modifying § 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 § 58.120(a)(3) that the protocol contain contact information for all persons conducting a phase of the nonclinical laboratory study.

Current § 58.120(a)(6) includes in the protocol the methods for controlling bias. We propose adding to this provision the analysis and reporting of study test results and procedures to be followed if a study includes a peer review of any phase. Also, for multisite studies, we propose adding a requirement that the protocol identify the person(s) conducting the phases of the nonclinical laboratory study.

We propose expanding current § 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 § 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 § 58.120(b) as § 58.120(d). In § 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 § 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 § 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 § 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 § 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 § 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 (§ 58.130)

We propose redesignating current § 58.130(a) through (c), as (d), (f), and (g) respectively. In new proposed § 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 § 320.29(a)).

In new § 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 § 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 § 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 § 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 § 58.130(h) (revised and redesignated current § 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 (§ 58.180)

We propose adding a new § 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 § 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 § 58.130(e). In § 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 § 58.180(b), we propose modifying and updating the provisions currently in § 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 § 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 § 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 (§ 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 § 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

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 effi

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A2016-19875. Public record. Not legal advice.