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Surveying stakeholder views on the current good laboratory practices (GLP) regulations and their proposed revisions
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Surveying stakeholder views on the current good laboratory practices (GLP) regulations and their proposed revisions
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Content
SURVEYING STAKEHOLDER VIEWS ON THE CURRENT GOOD LABORATORY
PRACTICES (GLP) REGULATIONS AND THEIR PROPOSED REVISIONS
by
Kerry Cobb
A Dissertation Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF REGULATORY SCIENCE
December 2024
Copyright 2024 Kerry Cobb
ii
Dedication
This dissertation is dedicated to my family whose support and encouragement was
instrumental in my educational journey. My parents, Gary and Sally, were my backbone
throughout my life, and I would not be where I am today without them. My husband, James, who
never let me quit, pushed me forward when I needed it and did it all with his calming and
inspiring smile. My sister, Kali, who was always just a phone call away with words of
encouragement.
“You are never too old to set another goal or to dream a new dream.” – C.S. Lewis
iii
Acknowledgements
Without the support and encouragement of my friends and family, this degree would not
have been possible. I want to thank each one of the people whose support of me and my
endeavors were unwavering.
First, my parents, my mother Sally and father Gary, who were constantly pushing me to
keep going and to never quit, I thank you and love you more than words could ever express.
To my sister, Kali, who was always a phone call away with words of encouragement and
support. You are the best sister anyone could ask for; thank you and I love you.
To my husband, James, you are my rock, the yin to my yang and the love of my life. I
could not have accomplished any of this without you and I can never thank you enough.
I also want to thank my advisor, Dr. Pacifici, who guided me through this process. I will
be forever grateful to you for allowing my dream and desire to complete this academic endeavor
to become a reality.
iv
Table of Contents
Dedication……………………………………………………………………………ii
Acknowledgements ....................................................................................................iii
List of Tables.............................................................................................................. vi
List of Figures............................................................................................................ vii
Abstract.....................................................................................................................viii
Chapter 1. Overview.................................................................................................... 1
1.1 Introduction ........................................................................................... 1
1.2 Statement of the Problem....................................................................... 4
1.3 Purpose of the Study.............................................................................. 5
1.4 Importance of the Study......................................................................... 5
1.5 Limitations, Delimitations, Assumptions.............................................. 6
1.6 Organization of Thesis........................................................................... 6
1.7 Definitions............................................................................................. 8
Chapter 2. Literature Review....................................................................................... 9
2.1 Literature Search.................................................................................... 9
2.2 History of GLP ...................................................................................... 9
2.2.1 Early History .......................................................................... 12
2.2.2 Strengthening the Laws and FDA .......................................... 13
2.2.3 Driving Forces of GLP........................................................... 16
2.3 Implementation of GLP....................................................................... 26
2.3.1 Early Days of GLP ................................................................. 26
2.3.2 Challenges.............................................................................. 29
2.3.3 Global Landscape................................................................... 31
2.3.4 Proposed Changes to GLP...................................................... 33
2.3.4.1 Animal Rule .............................................................. 35
2.3.4.2 Quality Systems......................................................... 36
2.3.4.3 Animal Welfare ......................................................... 37
2.3.4.4 Multisite Studies and Roles and Responsibilities...... 37
2.3.5 Proposed Regulations............................................................. 38
2.4 Responses from Industry on the Proposed Revisions.......................... 44
2.4.1 Other Responses from Industry.............................................. 47
2.5 Research Direction and Framework .................................................... 48
Chapter 3. Methodology............................................................................................ 51
3.1 Introduction ......................................................................................... 51
v
3.2 Identification of Survey Participants................................................... 51
3.3 Development of Survey ....................................................................... 52
Chapter 4. Results...................................................................................................... 55
4.1 Survey Logistics.................................................................................. 55
4.2 Demographics...................................................................................... 55
4.2.1 Respondent Demographics..................................................... 55
4.2.2 Company Demographics........................................................ 56
4.3 Exploration and Adoption.................................................................... 61
4.4 Quality of Communication .................................................................. 78
4.5 Competence ......................................................................................... 81
4.6 Cost of Implementation ....................................................................... 85
4.7 Final Thoughts..................................................................................... 88
Chapter 5. Discussion................................................................................................ 90
5.1 Overview ............................................................................................. 90
5.2 Study Methodology ............................................................................. 90
5.2.1.1 Framework ................................................................ 91
5.2.1.2 Respondent Demographics........................................ 93
5.2.2 Limitations ............................................................................. 93
5.2.2.1 Response Rate ........................................................... 93
5.2.2.2 Survey Design ........................................................... 94
5.2.2.3 Additional Insight Regarding the Results ................. 95
5.3 Discussion of Results........................................................................... 96
5.3.1 Demographics......................................................................... 96
5.3.2 Exploration and Adoption ...................................................... 97
5.3.3 Quality of Communication................................................... 103
5.3.4 Competence.......................................................................... 104
5.3.5 Cost of Implementation........................................................ 106
5.4 Final Comments................................................................................. 107
References ............................................................................................................... 110
Appendices .............................................................................................................. 115
Appendix A. 81 FR 58342.............................................................................. 116
Appendix B. 21 CFR Part 58.......................................................................... 156
Appendix C. 49 FR 43530.............................................................................. 175
Appendix D. Survey ....................................................................................... 184
vi
List of Tables
Table 1: Definitions ....................................................................................................................8
Table 2: BIMO Inspections and Actions ..................................................................................31
Table 3: Stages of Implementation ...........................................................................................49
Table 4: Survey Categories Informed by the Implementation and Customer Service
Frameworks................................................................................................................52
Table 5: List of Participants in the Focus Group ......................................................................53
Table 6: Actual Values (N=47) with Weighted Mean..............................................................69
Table 7: Actual Values (N=47) with Weighted Mean..............................................................71
Table 8: Actual Values (N=47) with Weighted Mean..............................................................74
Table 9: Actual Values (N=11) with Weighted Mean..............................................................76
Table 10: Actual Values (N=42) with Weighted Mean..............................................................79
Table 11: Actual Values (N=48) with Weighted Mean..............................................................81
Table 12: BIMO Inspections Ended and Actions Taken ............................................................99
vii
List of Figures
Figure 1: Steps in Drug/Biologic Development.........................................................................10
Figure 2: Distribution of Self-identified Level of Knowledge Regarding GLP (N=107)..........56
Figure 3: Distribution of Years of GLP Experience (N=100)....................................................56
Figure 4: Distribution of Type of Company (N=100)................................................................57
Figure 5: Distribution of Organization Size (N=100)................................................................58
Figure 6: Distribution of Years in Business (N=100)................................................................58
Figure 7: Distribution of Laboratories in the U.S. (N=73).........................................................59
Figure 8: Distribution of Laboratories Outside the U.S. (N=70) ...............................................59
Figure 9: Distribution of Laboratory Types (N=100) ................................................................60
Figure 10: Standards or Regulations Used (N=99)......................................................................61
Figure 11: Company Inspection Distribution (N=97)..................................................................62
Figure 12: Dates of Inspection (N=44) ........................................................................................62
Figure 13: Distribution of the Proposed Revisions (N=82) .........................................................63
Figure 14: Distribution of Sections to be Revised (N=26)...........................................................64
Figure 15: Distribution of Current Areas (N=41) ........................................................................65
Figure 16: Distribution of Proposed Areas (N=36)......................................................................67
Figure 17: Level of Challenge to Implement (N=47) ..................................................................69
Figure 18: Level of Benefit to Implement (N=47).......................................................................70
Figure 19: Benefit of ISO 9001 Distribution (N=38)...................................................................71
Figure 20: Level of Burden to Align GLP with ISO 9001 (N=47)..............................................73
Figure 21: Data Quality Distribution (N=48)...............................................................................74
Figure 22: Animal Rule Distribution (N=50)...............................................................................74
Figure 23: Addition of Animal Rule Distribution (N=15)...........................................................75
Figure 24: Distribution of Areas of Challenge (N=11)................................................................76
Figure 25: Inclusion of Tobacco Studies Distribution (N=41) ....................................................77
Figure 26: Statement Agreement Distribution (N=43) ................................................................77
Figure 27: Distribution of Agreement (N=46).............................................................................78
Figure 28: Ranking of Items in Terms of Helpfulness (N=42)....................................................79
Figure 29: Ranking of Unofficial Communication Routes (N=48) .............................................80
Figure 30: Distribution of Adequacy of Process (N=41).............................................................81
Figure 31: Disposition of Requesting Additional Comments (N=42) .........................................83
Figure 32: Selection of Areas for Additional Comment (N=10) .................................................85
Figure 33: Distribution of Enduring Cost of Implementation (N=46).........................................86
Figure 34: Cost Impact Distribution (N=46)................................................................................87
Figure 35: Distribution of Maintenance Cost (N=44)..................................................................87
viii
Abstract
Nonclinical studies (or preclinical studies), including animal studies, are integral to bringing a
new drug to the market. The United States Food and Drug Administration (FDA) expects
nonclinical studies in regulatory applications and submissions to follow Good Laboratory
Practices (GLP) standards. The GLP regulations aim to assure the quality and integrity of
submitted data and allow for the accurate reconstruction of a study. The current GLP regulations
were established in the United States in June 1979 and have not been significantly revised. As a
result, GLP regulations have not kept up with advances in science and technology, or with the
development of international guidelines. To address this issue, the FDA has been working to
update its GLP regulations. Discussions began in 2010 with an advanced notice of proposed
rulemaking (ANPRM), requesting comments and information, being published in the Federal
Register (75 FR 80011, 2010). In August 2016, the FDA proposed to revise the GLP regulations
with the notice of proposed rulemaking (NPRM) published in the Federal Register (81 FR
58342, 2016). These revisions have not yet been finalized and the plans for moving forward
have not been announced.
This study examined current industry perspectives on the proposed revisions to the GLP
regulations and their implementation to provide more insight into these questions. This study
also assessed the industry’s satisfaction with the FDA’s rulemaking process. The results of this
study point out the perceived burdens and benefits, but it also brought about several interesting
findings. Three key themes emerged. One was the need for revisions to the current GLP
regulations. The second was the need for increased FDA communication and the third was the
need for the regulatory revision process (ANPRM to NPRM to final rule) to be shorter. The
ix
findings from this study can be valuable for policy makers as they finalize the new regulations
and identify best practices in their implementation.
1
Chapter 1. Overview
1.1 Introduction
Good Laboratory Practices, the regulations that govern nonclinical studies, were
established in the U.S. where they have been in effect for over 40 years. Although scientific
aspects of these studies have evolved, and international guidelines have been adopted and
modified, the GLP regulations in the U.S. have remained essentially unchanged. In 2010, the
U.S. Food and Drug Administration (FDA) announced plans to modify the GLP regulations and
in 2016, issued its proposed changes. These changes were expected to harmonize the regulations
with international standards and reflect current practices in non-clinical studies. However, the
proposed changes have yet to be finalized, and it is unclear when or how the process will move
forward. From the industry’s perspective, comments were provided to both the ANPRM in 2010
and the NPRM in 2016. However, it is unclear how the stakeholders in the industry impacted by
these new proposed rules currently view the potential changes and their implementation.
Additionally, it is unknown how the industry perceives the FDA’s rulemaking process for the
new GLP regulations regarding transparency and engagement.
The U.S. FDA requires nonclinical studies, also called preclinical studies, to assist in
predicting the safety and potential efficacy of the drug candidates being tested (FDA, 2018d).
These studies are required for human and animal drugs alike to inform industry and regulators on
different facets of the articles being tested before initiating any human or animal clinical trials.
The outcomes of the nonclinical studies are used to make decisions that impact the health and
safety of clinical trial subjects during a product’s development process and the broader
population upon its commercialization. Therefore, nonclinical studies must be conducted under
strict controls to ensure that the data obtained is accurate and verifiable. However, without any
2
regulatory measures in place, early nonclinical studies were fraught with errors because they
neither adhered to scientific principles nor employed quality control measures. To improve the
reliability of data obtained during the nonclinical phase of medical product development, the
FDA issued the first GLP regulations in 1979. The GLP regulations establish standards for
operational resources and responsibilities, test article characterization, study conduct, reliability
of results and reporting, and quality assurance.
The GLP regulations have remained largely unchanged since their inception, with only
minor revisions made in 1987 regarding quality assurance, protocol preparation, test and control
article characterization, and sample and specimen retention. However, the science and
technology impacting non-clinical studies have continued to evolve. What was applicable in
1979 may not be relevant today. Additionally, many new additions to the nonclinical area were
not covered in the original regulations, including the use of multisite studies, applicability to the
Animal Rule, the inclusion of tobacco studies, and veterinary involvement. Over time, revising
the current U.S. GLP regulations has become necessary.
To modify an existing regulation, the FDA follows a regulatory process for rulemaking.
The need for change can be prompted through various mechanisms including petitions from
industry, requests from other agencies, new technologies, and current issues. The agency then
gathers information from industry and other stakeholders in informal discussions before
publishing an ANPRM in the Federal Register to formally request additional information.
Anyone can respond to the ANPRM. With assistance from the Office of Information and
Regulatory Affairs (OIRA), the President of the United States can review the rule if desired.
This typically happens if the rules are deemed significant in that they have large economic
effects or raise important policy issues (Office of the Federal Register, n.d.).
3
After the ANPRM, the FDA reviews comments and discussions and addresses and/or
incorporates them into the NPRM, which is issued in the Federal Register. The NPRM is the
proposed new rule that the agency plans to adopt, and it allows for another comment period from
the industry and the public. The final rule is based on the proposed rule and the corresponding
comments received. The typical comment period is thirty to sixty days but can be longer for
more complex rules or shorter if the agency can provide justification. The timelines can also be
extended if the agency does not receive enough feedback, or if the public has presented a reason
for allowing additional time. Public hearings can also be held to have further dialogue around
the subject. The agency must respond to each comment it receives (Office of the Federal
Register, n.d.).
Once the agency has put together its draft final rule, the President and OIRA again have
the opportunity to review it just as they did with the proposed rule. Once finalized, the new rule
is published in the Federal Register with a summary, effective date, and supplementary
information. The summary explains the purpose of the rule and why it was necessary. The
supplemental information describes the issues the rule addresses and the facts and data the
agency used to create it. The effective date is typically no less than thirty days from the date of
publication unless it is deemed significant, in which case it would become effective sixty days
post-publication. This period provides time for Congress and the Government Accountability
Office to review it before it becomes effective (Office of the Federal Register, n.d.).
To update the GLP regulations, the FDA convened a GLP Working Group consisting of
all the FDA centers and other Federal Agencies, including the Environmental Protection Agency
(EPA), the National Institute of Health (NIH), and the United States Department of Agriculture
(USDA) (FDA, 2017). The agency followed its regulatory process for rulemaking by publishing
4
an ANPRM in the Federal Register in December 2010 (75 FR 80011, 2010). There were
approximately ninety responses to the FDA request for comments in nine certain areas and
topics. These areas of interest were the GLP quality system, multisite studies,
electronic/computerized systems, sponsor responsibilities, animal welfare, information on quality
assurance inspectional findings, process-based systems inspections, test and control article
information and sample storage container retention. The ANPRM was followed by a NPRM,
containing the draft of the proposed regulations, which was published in the Federal Register
(Appendix A) in August 2016 (81 FR 58342, 2016). The highlights of the proposal in 81 FR
58342 consisted of the requirement for a complete GLP quality system, adding management
responsibilities and corresponding SOPs, and adding multi-site study requirements. There was a
ninety-day comment period with a sixty-day extension period that closed in January 2017. There
were seventy-eight respondents with multiple comments per response (FDA, 2017).
Since the closure of the comment period in 2017, the regulations have not been finalized
and no further updates or timelines have been discussed. As of the current year of 2024, fourteen
years since the ANPRM, industry is operating in a land of ambiguity—a land where the current
regulations are still in effect but provide a hint of what may or may not be to come. According
to the Preliminary Regulatory Impact Analysis, it was estimated that 2,193 sponsors of
nonclinical studies and approximately 300 testing facilities currently conduct nonclinical work
(OMB, n.d.). Many organizations will be affected by changes in the finalized rule and have a
vested interest in those revisions.
1.2 Statement of the Problem
The current GLP regulations have not been substantially revised since their inception in
1979. The proposed revisions, first discussed in 2010, were published in the Federal Register in
5
August 2016. As of this date they have yet to be finalized. This lack of progress places the
industry in a difficult position where the need for the revisions is apparent but there is still no
finalized directive for what those changes are nor a timeline for when they can be expected.
It is not known if the industry views the revision and revision process as having a positive
impact or if the view is that those new rules will be costly with little added benefit. Potential
perceived barriers could include cost, time, and resources. The research presented here attempted
to gain more insight into the perceived barriers and benefits affecting the industry if GLP
requirements are to be revised.
1.3 Purpose of the Study
The purpose of this study was to survey stakeholders in the U.S. pharmaceutical industry
on their views regarding the current GLPs and implementation of the proposed GLP revisions
purported to improve study conduct and the quality and integrity of the data. It also attempted to
understand the industry’s view on the transparency and communication of the FDA during the
revision process. This research utilized an electronic survey tool, Qualtrics, to provide the
survey, collect and assemble the responses and assist with statistical analysis. This study used
the adoption and implementation framework, with selected portions from the customer service
framework, to examine industry views on implementing the proposed GLP revisions.
1.4 Importance of the Study
The results of this study are intended to provide industry and regulatory stakeholders with
a better understanding of views associated with adopting the 2016 proposed revisions of the
GLPs. The results may assist industry stakeholders in recognizing best practices and overcoming
potential barriers that may prevent industry from adopting the revisions to GLPs to their fullest
6
extent. Identifying these observations will help the industry understand and evaluate any
potential shortcomings perceived in the implementation.
The results of this study may also inform regulators, who have been providing guidance
to industry on GLP study conduct. If the survey shows a lack of understanding about the
guidance that the FDA has provided regarding the implementation of the 2016 proposed
revisions, the results could inform policy going forward and guide revisions of available material
or additional material to be introduced by the FDA.
1.5 Limitations, Delimitations, Assumptions
Limitations of concern included identifying enough industry stakeholders to survey who
conducts this type of research. Because GLP nonclinical studies are performed by a small,
limited group of entities, the numbers and availability of the respondents may be limited. The
length of the survey was kept as short as possible to reduce the potential lack of participation
and/or completion, so the number of questions was too few. This limited the depth of the results
and conclusions. The survey responses were collected over a limited period, which also limited
the number of participants.
The survey was delimited to quality assurance, regulatory personnel or
managers/executives working in facilities that conduct GLP studies in pharmaceutical companies
within the United States. Views from industry outside of the U.S. were not included since this
regulatory pathway is only applicable to the U.S.
1.6 Organization of Thesis
This thesis was organized into three chapters as follows:
• Chapter 1 introduces the problem to be studied and summarizes the approach to
doing so.
7
• Chapter 2 reviews relevant literature and provided a history of the current U.S.
regulations and the current state of GLP.
• Chapter 3 describes the methods and questions utilized to conduct the survey.
• Chapter 4 presents the results of the research.
• Chapter 5 provides a detailed discussion of the results obtained during the
research, as well as final comments.
8
1.7 Definitions
Table 1: Definitions
Acronym/Term Definitions
ACT American College of Toxicology
ALCOA Accurate, Legible, Contemporaneous, Original and
Attributable
ANPRM Advanced Notice of Proposed Rulemaking
CA Control Article
CFR Code of Federal Regulations
EPA Environmental Protection Agency
FDA Food and Drug Administration
GLP Good Laboratory Practice
IACUC Institutional Animal Care and Use Committee
IND Investigational New Drug
NIH National Institutes of Health
NPRM Notice of Proposed Rule Making
OIRA Office of Information & Regulatory Affairs
OMB Office of Management and Budget
PD Pharmacodynamic
PI Principal Investigator
PK Pharmacokinetic
PRIA Preliminary Regulatory Impact Analysis
QA Quality Assurance
SD Study Director
SOT Society of Toxicology
SQA Society of Quality Assurance
TA Test Article
U.S. United States
USDA United States Department of Agriculture
9
Chapter 2. Literature Review
2.1 Literature Search
A review of current information on GLP in literature was conducted to better understand
the evolutionary history of the GLP regulations and their impact. Literature reviewed included
regulations, case studies, the federal registry, and journal articles. Other references for this
research project included the FDA website, professional organization websites, guidance
documents, directives and/or communications from FDA.
References that were identified as relevant to the history of the GLP regulations and the
current and proposed states of GLP were utilized. Also utilized were presentations from industry
and regulators and other materials, such as industry response pieces. Additional references
found within the chosen articles were also used to provide further and more in-depth insight into
these topics.
2.2 History of GLP
Regulations in the U.S. prohibit performing clinical studies (human studies) until
nonclinical studies have shown that the article being tested can be given safely to humans. Thus,
the test article progresses through the entire drug development process prior to market (Figure 1).
Certain expedited pathways exist to shorten the timelines of the developmental pathway, such as
the accelerated approval process. However, these expedited pathways do not exempt the
pharmaceutical company from completing a rigorous preclinical testing process to determine
safety before regulatory approval.
10
Figure 1: Steps in Drug/Biologic Development
The development process begins with discovery and development. Once a test article is
discovered, it can be progressed into the development phase if it is deemed to be a viable
candidate. Development of the test article requires additional pharmacological testing to obtain
additional information. This information can include properties of the article such as absorption,
distribution, metabolism and excretion, mechanisms of action and its potential benefits and side
effects or toxicity (FDA, 2018d).
If the article passes basic research, it continues on to nonclinical (preclinical) research.
Here, the article is tested to discover if it has the potential to cause harm or toxicity. The two
types of nonclinical research are in vitro (“in the glass” or test-tube/petri dish experiments) and
in vivo (“within the living” or in the whole, living organism or cells). The tests in the nonclinical
series of studies used to show safety are typically repeat dose toxicity, genotoxicity, and safety
pharmacology. All should be performed according to GLP, and several are to be conducted prior
to an Investigational New Drug (IND) submission to the regulatory agency (Parisotto, 2021).
The IND submission consists of not only the nonclinical and toxicity data but also
manufacturing information, information about the investigator, data from any previous human
studies and protocols for the clinical trials to be performed. Once the IND process and
submission to the agency are complete and approved, the article can move to the next phase of
11
clinical development, in which trials or studies are performed in humans. Phase 1 studies are
designed to assess safety and dosage, typically in normal subjects, and are usually only several
months long. Phase 2 studies are designed to provide early data on the efficacy and side effects
in patients and usually take several months to two years. Phase 3 studies are designed to assess
in more detail the efficacy and adverse event profiles and typically take one to four years (FDA,
2018d). As clinical trials progress, nonclinical testing generally continues with certain long-term
studies, such as reproductive toxicology studies.
If the test article successfully transitions through these steps in the process, a New Drug
Application (NDA) or Biologics License Application (BLA) is submitted to the agency for
review and approval. The NDA consists of all the prior data from nonclinical through Phase 3
studies, which will inform the proposed labeling and directions for use, safety updates, drug
abuse information, patent information, institutional review board (IRB) compliance and any data
from studies performed outside the U.S. If approved, the article can be marketed but still
typically will be subject to additional post-market studies to evaluate longer-term safety and
efficacy, expand indications or gather additional data needed for reimbursement purposes (FDA,
2018d).
The focus of this study was nonclinical studies. The regulations that govern nonclinical
studies were established in 1979. Prior to that, the quality of nonclinical studies was less than
desirable. The studies were not well documented and contained errors and discrepancies. As
typically seen in the history of food and drug law, several high-profile scandals led to the
creation of the GLP regulations. These events and issues surrounding the conduct of nonclinical
studies are discussed in detail in the following sections.
12
2.2.1 Early History
Although GLP regulations were established in the U.S. in 1979, the laws governing food
and drugs have been in existence for over a century. In the early years, a series of events led to
the creation of the first food and drug law and its amendments. These events identified areas that
could be better regulated so that the public could be protected from potential harm and were key
in the development of laws surrounding the drug development processes that are in place today.
The first major driver for legislation can be recognized as early as 1905. A series of
eleven articles on fraud in the pharmaceutical industry was published by Samuel Hopkins Adams
in Collier’s magazine. According to Fee, he was one of many writers called a muckraker by then
President, Theodore Roosevelt. These writers reported on the shadier side of corporate America.
Adams work, “The Great American Fraud,” exposed false claims made by manufacturers of
drugs that harmed the public more than they helped. His articles were transformed into a book
with the same title in 1906. The public was so outraged that Congress was able to enact the pure
food and drug laws in 1906 (Fee, 2010).
The Pure Food and Drug Act of 1906 prohibited foreign and interstate traffic in
adulterated drug products and required drug labels to list active ingredients which could not fall
below certain purity levels. This law, however, fell short of providing the protection that
Congress intended in that the law did not address false or misleading efficacy claims. Some drug
manufacturers, in response to this law, simply omitted active ingredient information from the
label to avoid a violation (FDA, 2018a). The new law also did not require the products to be safe
for human use. Hence, harmful products remained on the market.
The year 1911 revealed another loophole in the 1906 law. The case of U.S. vs. Johnson
was looking for an indictment of Dr. Johnson for a shipment that made the claim that the
contents were able to cure cancer even though the defendant knew that was inaccurate.
13
According to the U.S. vs Johnson case study, some of the labels stated they were “Cancerine
tablets” and they were “guaranteed under the Pure Food and Drugs Act, June 30, 1906.” The
indictment, however, was quashed by a district judge and was upheld by the Supreme Court
which ruled that the law did not prohibit a manufacturer from making false therapeutic claims,
but rather only from making false statements about ingredients or their drugs identity. Although
this view was not shared by the agency at the time, the ruling forced the FDA to prove that the
intent of the manufacturer was to defraud its customers, a benchmark that was very difficult to
reach (U.S. vs Johnson, 1911).
Then in 1912, in response to the ruling from the Dr. Johnson case, Congress enacted the
Sherley Amendment. This amendment added language that prohibited the intentional labeling of
drug bottles or packaging with false therapeutic claims (FDA, 2018a). This new amendment,
however, also required proof of “intent”, which was difficult to obtain. In the 1915 trial of U.S.
vs The Anglo-American Drug Co., which made “Mrs. Winslow’s Soothing Syrup” the
government alleged that the company misbranded its product by claiming therapeutic or curative
effects of the product including “regulating the bowels” and “invigorates the stomach and
bowels.” The contents of the product, upon testing, were found to contain sugar, alcohol,
essential oil, morphine, and vegetable extract. The manufacturer pled guilty and was fined $100
(U.S. vs The Anglo-American Drug Co., 1915). Still, the new law did not require that a company
demonstrate its products to be safe. Hence, the weak regulatory framework left the public
vulnerable to harmful products still on the market.
2.2.2 Strengthening the Laws and FDA
In the subsequent few decades, many recognized the need to revise and replace the
current law, but Congress could not seem to come to a resolution. However, in 1937, nearly
14
twenty-two years after the Sherley Amendment, an unfortunate event captured the public’s
attention and prompted action by the government. This event, the Elixir of Sulfanilamide
tragedy, was responsible for the death of one hundred and seven people, most of whom were
children, in fifteen states across the country. Sulfanilamide had been widely used safely in tablet
and powder form, mainly to treat streptococcal infections. Then, demand rose in southern states
for a liquid form of the drug suitable for children. The drug’s manufacturer, S.E. Massengill Co.,
identified diethylene glycol to be a suitable solvent and quickly manufactured and shipped the
new formulation to pharmacies across the country (Ballentine, 1981).
About a month after the first shipments were dispensed, a doctor in New York became
aware of certain unexpected deaths and contacted the FDA. The FDA investigators then learned
that company employees were already aware of the deaths and had issued a telegram asking for
the return of the product without alerting anyone about the serious adverse effects. The FDA
ordered the company to send another message stating that the drug can cause death and asking
for the products to be returned (Ballentine, 1981).
While the new formulation of the drug proved to be deadly, Dr. Massengill proclaimed
there was no error in the manufacture of the product. He stated,
My chemists and I deeply regret the fatal results, but there was no error in the
manufacture of the product. We have been supplying a legitimate professional
demand and not once could have foreseen the unlooked-for results. I do not feel
that there was any responsibility on our part (Ballentine, 1981).
The FDA was able to charge the company with misbranding, but only because “elixir”
connoted an alcoholic solution, but no alcohol was present in the product. This tragedy exposed
the urgent need to pass the new food and drug law already pending in Congress, which would
require companies to establish drug safety before marketing (Ballentine, 1981).
15
As the laws were created and strengthened, the FDA was also modified and strengthened.
The realization came that while laws were needed as well as an agency strong enough to enforce
them. In 1938, the Federal Food, Drug & Cosmetic Act (FDC&A) was enacted and gave FDA
the authority to oversee the safety of food, drugs, and cosmetics. The FDC&A included a
requirement for drugs to be labeled with adequate directions for use and prohibited false
therapeutic claims for drugs. It also contained a requirement for pre-market review of all new
drugs, based on proof of safety. The FDA was also given the authority to perform factory
inspections and prosecute manufacturers that did not comply with the new law (FDA, 2018b).
In so doing, it ushered in a new era that required the drug companies to generate, and the FDA to
review, safety data that may include both nonclinical and clinical test results. The conduct of
these studies became extremely important because their outcomes would determine whether a
product could be commercialized.
The FDA’s authority was further strengthened in 1941 when the Insulin Amendment was
enacted that allowed the FDA to test insulin products for their purity and efficacy. The FDA
certified batches of the drug but this became unnecessary with the introduction of recombinant
insulin and FDA testing ceased in 1998 (Goldstein & McCrary, 2020). Ten years later in 1951
the Durham-Humphrey Amendment was passed to define drugs that required medical oversight
or needed to be dispensed through a prescription. According to Goldstein, this also gave the
FDA the power to approve all new medications and to determine their status as either over the
counter (OTC) or prescription only. Goldstein goes on to state that the FDA determined that all
injectable drugs and drugs that have a potentially harmful effect, except for those under a
physician’s oversight, were to be prescription only.
16
Another tragedy, the 1962 Thalidomide disaster, revealed the need to further strengthen
the FDA’s regulatory framework. The drug, Thalidomide, was promoted as a sleep aid for
pregnant women with morning sickness and was widely used in Europe. By the time the drug
was linked to severe limb deformities in newborns, over 10,000 babies were affected. While in
the U.S., the FDA blocked this drug from being on the market, the tragedy brought attention to
the importance of regulatory oversight and safeguarding the public from potential harm of
powerful drugs (FDA, 2018c).
The Kefauver-Harris Drug Amendments of 1962, passed in response to the disaster,
increased restrictions over prescription, novel, and investigational pharmaceuticals and required
a review procedure for all approved drugs between 1938 and 1962. The Amendments also
required drug manufacturers to prove efficacy through well controlled clinical trials and gave
rise to the Phase 1, Phase 2 and Phase 3 paradigm of clinical trials that we have today (Greene &
Podolsky, 2012). With this increased support and improvements in the laws, focus now turned
to the safety testing and nonclinical studies of these drugs.
2.2.3 Driving Forces of GLP
Before the GLP regulations were implemented, the FDA operated under the assumption
that nonclinical studies were being performed properly and reported accurately. But, in 1969 it
became apparent to the Office of New Drugs and the Office of Marketed Drugs that many
studies had not been conducted as the agency had presumed (Baldeshwiler, 2003). Hence, its
inspection program was revised, with the assistance of the Office of Compliance, to include
directed or “for cause” inspections of companies that submitted studies with questionable
validity including those with inconsistencies in the data, or questionable study purpose/designs.
It also raised concern about organizations that simultaneously conducted large numbers of
17
complicated studies, or that were identified by a whistleblower who contacted the agency with
information indicating that studies were not being properly conducted (Baldeshwiler, 2003).
In the subsequent inspections conducted through the early 1970s, the FDA investigated
multiple cases of poor practices in nonclinical laboratories conducting toxicology testing. They
found many cases of poorly managed studies and inadequate training of personnel as well as
fraud. One of the more notorious labs inspected during this time was G.D. Searle & Company
(Smith, 1977). Questions about the data submitted by G.D. Searle & Company emerged around
1972 surrounding their long-term use studies of the prescription drug, Flagyl, which was already
FDA approved for limited use. An article submitted to the Journal of the National Cancer
Institute claimed that Flagyl caused cancer in nonclinical studies. These results led the FDA to
re-review Searle’s data, in which inconsistencies between summary data and individual data
were found. In response, Searle resubmitted the study but changed the individual data to match
the summary data instead of the reverse (Smith, 1977).
Around the same time, another study submitted by Searle was also being reviewed. This
study was for the prescription drug, Aldactone, which was shown also to cause cancer in
animals. The agency’s own review, however, resulted in different conclusions than those
reported by the company. As a result, the FDA inspected Searle’s facilities in 1975 and
reviewed its study data from 1968 to the time of inspection. The investigation was conducted by
six teams of FDA inspectors and took eleven years to conclude (Baldeshwiler, 2003).
Individual occurrences of the problems that were found by the inspectors were too
numerous to fit on a single Form 483. Individual results included not adhering to the protocol,
omitting data from reports, failing to identify data collectors and excising masses from live
18
animals. The outcome of the agency investigation required Searle to have warnings on the label
of both drugs regarding the cancer effects shown in the nonclinical studies (Baldeshwiler, 2003).
Searle was certainly not the only organization in which problems were found. In 1975,
the FDA received a notification that Industrial Bio-Test Laboratories (IBT) had submitted
questionable data. According to Smith, this occured by happenstance, as the tip originated from
a Syntex Corporation employee, and instead of picking up the Syntex file, the FDA investigator
chose an IBT file for inspection. As it turns out, IBT was a contractor of Syntex. The IBT study
was so poorly done that no conclusion of safety could be drawn (Smith, 1977).
As a result of that review, the FDA visited IBT in 1976. According to an article by
Schneider, they found falsified data as well as many facility issues, including a room, called the
“Swamp”, where studies were being run. Within this room, a malfunction in the watering system
was spraying water into animal housing and drowning animals. This room was still in use three
years after the defective watering system was installed. Similar objectionable conditions were
found in four other animal rooms (Schneider, 1983).
These findings called into question the safety of over two hundred pesticides. Over half
of the studies audited by the FDA were invalidated because discrepancies existed between the
data and conduct of the study (FDA, 2017). The Justice Department took further action in 1977
by seizing approximately thirty thousand documents proving the allegations of misconduct.
Three company officers were indicted by a federal grand jury and found guilty of mail fraud and
of providing the government with false statements (Benson, 1991).
The issues uncovered in nonclinical studies prompted Senator Edward Kennedy to hold
joint hearings on pharmaceutical testing in January 1976. He gave an opening speech which in
part stated:
19
Accurate science is the best protection the American people have from an unsafe
and ineffective drug supply. Inaccurate science, sloppy science, fraudulent
science – these are the greatest threats to the health and safety of the American
people. Whether the science is wrong because of clerical error, or because of
poor technique, or because of incompetence, or because of criminal negligence is
less important than the fact that it is wrong. For if it is wrong, and if, as in this
case, the FDA did not – indeed, under the current practice, could not – know it
was wrong, then the protective regulatory barrier between a potentially
dangerous drug and the patient is removed (Senator Edward Kennedy).
(US GPO, 1976).
The testimony the FDA gave during these hearings reflected widespread concern over the
lack of standards for conducting nonclinical studies. FDA described the inaccurate analysis and
reporting of studies, failure to follow protocols and document accurate observations,
inappropriate administration of test articles and inaccurate record keeping and transcription.
Other concerns noted by the FDA included a lack of management assurance that staff were
properly trained and monitored, and that data were reviewed appropriately. They also pointed to
the sponsor organizations as failing to monitor their contracted studies and failing to verify the
accuracy and completeness of the reports before submitting them to the agency (Kirsch, 1978).
The hearings clearly underlined a need for an improved inspection program and better
laws. In an ironic twist of events, staff from Searle were the ones to submit a draft of what
would become the GLP regulations to the FDA. Searle committed to implementing those
changes in their company and to working with others in the industry to follow suit. The draft
contained requirements for compliance, control of test substances, personnel, study design,
reporting of results, personnel, and animal care. The proposed regulations were published in
November 1976; the GLP Final Rule was published in the Federal Register on December 22,
1978, and made effective in June 1979 (FDA, 2017).
20
The GLP Final Rule was codified into 21 CFR Part 58 (2023), organized into eleven
subparts, two of which are reserved (see Appendix B). Brief descriptions of each part are
provided below.
Subpart A contains the scope of the regulations, definitions, applicability to studies
conducted under grants and/or contracts and the FDA inspection of a testing facility. This
section prescribes GLPs for conducting nonclinical laboratory studies that support applications
for research or marketing permits for products regulated by the FDA (food and color additives,
human and animal drugs, medical devices, and biological products). Definitions include, among
others, raw data which can include photographs, microfilm or fiche, computer printouts,
magnetic media, and recorded data from automated instruments. Raw data must be able to
reconstruct how the results were derived, the date and time data was collected, and everyone who
collected the data, analyzed the data and recorded the data. Definitions also include the study
director who is the single point of study control, the sponsor who initiates or supports a
nonclinical study or submits a study to the FDA or both, and the test system, which can be an
animal, plant, or microorganism that is administered a test or control article.
Subpart B describes the roles and responsibilities of personnel (including testing facility
management, study director, and the quality assurance unit (QAU)). Personnel must have the
appropriate education, training, and experience to perform their assigned functions. They are to
have a current summary of training and experience (C.V.) and a job description in their records.
Sufficient personnel should be in place for a study’s timely and proper conduct. Testing facility
management’s responsibilities include designating a study director, assuring there is a QAU, and
assuring that deviations reported by the QAU are reported to the study director and corrective
actions are taken. They also must assure study personnel clearly understand the functions they
21
are to perform and are trained. Testing facility management must also ensure that test and
control articles or mixtures have been thoroughly tested, that standard operating procedures
(SOPs) are adequate to ensure the quality and integrity of the data generated, and that they are
not involved in data collection or study conduct. The study director has overall responsibility for
the technical conduct of the study and represents the single point of control. The study director
is responsible for the interpretations and conclusions of the study and assures that the protocol
and all changes are approved and followed, data are accurately recorded and verified, unforeseen
circumstances are noted, GLPs are followed and raw data, specimens and the final report are
archived at the close of the study. The QAU assures management that the facilities, equipment,
personnel, methods, records, and controls comply with the GLPs. The QAU must be entirely
separate from and independent of the personnel engaged in the direction and conduct of the
study. They are to maintain a copy of the master schedule and study protocols, inspect each
study at adequate intervals and provide status reports to management. The QAU is also to
determine that no deviations from approved protocols or SOPs were made without proper
authorization and documentation; review the final report; and prepare and sign a QA statement
with the dates of inspections, dates when findings were reported to the study director and
management, and their signature/date to incorporate into the final report.
Subpart C describes facilities in general, animal care facilities, animal supply facilities,
facilities that handle test and control articles, laboratory operational areas and facilities that store
data and specimens. Facilities have three main requirements: limited access to buildings and
rooms and be of adequate size and have proper construction. The facility should have a security
SOP and ensure that data and equipment are not lost, altered, damaged, or tampered with. The
facility size and construct should be able to facilitate the proper conduct of studies and have a
22
degree of separation (physical and organizational) to prevent any adverse effect on the study.
There should also be enough animal rooms or areas to assure proper separation of species or test
systems, and quarantine of animals. Animal supply facilities should have storage areas for feed
and bedding that are separate from test system housing and have documented pest control.
Facilities for handling test and control articles should be separate to prevent contamination or
mix-ups. Laboratory areas should have separate spaces for routine and special procedures.
Storage areas include archives with limited controlled access, have a fire suppression system and
be environmentally controlled.
Subpart D speaks to equipment, including specifics on design and maintenance and
calibration. Equipment used for the generation, measurement or assessment of data is to be
tested, calibrated and/or standardized. This includes heating, ventilation, and air conditioning for
environmentally monitored areas, and environmental and stability chambers. There are to be
SOPs to include methods, materials, and schedules for routine inspection, cleaning, maintenance,
and testing and designate a person responsible for the performance of these operations. Records
should include all inspection, maintenance, testing and calibrating and/or standardization
operations. They should contain the date, whether routine or non-routine, the nature of any
defect, how and when it was discovered, and any remedial action taken.
Subpart E describes the operation of a testing facility. This included requirements for
standard operating procedures (SOPs), control of reagents and solutions, and adequate animal
care. SOPs are to contain methods that management is satisfied with and are adequate to ensure
quality and integrity of data. Examples of required SOPs include animal care, test system
observations, test and control article receipt, identification, storage, handling, mixing and
sampling, laboratory tests, necropsy and histopathology, data handling, storage and retrieval,
23
maintenance and calibration of equipment and animal transfer, placement and identification. All
deviations from SOPs shall be authorized by the study director and documented in the raw data.
Historical files of SOPs and revisions must be archived. This section also describes reagents and
solutions that shall be labeled with their identity, titer or concentration, storage conditions and
expiration date. Expired or deteriorated reagents and solutions should not be used. Animal care
is also described in this subpart. Animals should be isolated, and their health status evaluated
and are to be free of disease that might interfere in the study conduct at study initiation. Animals
should be housed separately by species, cages and racks are to be cleaned and sanitized, feed and
water should be analyzed, and adequate pest control measures should be in place.
Subpart F describes test and control article characterization, and handling as well as
mixtures of articles with carriers. Characterization includes ID, strength, purity and composition.
Stability must be determined before study initiation or concomitantly during the study. The
methods of synthesis, fabrication or derivation must be maintained. Marketed products utilized
can be characterized by their labeling. Storage containers should be labeled with name, chemical
abstract number or code number, batch number, expiration date and storage conditions. Reserve
samples of test and control articles are to be maintained if the study is over four weeks in
duration. Preparation documentation must be clear, and the receipt and distribution of each batch
is to be documented. Mixtures of articles with carriers are to be tested to determine the
uniformity of the mixture, the concentration of the test or control article periodically and the
stability of the mix.
Subpart G lists protocol requirements and contains requirements for the conduct of
nonclinical laboratory studies. There is to be an approved written protocol for each study that
contains items such as title, objective, the ID of test and control articles, sponsor name and their
24
approval date, test system, the procedure for ID of the test system, experimental design and
control of bias, dosage level, type and frequency of tests, records to be maintained and study
director’s signature. Any change to the protocol shall be in the form of an amendment and
contain items such as a unique number, the reason for the change, the section being amended, the
new instructions and signatures of the same individuals on the original protocol. The study must
be conducted in accordance with the protocol. Gross findings from necropsy should be available
to the pathologist when reviewing slides of tissues and specimens are to be identified by test
system, study, nature, and date of collection. All data generated during the conduct of the study
is to be recorded directly, promptly, legibly in ink and dated on the date of entry.
Subparts H and I are reserved.
Subpart J contains requirements for reporting the nonclinical study results, storage and
retrieval of records, and their retention requirements. Records must follow good documentation
principles such as signing/initialing and dating data, recording all deviations and reasons for
them, never obliterating original entries, describing statistical and calculation procedures, and
retaining all raw data in the study file. A final report shall be prepared for each study and
contain items such as the name and address of the testing facility, the dates that the study was
initiated and completed, objectives of the protocol, including any changes, statistical methods,
description of the test system, name of the study director and other scientists or professionals
involved in the study along with supervisory personnel, a signed QA statement, signed statement
by the study director, other signed and dated reports, and locations of specimens, data and final
report archival. This subpart also describes storage and retrieval of study records and specimens.
There must be archives for orderly storage and expedient retrieval, an individual is to be
25
identified as responsible for the archives, only authorized personnel shall enter and material in
archives shall be indexed.
Finally, Subpart K describes the disqualification of testing facilities. This section
describes the purpose for disqualification and that it is publicly available through the Freedom of
Information (FOI). The facility can be reinstated if it is proven capable of compliance.
To address the need for an improved inspection program, the FDA, in April 1976, opened
606 FDA positions to perform inspections of the nonclinical labs. This new program, which
became the Bioresearch Monitoring (BIMO) program, was introduced to ensure the quality and
integrity of the data submitted to the agency. It was also to protect the rights and welfare of
human subjects and animals involved in the studies. The focus of BIMO was on nonclinical
studies in animals, clinical investigations, and institutional review board (IRB) functions (FDA,
2023a).
The results of the pilot inspection program conducted in December 1976 of a
representative sample of testing facilities were reported in the OPE Study 42, “Results of the
Nonclinical Toxicology Laboratory Good Laboratory Practices Pilot Compliance Program.”
According to Kirsch, 39 laboratories and 67 studies were inspected by the FDA. These included
23 sponsor sites, 11 contract research facilities and five academic facilities. The FDA utilized a
checklist for the inspections to assess overall laboratory operations and the parts of the proposed
GLP that were applicable to the studies they were reviewing. The results showed that sponsor
sites performed better than contract facilities, which performed better than academia. The results
also indicated that ongoing studies were in better compliance to the proposed GLPs than the
completed ones, which may reflect the impact of the proposed requirements (Kirsch, 1978).
26
2.3 Implementation of GLP
The GLPs intended to assure the quality and integrity of data submitted to the FDA, to
allow for accurate reconstruction of a study, to promote the development of high-quality data and
to assist with the approval of products that are safe. It is a quality system of management
controls that would be utilized by laboratories conducting nonclinical health and environmental
safety studies. They were to help assure reliable study results, were process-oriented, were to
have no interference with lab management or scientific judgment and were to be within the legal
mandate and resources of the FDA (Baldeshwiler, 2003).
2.3.1 Early Days of GLP
Upon enactment of the GLPs, adoption and implementation by industry was well
underway. According to Smith, around 400 corporations were affected by the new regulations.
The agency anticipated that the new regulations would increase the cost of conducting the tests
by a minimum of twenty percent or an average of $150,000. For these reasons, the GLPs were
not well-received (Smith, 1977). Adding to the cost and labor were items such as retaining not
only a lab’s final report but all the corresponding files and records; this required additional
checking, approving, signing, and dating. The need to have a quality assurance unit was also
part of the regulations and would add to the labor-intensive review (Science News, 1979).
At the time of its implementation, in 1979, one requirement of GLP, the retention of test
material, became a particular point of contention between industry and the agency. Industry
complained that there could be large numbers of samples that would need special storage
conditions that would add to cost and space requirements. These samples would also need to be
regularly inventoried, which could be burdensome on staff and problematic to maintain.
27
Nonetheless, industry agreed with the FDA that the regulations would promote more accurate
study results in agency submissions (Science News, 1979).
With GLP regulations in place, the agency now had the ability to evaluate study data in
ways that they were not able to do before. According to Andrade, one way would be by
repeating all the tests/assays conducted during the study to see if the same results could be
obtained. Another would be to recreate, through the data, all the activities that occurred during
the study to see if the same conclusions would be reached. Since repeating the assays was
neither timely nor cost-effective, recreating the studies through documentation was considered
the best option. Rebuilding the study activities and arriving at the same conclusions would give
the regulators trust in the integrity of the data, and, ultimately, in the outcomes of the study
(Andrad et al., 2016).
The original GLPs focused mainly on the resources and processes in a nonclinical
laboratory. These included resources such as organization, personnel, facilities, equipment, test
systems and management responsibilities and processes such as study design, study conduct,
documentation, and quality assurance. Throughout their inception and implementation, industry
continued to have questions surrounding these areas of focus. In response the FDA compiled all
these together with the agency responses in the 1981 Good Laboratory Practice Questions and
Answers (FDA, 1981). According to that document, some of the questions from industry were
regarding Testing Facility Management and the Study Director. Specifically, the questions were:
“Can the study director be the chief executive of a nonclinical laboratory?” and “Is the study
director responsible for adherence to the GLP?” In addition were questions relating to each of
the subpart’s A-G and J as well as the conforming amendments and a general section.
28
Sensing a need for additional direction, in October 1984, the FDA published a proposal to
amend the GLP regulations in the Federal Register 49 FR 43530 (1984) (Appendix C). The
changes (outside of minor administrative and grammatical modifications) were limited to quality
assurance, protocol preparation, test and control article characterization and sample and
specimen retention. The major changes are described below in further detail.
The definitions section (58.3) included changes to the control article to exclude feed and
water that is given to the control group of animals, to the nonclinical laboratory study to allow
for multiple studies of one test article in the same protocol, and modification to the application
for research or marketing permit definition. Section 58.31 testing facility management allowed
documentation of replacement of the study director not to be considered raw data. The study
director section (58.33) removed the “and verified” statement. Section 58.35 quality assurance
unit clarified who can perform quality assurance duties, remove the requirement of final report
disposition on the master schedule, modify the inspection of study phases schedule and remove
the requirement to have all quality records in one location. Section 58.43 animal facility was
modified to clarify the separation requirement and section 58.45 animal supply added clarity on
the preservation of perishable supplies requirement.
The amendment also deleted section 58.53 which talked to administrative and personnel
facilities, the list of SOPs in 58.81(c) and the examples in 58.195(c) of materials to retain.
Section 58.63 allowed the discarding of equipment in lieu of having to repair it. Section 58.90
(animal care) modified the requirements for isolation and health evaluation processes to allow
more flexibility. The test and control article characterization (58.105) section added allotment to
have characterization done at other times rather than before the initiation of a study.
29
58.113 (mixtures of articles with carriers) clarified that stability data only needed to be collected
when necessary to accommodate conditions of use of the mixture.
The protocol section (58.120) clarified that only the sections listed that apply to the study
need to be included and removed requirements for proposed start and completion dates,
justification of the test system, dosing route and reason for its choice and method of absorption
of the test and control article. Section 58.190 now would allow certain specimens to be
discarded after evaluation. And finally, section 58.195 (g) allowed the retention of records as
original or true copies.
According to FDA, there were only 33 respondents to the proposed amendment including
19 from manufacturers, eight from testing or consulting labs, four from professional associations
and two from FDA staff. The majority endorsed the proposal, and some even requested
additional changes. The Final Rule was made effective in September 1987. The revisions,
according to FDA, would lessen the regulatory burden on industry.
2.3.2 Challenges
Despite the efforts of FDA to assist industry, deficiencies of implementation and
compliance in the field continued to suggest problems. For example, the Coulston Foundation
was disqualified by the FDA in 2003 for noncompliance with the GLP regulations. The
disqualification was based on compliance issues that adversely affected the validity of studies.
Although FDA issued two previous warning letters (one in December 1999 and one in October
2001) and a consent agreement (May 2002) the company continued to be noncompliant (FDA,
2003).
The specific areas of noncompliance of the Coulston Foundation included Organization
Personnel (Testing Facility Management, Study Director, Quality Assurance Unit), Testing
30
Facility Operations, Conduct of non-clinical laboratory studies, and Records and Reports
deficiencies. For example, Testing Facility Management failed to assure that corrective actions
were documented, that personnel had documented job descriptions with associated training, and
that a QAU monitored each study. Study directors did not function effectively as a single point
of study control as would be expected; they failed to assure that required study items were
transferred to archives, and that the protocol and any amendments were followed. The QAU
failed to maintain a copy of the master schedule, to assure that final reports were an accurate
documentation of raw data and to assure management that the GLPs were being followed (FDA,
2003).
Further, testing facility operations did not have adequate and current written SOPs to
assure the quality and integrity of data. A nonclinical laboratory investigation discovered that
there was no explanation for changes in automated data entries, the individual responsible for
input was not always identified and the information was sometimes inaccurate. Violations in the
records and reports section had violations of not keeping all raw data and documentation and
failing to prepare a final report for each study. According to the FDA, these deficiencies were so
widespread that the quality and integrity of the studies conducted by the company were affected
(FDA, 2003).
In the subsequent years, the FDA regulated industries continued to find themselves
vulnerable to quality issues as reflected by the number of deficiencies noted during GLP
inspections. The agency classifies their inspections into three categories: NAI (no action
indicated), VAI (voluntary action indicated) and OAI (official action indicated). Both VAI and
OAI are the result of findings being noted during an inspection. Reports of FDA’s Bioresearch
Monitoring (BIMO) program from 2017 to 2021 (including both domestic and international
31
inspections) revealed that 25-54% of GLP inspections resulted in VAI or OAI findings (Table 2).
Common deficiencies found during these inspections include inadequate personnel (including the
Study Director), inadequate documentation/records, inadequate equipment calibration, improper
labeling, lack of monitoring of facilities, inadequate archiving, and standard operating
procedures (FDA, 2023b).
Table 2: BIMO Inspections and Actions
(FDA, 2023b)
Year Number of Inspections Number of Inspections with actions
indicated (VAI or OAI)
2017 34 12 (35%)
2018 56 25 (46%)
2019 54 29 (54%)
2020 33 13 (39%)
2021 16 4 (25%)
Following an inspection, the FDA may issue what is called a “form 483” if findings
require the company to act. If the deficiencies are not rectified to the agency’s satisfaction, a
warning letter can be issued. Common issues noted repeatedly in warning letters include failure
of the quality assurance unit (QAU); lack of equipment inspection, inadequate cleaning and
maintenance processes; poor laboratory practices; lack of appropriate SOPs; lack of retention of
data and specimens; inadequate animal care and SOPs; and poor documentation practices
(Morgan, 2010). These quality issues that have persisted over the years were a key driving force
for the proposed modifications to the GLPs that have been under discussion for over ten years.
2.3.3 Global Landscape
While the FDA GLPs were implemented and utilized within the United States, other
standards were established by international organizations that impacted the industry as it became
32
globalized. One of these standards was ISO 9001 which originated in 1987 by the International
Organization for Standardization (ISO), a non-governmental body composed of national
standards bodies from 167 countries (ISO, n.d.) (www.iso.org/about-us.html). ISO 9001
specifies requirements for a quality management system (QMS) in which companies can become
certified if they demonstrate the ability to provide products and services that meet relevant
requirements.
The most recent version of this standard is ISO 9001:2015. It provides a process-oriented
approach based on the plan-do-check-act methodology. The basis of the requirements is put
forth to document and review the procedures, structure and responsibilities that are required to
attain an effective quality management system. Specific sections of the ISO 9001 standard are:
Context of the organization, Leadership, Planning, Support, Operation, Performance Evaluation
and Improvement (ISO, n.d.) (www.iso.org/about-us.html).
Another international organization that produces standards and requirements is the
Organisation for Economic Co-operation and Development (OECD). The OECD was formed in
1960 to establish standards across various sectors with an initial focus on European member
countries. At their first meeting on research, which took place in 1966, discussion focused on
the unintended presence of pesticides in the environment and prompted a program to examine
chemical safety (OECD, n.d.).
The first high level meeting of the chemicals group was in May 1980 where the topics
included the principles of GLP, test guidelines and criteria for the Mutual Acceptance of Data
(MAD). The MAD agreement allows participating countries to share the results of nonclinical
tests done on chemicals. There are thirty-seven-member countries in the OECD, one of which is
the United States. A set of OECD Council decisions make up the MAD system which includes
33
the OECD Guidelines for the Testing of Chemicals and OECD Principles of Good Laboratory
Practice. The Council decision on establishing procedures to monitor GLP compliance and
international cooperation among monitoring and data-receiving authorities came in 1989
(OECD, n.d.).
These GLP principles govern facilities that perform studies for submission to assess the
health and environmental safety of chemicals and chemical products. These can include
pharmaceutical, pesticide, and cosmetic products as well as veterinary drugs and food additives.
These may also apply to medical devices and other products depending on the jurisdiction. The
OECD principles of GLP consist of a series of approximately 17 guidance documents including
The Application of the OECD Principles of GLP to the Organisation and Management of Multisite Studies, The Role and Responsibilities of the Study Director in GLP Studies, The
Application of the Principles of GLP to Computerised Systems and Quality Assurance and GLP
(OECD, 2005).
As ISO and OECD standards became accepted globally, it became clear that the US GLP
needed to be updated to ensure alignment with them. Some of the high-level differences include
the US GLP is mute on the topic of multisite studies, whereas the OECD has a guidance
document on the topic. Neither the US GLP nor OECD discusses process improvement,
occurrence management or customer service although ISO:9001 does.
2.3.4 Proposed Changes to GLP
The proposed changes to GLP regulations are intended to decrease the quality challenges
described above while allowing a flexible approach to implement a complete quality system and
allow industry to understand the expectations of the FDA. According to the FDA, the resulting
34
expectation is a higher quality study with increased data integrity that the agency can rely upon
for regulatory decisions (Docket FDA-2010-N-0548) (Eitzen, 2017).
To begin, the FDA implemented a GLP working group with Dr. C.T. Viswanathan, now
retired, as the chair. The group consisted of members from all the FDA centers as well as other
agencies like EPA, NIH/OLAW and USDA. The team asked for input from industry and the
individual FDA Centers. In December 2010, an ANPRM requesting information and comments
from industry was published (75 FR 80011, 2010). The advanced notice provided the
opportunity for the public to participate in shaping the proposed rule. There were approximately
90 commenters which included pharmaceutical companies such as Pfizer, AstraZeneca and Teva
as well as associations such as Society of Quality Assurance and the European Union GLP
Working Group, universities such as The University of Texas MD Anderson Cancer Center, as
well as individuals. The areas in which the FDA was requesting comments included
requirements relating to animal welfare, electronic/computerized systems, GLP quality system,
information on QA inspectional findings, multisite studies, process-based systems inspections,
sample storage container retention, sponsor responsibilities and test and control article
information (75 FR 80011, 2010).
On August 24, 2016, a notice of proposed rulemaking was published with considerations
taken from ANPRM comments and consistency with OECD guidance (81 FR 58342, 2016). Per
the NPRM the FDA writes,
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 (21CFR Part 58, 2023).
35
The comment period, which consisted of a ninety-day comment period with a sixty-day
extension, closed on January 21, 2017. There were 78 commenters with multiple comments per
submission (81 FR 58342, 2016) (Appendix A).
Some key highlights of the proposed changes include a requirement for a quality system
approach, including multisite study requirements, consistency with OECD wording, the addition
of animal welfare provisions and a request for comments on including certain Animal Rule
studies to the GLP scope. The FDA took more specified considerations, and more in-depth
requests for comments, for certain proposed changes. These included the addition of certain
Animal Rule studies; the ISO 9001 and GLP Quality System; Animal welfare and the agencies
encouragement of the use of the “3Rs” (reduce, refine, and replace) approach for animal use in
testing where non-animal, scientifically satisfactory methods are appropriate; Multisite studies to
harmonize with OECD standards; and GLP roles and responsibilities to ensure these are
unaltered by the proposed changes in other areas (Docket FDA-2010-N-0548) (Eitzen, 2017).
Further elaboration on these aspects will be provided below.
2.3.4.1 Animal Rule
The Animal Rule allows the FDA to rely on animal studies in lieu of human clinical trials
for evidence of the effectiveness of certain products. The drug products that fall under this rule
are those with which conducting clinical trials would not be feasible. According to 21 CFR
314.600 and 21 CFR 601.90, these products would be for “serious or life-threatening conditions
caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or
nuclear substances.” Companies performing Animal Rule studies have been strongly encouraged
by the FDA to utilize Good Laboratory Practices during study conduct. However, there is
currently no regulatory requirement for industry to adhere to the GLP regulations.
36
The FDA’s Chapter 48 – Bioresearch Monitoring guide entitled Inspection of Nonclinical
Laboratories Conducting Animal Rule-Specific Studies implemented in 2019 states: “The Good
Laboratory Practice (GLP) regulations (21 CFR part 58) were developed as a quality system for
nonclinical safety studies, and, thus, do not address the Animal Rule-specific studies” (FDA,
2019). FDA, however, considers the GLP regulations to be a well-established and relevant
framework (e.g., definitions, procedures, roles and responsibilities, and controls) for ensuring
data quality and integrity in Animal Rule-specific studies. Currently, FDA recommends the use
of the GLP regulations, to the extent practicable, for adequate and well-controlled animal
efficacy studies, and the PK and/or PD studies in animals used to select a dose and regimen in
humans, because these studies serve as the basis for a regulatory action. Qualification of an
animal model through the Animal Model Qualification Program (AMQP) is a regulatory
conclusion. Therefore, FDA also recommends the use of the GLP regulation, to the extent
practicable, for the model-defining natural history studies submitted to the AMQP to support
qualification of an animal model.
The guide goes on to state:
There may be justifiable limitations to conducting these studies using GLP
regulations, especially for those studies requiring high containment facilities
(e.g., biosafety levels 3 and 4 facilities). In such circumstances, sponsors and
requestors should propose methods to ensure data quality and integrity for
aspects of the studies anticipated to be a challenge with regard to the GLP
regulations and seek concurrence from FDA on the proposed plan prior to the
initiation of the studies (21CFR Part 58, 2023).
Therefore, the FDA requested specific comments on this section.
2.3.4.2 Quality Systems
Regarding ISO 9001 and the GLP quality system, the FDA had previously received
comments on the ANPRM regarding the generality of ISO and how not all the provisions apply
37
to GLP. However, the aspects of ISO being proposed are consistent with 21 CFR Part 820
quality system regulations for current good manufacturing practices for medical devices to
promote a broader application of a quality system approach. Comments also suggested that
consistency with ISO could be attained if the present flexibility of the GLP was maintained. The
proposed changes were consistent with OECD guidance documents to the extent possible.
Therefore, the FDA also requested specific comments here (Docket FDA-2010-N-0548) (Eitzen,
2017).
2.3.4.3 Animal Welfare
Comments received in response to the ANPRM included concerns related to animal
welfare. Section 58.90 of the current GLP regulations speaks to animal care, but the Animal
Welfare Act and public perception of animal welfare has changed since the GLPs were enacted.
The proposed changes require specific responsibilities for animal welfare to preserve the quality
and integrity of nonclinical studies. Additionally, there is an emphasis on utilizing non-animal
testing methods whenever feasible. This aligns with Docket No. FDA-2007-P-0109 which
reflects the FDA’s response to the Mandatory Alternatives Petition Coalition’s request for
scientifically applicable, non-animal test methods instead of animal testing. Therefore, the FDA
requested specific comments here (81 FR 58342, 2016).
2.3.4.4 Multisite Studies and Roles and Responsibilities
Regarding multisite studies, the feedback received in response to the 2010 ANPRM
indicated a desire for alignment with OECD guidance titled, The Application of the OECD
Principles of GLP to the Organisation and Management of Multi-Site Studies (Ref. 6). However,
some suggested that the additional guidelines should be less rigid than the OECD document.
Consequently, the FDA specifically requested input on this matter (81 FR 58342, 2016).
38
The request for comments on GLP roles and responsibilities was initiated by the FDA to
ensure that management, the study director, and the QAU roles continue to complement each
other effectively while remaining flexible enough to facilitate nonclinical studies. It is important
to note that the intent was not to undermine these roles (81 FR 58342, 2016).
2.3.5 Proposed Regulations
The comments from stakeholders helped to shape the proposed changes to each of the
following sections: 58.1 (Scope), 58.3 (Definitions), 58.5 (Sponsor Responsibilities), 58.15
(Inspections), 58.31 (Testing Facility Management with Executive Responsibility), 58.33 (Study
Director), 58.35 (Quality Assurance Unit), 58.37 (Contributing Scientist), 58.39 (Principal
Investigator), 58.105 (Test, Control, and Reference Article Characterization), 58.130 (Conduct of
a Nonclinical Laboratory Study), 58.180 (Data Quality and Integrity), 58. 185 (Reporting of
Nonclinical Laboratory Study Results), 58.190 (Storage and Retrieval of Records and Data). See
Appendix A for 81 FR 58342.
Changes to these sections, once implemented, would allow nonclinical studies to be
conducted under a complete quality system aimed at improving compliance and accountability.
The proposal would also serve to align the FDA GLP regulations to other quality entities such as
OECD GLP and ISO. Some of these proposed changes could have a profound impact on
industry and how they currently operate. Other proposed changes are considered more
administrative in nature or having a smaller, less substantial impact, including definitions (58.3),
personnel (58.29), transfer of responsibilities (58.10), and mixtures of articles with carriers
(58.113) sections. For example, the proposal adds the words “or retention” to the end of the
definition of specimen to include specimens collected just for retention purposes. Another
example is the proposed modification to 58.113 that added a requirement that the results of the
39
analyses of the mixtures of test articles with carriers are provided to the study director as soon as
available (81 FR 58342, 2016).
One of the more impactful proposed changes included in the 2016 NPRM was the
inclusion of new types of studies under the section on scope (58.1), which are currently not
covered by GLP regulations. This would expand the GLP scope to include tobacco studies
currently under sections 905, 910 and 911 of the FD&C Act, toxicity studies and an expansion of
the device coverage to include device studies governed by the Center for Veterinary Medicine
(CVM). These would now need to comply with GLP. This section would also specify that the
regulations would govern studies that are for any application or submission, not just for research
or marketing and those that are intended to support an application or submission. For example, it
would include applications and submissions for tobacco products and the medical device
premarket notification (510(k)) submissions (81 FR 58342, 2016).
This section also contains the addition of Animal Rule studies, which as discussed
previously are currently exempt, and would require certain specific Animal Rule studies to be
compliant with GLP. The studies included are adequate and well-controlled animal efficacy
studies, PK and/or PD studies used to select a dose in humans and model-defining natural-history
studies if they are being used for the Animal Model Qualification Program. These expansions of
scope would increase the number and type of studies that would be governed by the regulations.
It would require compliance for companies that did not have to comply with GLP in the past (81
FR 58342, 2016).
Another large area of potential impact would be the addition of multi-site sections which
are currently not covered by current regulations. This adds the specific requirements for a study
that has phases at more than one site, the site at which the phase is conducted and the person that
40
is delegated responsibility for those phases (81 FR 58342, 2016). These additions are added to
align with OECD standards. Currently, industry is left to implement what they think is best
using SOPs based off OECD guidance, The Application of the OECD Principles of GLP to the
Organisation and Management of Multi-Site Studies (Ref 13) or not addressing them at all.
Globalization in recent years has increased the need for these types of requirements to maintain
the quality and integrity of multi-site studies. Sections proposed that speak to multisite studies
include Lead QA (58.35) which would be at the Testing Facility, Test Site (58.3), Test Site
Management with Executive Responsibility (58.32), PI (58.39), and Multisite Study (58.3). This
adds the specific requirements for a study that has phases at more than one site, the site at which
the phase is conducted and the person that is delegated responsibility for those phases (81 FR
58342, 2016).
More specifically, test site management would be required to comply with the applicable
requirements set forth for testing facility management as well as maintaining the relevant SOPs
required within that section of the regulations. The PI at the test site would be required to
comply with GLP regulations for their delegated portion of the study, including the requirement
for a QAU and report all deviations to the SD. The Lead QA, located at the testing facility, will
now have the responsibility to not only audit the portion of the study conducted at the testing
facility, but also audit all contributing scientist and PI reports in addition to the final report to
ensure that the data is reported and reflects the protocol and applicable SOPs. Current regulation
does not require the Lead QA to audit the test site-generated reports as the test site QA is
responsible for that. A separate, but related addition to the regulations will allow the FDA to
inspect all QAU records when necessary to ensure compliance. As of today, QA records are out
of scope of FDA inspections (81 FR 58342, 2016).
41
Other areas of potential impact such as Testing Facility Management with Executive
Responsibility (58.31) were added to be consistent with the ISO 9001 definition. With this
addition, management responsibilities have been expanded to Test Sites as we described above,
as well as at the testing facility. Testing Facility Management would be ultimately responsible
for the GLP quality system, which defines the framework for building quality into the study
process while still allowing a flexible approach. This includes a Quality Policy and establishing
objectives for the quality system and essential SOPs. Testing Facility Management would also
be required to perform other functions. For example, they would need to appoint a management
representative to review and document that the quality system requirements are maintained and
appoint a person to maintain the master schedule. Management must also ensure that all
personnel are trained and follow equipment-related SOPs at all sites. The protocol is to be
reviewed by management, with the review documented, to ensure there are no issues that could
affect or bias the conduct of the study. Management is to review the function and processes of
the QAU and designate a Lead QAU. They are also to establish SOPs for archival activities,
which include the assignment and replacement of the archivist and the archivists’ staff (81 FR
58342, 2016).
The Attending Veterinarian (AV) requirements (58.3 and 58.90) are new as well and
could impact how the study is conducted and documented. The current GLP regulations do not
mention veterinarians or attending veterinarians. The AV definition would be the same as is in
USDA Animal Welfare Regulations (9 CFR 1.1, 2012) only without specifics around education
requirements. There is an additional requirement to conduct periodic animal health status reports
and the IACUC (of which the veterinarian is a member of) must review and approve the animal
sections of the protocol and any applicable amendments. The Study Director (SD) would now
42
also need to defer to the AV regarding animal welfare decisions, especially if an animal is in pain
or distress. This is a new paradigm for the conduct of the study as currently, the SD has the final
say, in consultation with the AV, in these matters (81 FR 58342, 2016).
Other small changes that could have a large potential impact include a change of the
definition (58.3) of raw data to include the signed/dated pathology report and exact copies of
data made per certified copy procedures as well as correspondence and other documentation
regardless of capture medium. This will include the retention/archival and documentation
requirements surrounding raw data for exact copies and correspondence as well as require a SOP
on certified copy procedures. Data integrity (58.180) is a newly added section which plays a part
in adding additional documentation requirements including ALCOA and electronic records
systems must be Part 11 compliant. The term validation (58.3) has been added and defined, to
include a requirement for objective evidence and requirements for the intended use of a system
or process to be confirmed. Similarly, the equipment section (58.61) was expanded to state that
equipment includes computerized systems and adds to that equipment used for maintenance,
archiving, and retrieval of data. These pieces of equipment are currently not in scope and
computerized systems are not currently considered equipment (81 FR 58342, 2016).
The new additions and modifications described above could increase the number of SOPs
needed, subsequent documentation and the number of documents to be retained. However, there
were also some changes that could have potential benefits including a reduced workload and
immediate efficiencies. One of these is the need for QA (58.35) to only have access to, either
electronically or paper, the master schedule, and protocols/amendments. This will decrease the
documentation retained as currently QA must maintain an additional electronic or paper copy of
the master schedule and each protocol/amendment that must be retained. Another potential
43
benefit to QA is the ability to separate inspections into facility-based, study-based, and processbased to be consistent with OECD. This addition could decrease duplication in inspections with
the ability to utilize a combination of study and process-based inspections to accommodate short
term studies.
Saving facility space could be another benefit by the proposed removal of the
requirement to retain empty test article (TA) containers. Currently, facilities must retain empty
TA containers through the end of the study they were used on. The proposal would remove that
requirement and allow the disposal of the containers earlier, saving space and labor. The only
additional requirement would be that the SD would verify and document the distribution and
final distribution of the TA.
However, even with the potential benefits and efficiencies, the potential drawback of the
potentially impactful additions and/or modifications could be high in that there may be an
increase in cost and labor while the implementation is conducted and for maintenance and
continuance thereafter. The FDA needed to seek Office of Management and Budget approval for
the information collection provisions of their proposal. One example, according to the OMB, is
that the changes needed for reporting and recordkeeping may increase costs. In their supporting
statement, the FDA iterated how important the reports and data they receive are in making
difficult decisions on safety and toxicity of products. FDA further noted that approximately 90%
of the information will be electronic in nature. Therefore, the need to ensure the quality and
integrity of present technology, thereby reducing paper records, is necessary (OMB, n.d.).
The FDA did not see any significant difference in the burden posed for small vs. large
companies and estimated an annual reporting cost of the proposed rule across all entities of $5.8
million. These costs would mostly be covered by sponsors funding the studies. The annual cost
44
estimate for the recordkeeping was $27.6 million, again, mainly paid by sponsors (OMB, n.d.).
These estimates, however, do not reflect operational costs such as time and resources.
2.4 Responses from Industry on the Proposed Revisions
Two of the biggest and most influential respondents from industry to the proposed new
regulations were The Society of Quality Assurance (SQA) and the Pharmaceutical Research and
Manufacturers of America (PhRMA). Each organization convened a working group to submit
comments to the FDA. While some items were agreed upon by the two organizations, there were
other items where their opinions differed.
There were five comments provided by the PhRMA. These included a request to add a
definition of the role of a PI for multisite studies as the current regulations do not define this.
Another request was to only require QA to have access to the master schedule as the current
regulations require QA to maintain the master schedule and it may be more appropriate for
another business area to maintain it. It was requested that the requirement for separate signed
contributing scientist reports be removed in favor of an integral final report signed by all
contributors. Currently the requirement is that each report is signed by the scientist and appended
to the final report (Rumsey, 2017).
Additionally, a request was made to only require having a GMP certificate of analysis for
test article characterization for a GLP study. Currently, characterization is required in the GLP
and therefore is required to be conducted to GLP not GMP. The argument by PhRMA is that
industry is more aligned to conduct characterization to GMP requirements. Finally, the request to
remove the requirement for a final study report for compounds terminated prior to IND and not
submitted to the FDA was made. PhRMA argues that because the compound was terminated,
generating a final report is not necessary and instead allow a protocol amendment to be
45
generated which states why the study is terminated along with archival of the data (Rumsey,
2017).
The Society of Quality Assurance comments were a bit more direct. They stated in a
memo to the FDA that they believed the proposed regulations not only would increase costs and
create a larger burden on industry which would in turn create less consistency between
laboratories, but that they also clouded the currently defined roles and responsibilities of the
sponsor, study director, QAU, testing facility management instead of making them clearer. They
went on to say that accountability for pieces of a study is unclear in the proposed rule,
specifically the contributing scientist vs. a PI and does not allow the study to be performed by the
study director and testing facility management (Eitzen, 2017).
SQA did agree, however, that the current regulations should undergo a review to
minimally modernize the language. They also discussed key concerns around specific sections of
the proposed rule. One of these was on the animal rule/animal care. They suggested the Animal
Rule studies be conducted under their own regulations and that the animal care section blurs the
responsibilities of the study director/management with the attending veterinarian/Institutional
Animal Care and Use Committee (Eitzen, 2017).
Another concern was around the conflict with OECD in scope as the OECD GLP were
developed to govern environmental chemicals and not pharmaceuticals/devices. These have
been commonly included in OECD countries however, as the regulatory bodies are the same, but
SQA argues, it may not be the appropriate model for the United States FDA-governed studies.
SQA also had concerns about multisite study requirement additions that will not add value and
could add complexity instead. SQA also believes the new definition of a quality system
diminishes the single point of control being the study director by placing other people in
46
equivalent or superior roles involving study control. Another area discussed was archival. The
additional requirement to notify FDA when archived materials are moved would require
additional record-keeping and reporting when the current process of tracking materials within the
facility/site is enough (Ault, 2011).
An additional area of concern for SQA was the separation of QA inspections into
facility-based inspections, process-based and study-based inspections. SQA stated this adds
complexity as the current regulations are flexible enough to allow QA to determine the type of
audit/inspection to perform. SQA goes on to state that tracking of draft reports would not be
enforceable by the FDA. This is due to the inability to tell at what point a final draft is a final
draft. To define this, track it and archive them all would add unnecessary burden and the study
director’s signature on the final report should be maintained. Finally, the modification to the
testing facility definition to remove it from being the location where the test article is
administered to the test system, will have implications on the quality of the study. The new
definition could allow anyone, such as a sponsor, to state they are the testing facility and have
their QA oversee the study, when in fact they are not part of the conduct of the study. (Eitzen,
2017)).
SQA did agree with PhRMA that PI role needed to be defined, and that QA should only
need access to the master schedule. They also added that QA should only need access to
protocols as well instead of retaining a copy. SQA disagreed with PhRMA in that they support
having individual contributing scientist reports to maintain clarity on who is saying what within
the report. The society also agreed with PhRMA in supporting GMP characterization testing but
added that the extent of and who performs the testing should be defined. The society also
recommended removing the requirement for retention of empty TA containers and the
47
requirement for a final report for studies terminated prior to IND and not used in submissions.
SQA also suggested utilizing guidance documents for FDA’s current expectations for some
activities (Rumsey, 2017). Ultimately, SQA recommended withdrawing the proposed rule as
they believe it would be counterproductive to the perceived goal of increased data integrity and
quality (Eitzen, 2017)).
2.4.1 Other Responses from Industry
Comments on the proposed rule were also received from businesses within the industry.
These included sponsor organizations, contract research organizations and individuals working
within the industry. In reviewing the comments, certain themes emerged. While many agreed
that revisions to the GLPs are needed to modernize the requirements, they also stated that they
may cause unnecessary burdens and costs. For example, Merck Pharmaceuticals stated in their
response letter dated January 21, 2017:
We are concerned that, as written the proposed requirements place unnecessary
burdens on industry by introducing redundancies and administrative steps that do
not contribute to data quality or integrity. Further, we suspect that the time and
cost estimates outlined in the docket are underestimated and do not reflect the
true economic impact of the proposed changes. (Mahoney, 2017)
Another theme that emerged was the thought that while very important, animal welfare is
already covered by the USDA regulations and adding this to the GLPs would be redundant. As
stated by Animal Preclinical Services (APS), “APS agrees that animal welfare is an important
and critical element of study conduct. APS believes USDA has clear statutory authority in this
area.” Zoetis, a global animal health company, commented in their response dated January 19,
2017, that, “Incorporating animal care and use and animal welfare requirements into the
proposed rule is not necessary as these already exist outside of the GLP regulations.”
48
A third theme that emerged was related to the multi-site study requirements. These
additions are generally welcomed because the industry has been conducting GLP work in
multiple sites, sometimes, across the globe. Takeda Pharmaceuticals stated in their response
letter dated January 19, 2017, “We agree with the proposed changes as they are consistent with
the OECD consensus document and aligned with global industry.” However, some revisions
were thought to be excessive. Sanofi, a leading immunology healthcare company, in their
response letter dated January 19, 2017, stated, “Although the current proposal includes some
harmonization of definitions with the current OECD GLPs, many definitions have been added
that are not consistent globally and may affect compliance in terms of global, multisite studies.”
2.5 Research Direction and Framework
The literature review presented above described the current and proposed state of the
GLP regulations and how they came to be. The changes have come under scrutiny by several
organizations who have provided formal feedback through written comments to the FDA.
However, these comments give limited insight into how the anticipated changes are being
viewed by the individual companies themselves. This study used the adoption and
implementation framework combined with the customer service framework to evaluate industry
views associated with adopting the proposed revisions of GLP. In identifying these
observations, it will help the industry understand and evaluate any potential shortcomings
perceived in the implementation.
As my interest lies in the views of industry on potential adoption and implementation of
the proposed revisions to the GLPs, one appropriate approach to frame the research came from
the field of implementation science. A recognized developer of an accepted implementation
framework is Fixsen. His construct consisted of four stages of implementation: exploration and
49
adoption, installation, initial implementation, and full implementation (Table 3). The entirety of
the process can take up to four years or in as little as two years to complete (Fixsen et al., 2009).
Industry is predicted currently to be in Stage 1 of exploration and adoption. This study looked at
how well industry and the FDA have explored the new proposals and how the adoption of these
would change industry’s current practices.
Table 3: Stages of Implementation
Stage Description
1 – Exploration and Adoption
This is the stage we are at with the proposed changes to
the GLP.
The need for change has been defined. We examined
intervention components and implementation drivers.
Companies now are educating themselves about the
upcoming potential changes and assessing gaps between
current practices and the proposed changes.
2 – Installation In this stage, resources and partnerships are put into
place. Roles and responsibilities are identified and
established. The organization and staff are prepared for
the changes.
3 – Initial Implementation The first use of innovation is based on the lessons
learned and solutions from the first two stages. The
changes are managed, and new systems and
improvements are initiated.
4 – Full Implementation This is the final stage where industry finalizes its
practices, and the team can evaluate the new practices
and ensure sustainable progress and compliance to the
new requirements.
Another appropriate approach, which was partially utilized and woven in to frame this
research came from the customer service framework. Andaleeb published a paper in 1998
utilizing a set of principles in determining customer satisfaction in the healthcare delivery
industry where satisfaction was assessed relative to a patient’s experience (Andaleeb, 1998).
The framework that resulted contained variables and language used by patients to express their
level of satisfaction and that could be acted upon by industry. There were five constructs;
Increased perceived quality of communication equates to higher satisfaction, increased perceived
50
competence equates to higher satisfaction, increased perceived quality of facilities equates to
higher satisfaction, better staff demeanor equates to higher satisfaction, perception of higher
costs equates to lower satisfaction (Andaleeb, 1998).
Three of these five areas were utilized in a survey of industry on their satisfaction with
the revision process utilized by the FDA. One was the perceived quality of communication
which can assess how well FDA has communicated their process and content of the proposed
rule to industry. Collaboration perception on the part of industry was also assessed under the
quality of communication. Another construct was the competence of the agency. This assessed
if, in the industry’s view, the FDA understood their needs and can integrate them into
requirements and regulations. Lastly, the costs of implementation of the proposed changes were
explored. This assessed industry’s perception of the cost of establishing programs to meet the
new requirements and maintenance of the programs after implementation.
These frameworks were used to provide a basis for the survey development. The survey
discussed in the next chapter collected industry views on adopting the proposed revisions of
GLP. It also looked to identify any perceived barriers to the implementation of the proposed
revisions and their views on the process.
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Chapter 3. Methodology
3.1 Introduction
This research study explored views of stakeholders in the U.S. pharmaceutical industry
regarding the current GLPs and implementation of the proposed GLP revisions purported to
improve study conduct and data quality and integrity. It also looked to understand the views of
industry on the satisfaction of the FDA’s process of revision. An interactive focus group was
used to guide the development of the self-administered online survey. The participants consisted
of research professionals conducting work in the U.S. GLP nonclinical space.
3.2 Identification of Survey Participants
Participants were selected based on predefined criteria which included current or past
employment in the U.S. pharmaceutical industry in areas relevant to the performance, oversight,
or auditing of GLP studies. Respondents were drawn from pharmaceutical companies
sponsoring or carrying out such studies, contract research organizations specializing in GLP
studies, and consultants who advise on or support GLP studies. Many of these individuals were
members of professional societies such as Society of Toxicology (SOT), the Roundtable of
Toxicology Consultants, SQA and their specialty sections. Using a Google search, a list of
companies across the U.S. that participate in this type of research was identified. An effort was
made to identify participants in all areas of the U.S. The author also reached out to the
leadership of the professional societies to ask that their applicable members participate as well.
The survey was available to participants for approximately five months. Each participant
received a link to the survey accompanied by a short message introducing the survey and
describing its purpose. The survey was completely anonymous, and no compensation was
provided.
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3.3 Development of Survey
A self-administered online survey was developed utilizing Qualtrics
(https://www.qualtrics.com/). It included 36 questions covering the five topic areas based on the
frameworks chosen (Table 4). The final survey is provided in Appendix D.
Table 4: Survey Categories Informed by the Implementation and Customer Service
Frameworks
No. Question Category
1 Demographics
2 Exploration and Adoption
3 Quality of Communication
4 Competence
5 Cost of implementation
Once the initial questions were generated, they were validated through a focus group.
This group consisted of individuals from industry, academia, and professional organizations.
This group evaluated the questions on adequacy, clarity and the structure and provided
recommendations as necessary. The list of participants is presented in Table 5.
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Table 5: List of Participants in the Focus Group
No. Name of Participants Description of Participant Professional Background
1 Mary Ellen Cosenza, PhD, DABT, ATS,
ERT, RAC
Regulatory Toxicology Consultant; Adjunct Professor,
University of Southern California School of Pharmacy
2 Frances J. Richmond, PhD Director, D K Kim International Center for Regulatory
Science, University of Southern California
3 Susan Bain, DRSc Professor, Quality and Compliance Professional
4 Eunjoo Huisung Pacifici, PharmD Chair and Associate Professor, Department of Regulatory
and Quality Sciences at USC Alfred E. Mann School of
Pharmacy and Pharmaceutical Sciences
5 Barry Francis, RQAP-GLP, RQAP-GCP Quality Assurance Professional in GLP and GCP.
6 Debi Garvin, MS, RQAP-GLP Quality Assurance Professional in GLP and GCP.
Prior to the meeting, all participants were provided an electronic copy of the Abstract and
Chapter 1 used in support of the Qualifying Exam, and a copy of the sample online survey
instrument. They were provided with instructions to attend the meeting via video conferencing,
and the proceedings were recorded with the consent of participants.
The focus group was convened on October 30, 2023. The author served as the moderator
for the meeting. The author provided a brief overview describing the expectations, including the
meeting to last approximately 60 minutes. Each question in the survey questionnaire was then
reviewed sequentially and debated as needed. The author then requested any remaining
additional feedback, and the survey was updated as needed.
After the survey questions were finalized, they were input into the Qualtrics software.
The survey was then deployed on November 28, 2023. Direct emails were sent to 35 participants
and posted to LinkedIn on December 9, 2023. On February 5, 2024, the survey was posted to
the Roundtable of Toxicology Consultants blog and the leadership of American College of
54
Toxicology (ACT) and Society of Toxicology (SOT) were sent a request to provide the survey to
their members. The survey was also posted to the SQA RQAP-GLP and GLP specialty sections
discussion boards. The survey closed on April 28, 2024.
The questions along with the results are stored electronically within Qualtrics. The
results were analyzed to identify trends and correlations. Open text and comment fields were
qualitatively analyzed to identify patterns and common elements. The Qualtrics software
provided percentages based on the response output and displayed them graphically.
55
Chapter 4. Results
4.1 Survey Logistics
The survey was published on November 28, 2023, and closed on April 28,2024. During
this time direct emails were sent to 35 recipients who were also encouraged to invite their
colleagues to complete the survey. The survey was posted on social media LinkedIn to allow me
to share the survey publicly in December 2023. In February 2024 the survey was posted to the
Roundtable of Toxicology Consultants. The author also sent emails to ACT and SOT leadership
asking them to provide the survey to their members. Also, during this time, the survey was
posted to the discussion boards of the SQA GLP specialty section and the SQA RQAP-GLP
specialty section. From these avenues, there were 132 total respondents. One respondent
discontinued after answering “none” to question number two, “What is your level of familiarity
with the proposed revised GLP regulations?”. Survey question number two used skip logic
methodology, designed to eliminate respondents who did not have the GLP knowledge to
participate and sent them to the end of the survey.
In summary, the total number of completed and partially completed surveys was 132.
Since not all questions were answered by all participants, the number of responses for each
question is provided.
4.2 Demographics
The survey obtained demographic data regarding respondents, the organization the
respondents represented, and the experience of the respondents and their organization with GLP.
4.2.1 Respondent Demographics
The respondents were asked to rank their level of familiarity with the proposed revised
GLP regulations. Respondents answered “High” (18%, 19/107), “Medium” (50%, 53/107), and
56
“Low” (32%, 34/107). One respondent answered “None” (Figure 2). Using the “skip logic”
capability of Qualtrics survey software, the survey ended for the respondent who answered
“None”.
Figure 2: Distribution of Self-identified Level of Knowledge Regarding GLP (N=107)
(Q2 – What is your level of familiarity with the proposed revised GLP regulations?)
Respondents were also asked how many years of personal experience they had working
in the GLP field. Over half of the respondents had greater than 20 years of experience (54/100),
followed by 11 to 20 years of experience (28/100), five to 10 years of experience (13/100), and
less than five years of experience (5/100) (Figure 3).
Figure 3: Distribution of Years of GLP Experience (N=100)
(Q8 – How many years of personal experience do you have working in the GLP field?)
4.2.2 Company Demographics
The type of organization with which respondents were affiliated was identified as either a
contract research organization/GLP testing facility (36/100 or 36%), a
pharmaceutical/biotechnology company with (12/100 or 12%) and without (10/100 or 10%) GLP
None [1%, 1]
High [18%, 19]
Medium [50%, 53]
Low [32%, 34]
5
13
28
Less than 5 years
5-10 years
11-20 years
Greater than 20 years 54
57
labs, consulting company (30/100 or 30%), a medical device company with (1/100 or 1%) and
without (1/100 or 1%) GLP labs or other (10/100or 10%) (Figure 4).
Figure 4: Distribution of Type of Company (N=100)
(Q3 – Which of the following best describes your organization?)
Respondents were asked to provide their organization type if “other” was chosen. Ten
respondents chose “other”, of whom nine provided additional information. Comments are shown
below:
Academia/National Laboratory
AgChem with GLP Labs
CRO/GLP Test Site
Freelance GLP Consultant
Independent Consultant
Rather not say
Regulatory NQCL
University Veterinary Diagnostic lab with certain GLP capable labs
No comment
36
30
20
10
0
Contract
Research
Organization/
GLP Testing
Facility
Pharma/
Biotech with
GLP lab
Pharma/
Biotech
without GLP
lab
Consulting
Company
Medical
Device
Company
with GLP
lab
Medical
Device
Company
without
GLP lab
Other
30
12 10 10
1 1
58
The organization’s size was gauged by the number of employees. Choices included less
than 100 (55/100 or 55%), between 100 and 1000 (20/100 or 20%), between 1001 and 10000
(14/100 or 14%), or more than 10000 (11/100 or 11%) employees (Figure 5).
Figure 5: Distribution of Organization Size (N=100)
(Q4 – What is the size of your company based on the number of employees?)
A series of related questions were used to evaluate the organization further. These
included the length of time the organization had been in business, whether the organization had
laboratories in the U.S. or outside of the U.S., the biosafety level of the laboratory used by the
organization and the standards and regulations the organization complied with. The length of
time the organizations were in business ranged from less than five years (10/100), between five
and 10 years (8/100), between 10 and 15 years (16/100), greater than 15 years (65/100) and a
choice of “do not know” (1/100) (Figure 6).
Figure 6: Distribution of Years in Business (N=100)
(Q5 – How long has your organization been in business?)
1001-10000 [14]
100-1000 [20]
Less than 100 employees [55]
More than 10000 [11]
Less than 5 years [10%, 10]
5-10 years [8%, 8]
10-15 years [16%, 16]
Do not know [1%, 1]
More than 15 years [65%, 65]
59
The next two questions asked were if they had laboratories in the U.S or outside the U.S.
If they had laboratories outside the U.S., the respondents were asked to list the countries where
the laboratories were located. Of 73 respondents, 66% had laboratories in the U.S. and 34% did
not have laboratories in the U.S. (Figure 7). In contrast, respondents stated that 61% did not have
laboratories outside of the U.S. and 39% did have laboratories outside the U.S. (Figure 8).
Figure 7: Distribution of Laboratories in the U.S. (N=73)
(Q6 – Do you have laboratories in the United States?)
Figure 8: Distribution of Laboratories Outside the U.S. (N=70)
(Q7 – Do you have laboratories outside the United States? If so, please list the countries)
Of the 27 respondents who stated that they did have laboratories outside the U.S., 25
entered additional text on the location of the laboratories. Comments are shown below:
All countries unknown. I only support our US labs.
Australia, Germany
Canada
Canada, Europe, others
Croatia
Europe
Europe and Asia
No [34%, 25]
Yes [66%, 48]
Yes [39%, 27]
No [61%, 43]
60
France
Germany
Germany
Germany
INDIA
India
Netherlands, Germany
St. Kitts
Taiwan
Taiwan
UK
UK
UK, several EU countries
Unsure exact locations
We are a Sponsor who contracts lab facilities to perform studies
Worldwide
Germany
Germany
A question was then asked about what type of laboratory was used to conduct the GLP
studies. Out of 100 respondents, over half (59/100 or 59%) indicated they utilized BSL 1 labs.
This was followed by BSL 2 lab (35/100 or 35%), “not applicable” (32/100 or 32%), BSL 3 lab
(8/100 or 8%) and BSL 4 lab (3/100 or 3%) (Figure 9).
Figure 9: Distribution of Laboratory Types (N=100)
(Q9 – What type of laboratory are you using to conduct GLP studies? Please check all
that apply.)
59
35 32
8
3
BSL 1 (Tox in-vitro
labs, Bioanalytical
labs, etc.)
BSL 2 BSL 3 BSL 4 Not Applicable
61
The final question in the demographics section was regarding the standards or regulations
with which the organization complied. The majority complied with FDA GLP (89/99, 89%),
followed by OECD GLP (49/99, 49%), EPA GLP (26/99, 26%) and ISO (21/99, 21%). Nine
respondents indicated that their organization followed “other” standards or regulations.
(Figure 10).
Figure 10: Standards or Regulations Used (N=99)
(Q10 – What standards or regulations does your company comply with? Please check all
that apply.)
Of the nine respondents that chose “other”, seven wrote in text describing the standards
or regulations they utilized at their organization. Comments are shown below:
USDA
ICH E6 R2
WHO
We also cover GCP and GMP
Taiwan FDA GLP
GCP and GMP
FDA Animal Rule
4.3 Exploration and Adoption
The questions in this section of the survey revolved around the proposed revisions to the
GLP regulations and FDA inspections. The first question asked if the respondent’s company had
been inspected by the FDA for GLP studies. Out of 97 responses, 46 (47%) had been inspected,
OECD GLP 49(49%)
ISO 21(21%)
FDA GLP 89(89%)
EPA GLP 26(26%)
Other 9(9%)
62
48 (49%) had not been inspected and 3 (3%) did not know if they had been inspected or not
(Figure 11).
Figure 11: Company Inspection Distribution (N=97)
(Q11 – Has your company been inspected by the FDA for GLP studies?)
The next question followed the inspection premise and asked respondents to identify the
most recent date of FDA inspection. Using the “skip logic” capability of Qualtrics survey
software, this survey question was skipped for the respondents who answered “No” or “Do not
know” to the previous Question 11.
Of 44 responses, most (36/44, 81%) stated that they had been inspected after 2016,
followed by those who were inspected between 2010 and 2016 (5/44, 11%), and those who were
inspected prior to 2010 (3/44, 6%) (Figure 12).
Figure 12: Dates of Inspection (N=44)
(Q12 – What was the most recent date of FDA inspection?)
Do not know [3%, 3]
Yes [47%, 46]
No [49%, 48]
36(81%)
3(6%) 5(11%)
Prior to 2010 Between 2010 and 2016 After 2016
63
The next series of questions in the section referred to the proposed revisions to the GLP
regulations. The first question asked respondents if they thought the proposed revisions should
be accepted as is, revised and then adopted, or rejected. There were 82 responses. Most
respondents believed that they should be revised and then adopted (68/82, 82%) followed by
adopted as is (9/82, 10%) and then rejected (5/82, 6%) (Figure 13).
Figure 13: Distribution of the Proposed Revisions (N=82)
(Q13 – Do you think the proposed revised GLP regulations should be:)
The next question expanded on the revised and adopted responses from the previous
question and asked which sections should be revised. Using the “skip logic” capability of
Qualtrics survey software, this survey question was skipped for the respondents who answered
“Adopted as is” or “Rejected” to the previous Question 13.
Of the 26 responses, the majority chose the GLP quality system (21/26, 80%), followed
by multisite studies (17/26, 65%), sponsor responsibilities (14/26, 53%), animal welfare and test
and control article with each having (12/26, 46%), and “other” (5/26, 19%) (Figure 14).
68
9 5
Adopted as is Revised and Adopted Rejected
64
Figure 14: Distribution of Sections to be Revised (N=26)
(Q14 – If revised and adopted was selected, which sections do you think should be
revised? Select all that apply. Please elaborate in the comment fields provided.)
There were 16 comments added within the comment fields. Comments are shown below
per category above:
GLP quality system (3) – No revisions; Addition of an additional person to the quality system
requires us to hire another person. We highly reject this aspect as it would cause undue harm
to our company; More balance to current industry practices.
Multisite studies (4) – No revisions; Clarify what some things mean in practical terms; More
balance to current industry practices; Particularly as there has been extensive high level
consolidation of CROs, ensuring that no one CRO site can perform all the aspects of a
complex study, there needs to be a change so that there is true oversite of QA/GLP aspects for
a study is coordinated central QAU "study team leader".
Sponsor responsibilities (2) – Clarify; More balance to current industry practices.
Animal welfare (4) – No revision; Seems redundant to other requirements; Belongs with
USDA; This is going to be hard, with multiple regulatory bodies within countries and multiple
countries, AND the need to protect human patient populations and yet make progress in
accordance with the 3/4 Rs with wishful thinking as to the acceptance of computer, in silico
and in vitro test systems.
Test and Control article information (1) – No revision.
Other (2) - QAU - lead QAU and oversite of sites in multisite studies; Certain definitions do
not seem necessary, for example, "Management with Executive Responsibility".
The next question concerned the current GLP regulations and asked which they thought
were most difficult to implement. Of 41 responses, most stated that Test article/Control article
was the most difficult (20/41, 48%), followed by “other” (7/41, 17%), Personnel/management
(6/41, 14%), a tie with Equipment and Documentation/SOPs (3/41, 7%) and QAU (2/41, 4%)
(Figure 15).
17(65%)
14(53%) 12(46%)
12(46%)
5(19%)
GLP quality system 21(80%)
Multisite Studies
Sponsor Responsibilities
Animal Welfare
Test and Control Article Information
Other
65
Figure 15: Distribution of Current Areas (N=41)
(Q15 – Thinking about the current GLP regulations, what has been the most difficult
area to implement? Please elaborate in the comment fields provided.)
2 (4%)
3 (7%)
6 (14%)
0 (0%)
3 (7%)
7 (17%)
QAU
Documentation/SOPs
Personnel/Management
Test Article/Control Article ... 20 (48%)
Test system requirements
Equipment
Other
66
There were 24 comments added in the comment fields provided. Comments are
shown below per category above:
Documentation/SOPs (1) – Keeping up to date.
Personnel/Management (5) - Following SOPs, maintaining current training records, study
task prep, data management; Turnover in personnel and availability and suitable training and
oversite of personnel while meeting economic goals. Lots of experienced people retiring;
Organizational structure in small facilities and universities; Test Site Management
understanding their responsibility, same with SOP-designated PIs. Also, getting the company
to invest in adequate training for TSM and PI roles; More specificity on management role.
Test Article/Control Article requirements (9) - For medical devices hard to characterize;
Working jointly with GMP, CMC, and others to align with GLP requirements and guidelines;
TA characterization shouldn't be done per GLPs. These are made in GMP type facilities, and
the majority of them have no capacity to inspect per GLP (GLP training, QMS is different,
reporting is totally different); Obtain characterization, if any; Test article/control article are
generally provided by the sponsor who are not regulated under GLP; Being provided or
ensuring stability/characterization; The interpretation of the regs keep changing as the FDA
conducts inspections at different CRO's and companies. There are a lot of inconsistencies;
Most sponsors do not want to provide this information; Although required to be GLP,
Sponsors are not using GLP for characterization.
Equipment (2) – Validation is time consuming and costly; Validation of equipment.
Other (7) – None; I think they are all equally able to be implemented; N/A; No attempt to
implement yet, still TBD on what they will eventually be; The study director should be located
at the analytical facility as they have the qualifications to interpret the data; Varying
interpretation among regulators/inspectors regarding expectations for the oversight role of the
Study Director, especially on multi-site studies; Part 11 compliance.
The next question pivoted from the current GLP regulations to the proposed revisions to
the GLP regulations. This question asked about the area of the proposed revisions that they felt
would likely be most difficult to implement. The quality system was thought to be the most
difficult (13/36, 36%), followed by “other” (9/36, 25%), management requirements (7/36, 19%),
multisite requirements with (4/36, 11%) and new/revised SOPs with (3/36, 8%) (Figure 16).
67
Figure 16: Distribution of Proposed Areas (N=36)
(Q16 – Thinking about the proposed revisions to the GLP regulations, what will likely be
the most difficult area to implement? Please elaborate in the comment fields provided.)
There were 18 comments added in the comment fields provided. Comments are shown
below per category above:
Multisite requirements (1) - Getting everyone to align with an understanding of what the GLPs
require can be a struggle with international companies.
Management requirements (2) - Unclear responsibilities and lack of point of control; It is hard
to educate the sponsor that they also have to comply with GLP.
Quality system (7) – This is a vague requirement; Too much GMP-like focus on QMS process
changes; Due to having to employ another person in the management structure; Additional
resources needed for implementation, maintenance and oversight; The interpretations of this
philosophy may age different in different types of companies (sponsors vs CROs); Resources
will be required; The influence of ISO negates what GLPs are all about. QA is an oversight
function - the quality system has to be driven by management, not QA. Quality Assurance in
GLP is not the Quality group.
Other (8) – Sponsor and AAALAC accredited sites; None; Additional requirements that will
need QAU involvement; None. My current company, as with previous companies, have created
systems and SOPs to reflect an amalgamation of FDA, EPA, OECD, and ISO guidelines.
While we do not claim OECD (or ISO) compliance, many Sponsors expect to see
processes/verbiage used in the OECDs, for example Principal Investigator, Lead QA,
experimental start date, etc. These have already been adopted and are used in protocols and
final reports. With regards to a Quality System, validated computer software for data
collection/correction, master schedule entries, and QA audit reporting, have been
implemented in every company I have worked for. I see no difficulties in implementing the
proposed revisions to the GLP regulations at my current company; Changes in study design
and conduct to meet the demands of evolving guidelines and technology; Depends on the final
13(36%)
9(25%)
7(19%)
4(11%)
3(8%)
Multisite
requirements
Management
requirements
New/revised SOPs Quality System Other
68
version; Sponsor roles; Animal Rule is outside the scope of the GLP regulations and are
efficacy, not safety, studies.
The next set of questions asked respondents to rank areas based on challenges and
benefits to implement. The first question asked the respondents to identify the level of challenge
for certain areas during the implementation of the proposed revised GLP regulations. There
were 47 responses (Figure 17). The ranking was to be from the highest challenge in order to
implement (ranked as 1) to the lowest challenge in order to implement (ranked as 3).
Actual values are presented (Table 6) and associated with the results in Figure 17. The
weighted means of the responses were calculated to fine-tune the ranking of the challenge. The
number of responses within each type and rank was multiplied by the rank value. Values were
added for each type and then divided by the number of responses within that type. The most
challenging perceived was resistance by personnel (1.6), higher cost (1.6), additional
documentation (1.7), and longer timeline (1.8).
69
Figure 17: Level of Challenge to Implement (N=47)
(Q17 – What would be the level of challenge for the following areas during
implementation of the proposed revised GLP regulations?)
There were five additional comments in the “other” category. Comments are shown
below:
This really depends on what section you are talking about. Question is too general.
Lack of clarity.
Conflicting responsibilities and control.
TBD, not clear what the final version will actually be or when.
It won’t work – a system that has been used for over 50 years is being completely changed
as far as the QAU is concerned.
Table 6: Actual Values (N=47) with Weighted Mean
Ranking 1 2 3 Total Weighted Mean
Resistance by
Personnel
24 13 7 44 1.6
Higher Cost 22 15 5 42 1.6
Additional
Documentation
19 16 7 42 1.7
Longer Timeline 14 23 4 41 1.8
13
7
1 1
2
0
23 24
22
19
3
Longer timeline Higher cost Resistance by
personnel
Additional
documentation
Other
High Medium Low Do not know
14
4 4
15
5
2
16
7
2
70
The next question asked about the level of benefit associated with specific areas when
implementing the proposed revised GLP regulations. The ranking was to be from the most
benefit (ranked as 1) to the least benefit (ranked as 3). There were 47 responses (Figure 18).
Actual values are presented (Table 7) and associated with the results in Figure 18. The
area perceived to be most beneficial was improved multisite oversight (1.6), followed by
inclusion of additional types of studies (1.7), increased management oversight (1.8) and
improved QAU oversight (2.2).
Figure 18: Level of Benefit to Implement (N=47)
(Q18 – What would be the level of benefit associated with the following areas when
implementing the proposed revised GLP regulations?)
There were three additional comments in the “other” category. Comments are shown
below:
Where did #3 come from? What additional studies?
TBD
Increased sponsor responsibilities
21 20
3
1
15
9
3
12
9
6
14
11
1 2 3
1 0
18 18 18
Increased
management
oversight
Improved
multisite
oversight
Inclusion of
additional types
of studies
Improved QAU
oversight
Other
High Medium Low Do not know
71
Table 7: Actual Values (N=47) with Weighted Mean
Ranking 1 2 3 Total Weighted Mean
Improved multisite
oversight
21 20 3 44 1.6
Inclusion of additional
types of studies
12 18 11 44 1.7
Increased
management
oversight
18 15 9 42 1.8
Improved QAU
oversight
14 18 9 38 2.2
The next set of questions was specific to certain changes in the proposed revised GLP
regulations. The first two concerned the alignment of ISO 9001 with GLP. The first question
asked if alignment would be beneficial. Most of the 38 respondents disagreed (24/38, 63%),
while the remaining agreed (14/38, 37%) (Figure 19).
Figure 19: Benefit of ISO 9001 Distribution (N=38)
(Q27 – Alignment of GLP with ISO 9001 will be beneficial. Please elaborate in the
space provided.)
There were six additional comments for the 14 respondents who agreed. Comments are
shown below:
The GLPs are a quality requirement not a quality system. ISO9001 is a quality
system.
The spirit of GLP and ISO 9001 are the same to endure the quality culture is
implemented in the facility.
Many Sponsors inquire about certifications/accreditations. Since FDA and EPA do
not certify facilities, alignment of GLP with ISO may lessen a Sponsor’s concerns
regarding a testing facility if said testing facility is not ISO accredited.
Agree [37%, 14]
Disagree [63%, 24]
72
Consistency between the two will ensure quality and integrity.
It will provide justification those facilities already dealing with GLP and ISO
standards to cite back to management to support their case when debating reasons
“why we need to do” something a certain way.
Increased focus on quality and integrity of data essential to assess the safety and
effectiveness.
There were 15 additional comments from the 24 who disagreed. Comments are
shown below:
It is unnecessary
We are not ISO
Inconclusive
Not needed. GMP creep. Other than one-off individual investigators (mom-andpop shops) running GLP studies, what are the significant areas of non-compliance
observed from larger facilities in the last 10 years? (Answer: Probably not much!)
Addition of another person to management structure is not possible for some small
organizations.
ISO 9001 is a mgmt. system which GLP already is.
I predate GLPs and predate the current testing requirements for medical devices.
My last 30 years has seen my realm of activity evolve to a near even split between
drugs (here you call GLPs) and Devices (ISO). Trying to force fit the two into a
single paradigm requires a lot of compromises that may not be desirable.
No one knows because it is too expensive to purchase ISO guidelines.
9001 is tailored for manufacturing operations and multiple requirements are not
applicable for R&D.
GLP focuses on data and documentation, whereas ISO focuses on process.
Personnel responsibilities differ in both regs
ISO standards are not enforceable. They need to remain separate.
ISO will implement more GLP terminology which could cause confusion in the
industry, however if differences in quality management systems are considered and
appropriate terminology can be used, this may be beneficial but will take time to
establish procedures to support.
Not necessary.
Totally different scope and purpose between ISO and GLP.
73
The second question explored the level of burden associated with aligning ISO 9001 with
GLP. The ranking was from the highest level of burden (ranked as 1) to the least level of burden
(ranked as 3). There were 47 responses (Figure 20).
Actual values are presented (Table 8) and are associated with the results displayed in
Figure 20. The highest burden level was thought to be maintenance of 2 separate quality systems
(1.3), followed by terminology (1.6) and personnel responsibilities (1.7).
Figure 20: Level of Burden to Align GLP with ISO 9001 (N=47)
(Q19 – What would be the level of burden in aligning GLP with ISO 9001 in the
following areas?)
There were four additional comments in the “other” category. Comments are shown
below:
For those of us who are not ISO certified, paying for ISO to find out what the
requirements are is ridiculous when the GLPs are a quality system.
Loss of individual study control and meeting objectives of that study.
TBD
The requirement to obtain so many tissue samples.
8 7
10 10
4 4
27
19
16
Personnel
Responsibilities
Terminology Maintenance of 2
separate quality
systems
Other
High Medium Low Don't know
11 12
5 3
6
1 0
74
Table 8: Actual Values (N=47) with Weighted Mean
Ranking 1 2 3 Total Weighted Mean
Maintenance of 2
separate quality
systems
27 4 4 35 1.3
Terminology 19 8 7 34 1.6
Personnel
responsibilities
16 11 5 32 1.7
The next question asked respondents if the proposed revisions to the GLP regulations
would improve data quality over the current regulations. Slightly more than half of the 48
responses were “yes” (27/48, 56%) and the remaining were “no” (21/48, 44%) (Figure 21).
Figure 21: Data Quality Distribution (N=48)
(Q20 – The proposed revised GLP regulations would improve data quality over the
current GLP regulations)
The next three questions were about the Animal Rule. The first question asked if the
respondent was involved with Animal Rule studies. There were 50 responses. Most responded
“no” (35/50, 70%) slightly less than a third responded “yes” (15/50, 30%) (Figure 22).
Figure 22: Animal Rule Distribution (N=50)
(Q21 – Are you involved with Animal Rule Studies?)
No [44%, 21]
Yes [56%, 27]
Yes [30%, 15]
No [70%, 35]
75
Respondents who answered yes to Question 21 were asked if they thought these studies
should be added to the scope of the proposed revised GLP regulations. The majority responded
“yes” (12/15, 80%), and only a few (3/15, 20%) said “no” (Figure 23).
Figure 23: Addition of Animal Rule Distribution (N=15)
(Q22 – Should Animal Rule studies be added to the scope of the proposed revised GLP
regulations?)
Only 11 of the 15 respondents answered Question 23 which asked what areas of the
proposed revised GLP regulations would be challenging to implement for Animal Rule studies
(Figure 24). The ranking was from the most challenging (ranked as 1) to the least challenging
(ranked as 2).
Actual values are presented (Table 9) and are associated with the results displayed in
Figure 24. All the areas were roughly perceived to be the same with documentation and animal
welfare requirements coming in as the most challenging (1.7) followed by the other three areas
of record retention requirements, personnel requirements and QA/QC (1.8).
No [20%, 3]
Yes [80%, 12]
76
Figure 24: Distribution of Areas of Challenge (N=11)
(Q23 – Which of the following areas would be challenging to implement if the proposed
revised GLP regulations included Animal Rule studies?)
Table 9: Actual Values (N=11) with Weighted Mean
Ranking 1 2 Total Weighted Mean
Documentation
requirements
3 8 11 1.7
Animal welfare
requirements
3 8 11 1.7
Record retention
requirements
2 9 11 1.8
Personnel
requirements
2 9 11 1.8
QA/QC 2 9 11 1.8
The next question explored whether tobacco studies should be included in the scope of
the GLP regulations. The majority of 41 respondents stated “yes” (25/41, 60%) they should be
included and (16/41, 39%), stated “no” (Figure 25).
2
0
9 9 9
8 8
1 1
Record
Retention
Requirements
Documentation
Requirements
Personnel
Requirements Animal Welfare
Requirements
QA/QC Other
Challenging Not challenging Don't know
2
0
3
0
3
0
2
0
0
77
Figure 25: Inclusion of Tobacco Studies Distribution (N=41)
(Q24 – Should tobacco studies be added to the scope of the GLP regulations?)
The next area asked respondents to agree or disagree with 3 statements related to animal
welfare requirements. Most of 43 respondents agreed with all three statements. They agreed
that the proposed revised GLP regulation would promote non-animal test methods (agree: 19/43,
44%; disagree: 12/43, 27%; cannot say: 12/43, 27%), improve the quality and integrity of the
studies (agree: 23/43, 53%; disagree:13/43, 30%; cannot say: 7/43, 16%) and strengthen animal
welfare in the studies (agree: 19/43, 44%; disagree: 5/43, 34%; cannot say: 9/43, 20%)
(Figure 26).
Figure 26: Statement Agreement Distribution (N=43)
(Q25 – Regarding the additional animal welfare requirements in the proposed revised
GLP regulations, with which of the following statements do you agree?)
The last question of the section explored the benefits of harmonization with OECD on
multi-site studies. The majority of 46 respondents agreed that harmonizing with OECD on
multi-site studies in the proposed revised GLP regulations will increase the quality of the studies
No [39%, 16]
Yes [61%, 25]
13
7
23
19 19
Will promote non-animal
test methods.
Will improve the quality
and integrity of nonclinical
studies.
Will strengthen animal
welfare in nonclinical
studies.
Agree Disagree Cannot say
12 12
15
9
78
(33/46, 72%). In comparison, 5/46 (11%) did not agree, and 8/46 (17%) did not know
(Figure 27).
Figure 27: Distribution of Agreement (N=46)
(Q26 – The harmonization with OECD on multisite studies in the proposed revised GLP
regulations will increase the quality of the studies performed across multiple sites. Do
you agree with this statement?)
4.4 Quality of Communication
Two questions in this section revolved around FDA’s communication routes. The first
asked respondents to rank different communication types in order of their helpfulness in
understanding the proposed revisions. The ranking was to be from the most helpful (ranked as 1)
to the least helpful (ranked as 7). There were 42 responses.
The results in Figure 28 were converted to the weighted means in Table 10. The number
of responses within each type and rank was multiplied by the rank value. Values were added for
each type and then divided by the number of responses within that type. The Q&A with the
FDA was reported as most helpful (2.7), followed by training programs for companies provided
by the FDA (3.1), new regulations (3.2), working groups consisting of industry and FDA
representatives (3.5), and new guidance documents (3.7). Industry working groups on the topic
(5.1) and industry literature (6.7) were identified as the least helpful (Table 10).
Don't know [17%, 8]
No [11%, 5]
Yes [72%, 33]
79
Figure 28: Ranking of Items in Terms of Helpfulness (N=42)
(Q28 – Rank the following items in order of helpfulness with understanding the proposed
new GLP regulations (most helpful item at the top).
Ranking is shown from 1 (most helpful) to 7 (least helpful).
Table 10: Actual Values (N=42) with Weighted Mean
Ranking 1 2 3 4 5 6 7 Total Weighted
Mean
Q&A with the FDA 7 13 11 9 2 0 0 42 2.7
Training programs for companies provided by the
FDA
9 9 10 4 2 7 1 42 3.1
New regulations 14 4 7 5 4 4 4 42 3.2
Working group consisting of industry and FDA
representatives on the topic
8 4 6 6 17 1 0 42 3.5
New guidance documents 3 10 6 9 8 4 2 42 3.7
Industry working group on the topic 1 2 2 9 4 22 2 42 5.1
Industry literature 0 0 0 0 5 4 33 42 6.7
New New Training Q & A with Working Industry Industry
regulations guidance programs the FDA group working literature
documents for consisting group on
companies of industry the topic
provided by and FDA
the FDA representative
1 2 3 4 5 6 7
80
The second question in this section concerned unofficial communication routes.
Respondents were asked to rank which of the 5 routes from extremely beneficial (ranked as 1) to
extremely unbeneficial (ranked as 5). There were 48 responses (Figure 29).
Actual values are presented (Table 11) and associated with the results in Figure 29. The
perceived most beneficial was a 3-way tie across responses to questions submitted to the agency,
clarity of communications regarding the proposed changes and timelines and FDA talks at
meetings (1.3), followed by impromptu information sharing during encounters with FDA
personnel (1.8).
Figure 29: Ranking of Unofficial Communication Routes (N=48)
(Q29 – Which of the following unofficial communication routes do you think are
beneficial?)
10
3
0 0
12
3
0 0
35
31 32
24
2
0 1 0 0
Impromptu
information
sharing during
encounters
with FDA
personnel
(including ...
Responses to
questions
submitted to
the agency
Clarity of
communicatio
ns regarding
the proposed
changes and
timelines
FDA talks
at
meetings
Other
Extremely beneficial Somewhat beneficial Neither beneficial nor unbeneficial Somewhat unbeneficial
Extremely unbeneficial
13
7
3
1
17
0 0 0
81
Table 11: Actual Values (N=48) with Weighted Mean
Ranking 1 2 3 4 5 Total Weighted Mean
Responses to
questions submitted to
the agency
31 17 0 0 0 48 1.3
Clarity of
communication
regarding the
proposed changes and
timelines
35 10 3 0 0 48 1.3
FDA talks at meetings 32 12 3 0 0 48 1.3
Impromptu
information sharing
during encounters
with FDA personnel
24 13 7 3 1 3 1.8
There were two additional comments in the “other” section. Comments are provided
below:
Guidance documents
What communications regarding proposed changes?
4.5 Competence
This section consisted of a series of three questions about the FDA’s process for
stakeholder input and requests for comments. The first question asked if the solicitation process
for input was adequate. There were 41 responses. Over half of respondents reported that the
process was adequate (24/41, 59%) whereas the remainder did not (17/41, 41%) (Figure 30).
Figure 30: Distribution of Adequacy of Process (N=41)
(Q30 – Do you think the FDA’s solicitation process for stakeholder input was adequate?
Please elaborate in the space provided.)
No [41%, 17]
Yes [59%, 24]
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There were 5 additional comments in the “yes” category. Comments are provided below:
I think so but I really don’t know – depends on how involved the SQA was in the
process.
The FDA solicited comments and the timeline for reviewing those comments has
been more than adequate.
Engaged parties had the opportunity to do so.
Seems ok.
Providing industry the opportunity is encouraged, however this can also delay the
process since they received a large amount of feedback.
There were nine additional comments in the “no” category. Comments are provided
below:
Information is only as good as advertised. There is not one central clear
source where information is shared.
Nobody likes this new rule. But yet we’ll still get changes.
Yes, in that they got the input, but no in that they have to completely revise the
proposed regs and won’t be having a second time for input on these new
revisions.
It would have been but it’s been close to 10 years since the feedback.
See below.
Their silence for so many years now is frustrating. I know something like this is
a significant undertaking and does require a great deal of time. However, it
has now been so long that it is frustrating and being unable to go to upper
management/leadership without anything concrete fosters an environment
where QA objectives can be scrutinized even more.
Limited available time for participation by those actually involved and
confusion as to what is said and what is implemented.
Too long now.
Its been 13 years and I hadn’t really heard anything about it.
The second question in this section was whether the FDA should request additional
comments prior to finalizing the proposed new GLPs. There were 42 responses. Of these
responses, three out of four stated “yes” (31/42, 74%) while the remainder stated “no” (11/42,
26%) (Figure 31).
83
Figure 31: Disposition of Requesting Additional Comments (N=42)
(Q31 – Do you think the FDA should request additional comments before finalizing the
proposed new GLP’s? Please elaborate in the space provided.)
Of the 31 responding “yes” 11 provided additional comments. Comments are provided
below:
The FDA does not have a good read on the lack of cost benefit of the new
GLPs.
The proposed GLPs have been out for so long that we need another round of
comments.
Too much non-value-added work.
Since they indicated so much had changed, I do think additional comment time
is necessary.
Expected changes to ISO 9001 may provide additional guidelines if the
regulations are to be aligned. Although ISO standards are updated approx.
every 6 to 10 years and it takes FDA regs much longer for any updates. This is
why their alignment may need to be in guidelines and regulations be very clear
delineating the most crucial processes and definitions.
Publish updated proposal based on all comments received and reinitiate
comment period. I think the proposed regulations are necessary for
consistency with OECD but too many new areas of concern have also been
included in the proposed rule.
So many of the original FDA staff involved in the proposal have left.
Too much time has passed, too many comments, new folks involved, etc.
Would be good to hear the latest comments before approving.
I believe a small subset of industry professionals should be selected to provide
final feedback. But this should be limited to avoid exuberant amounts of
feedback.
There were so many comments during the first round that it would be useful for
people to be able to re-read a revised version.
No [26%, 11]
Yes [74%, 31]
84
Of the 11 responding “no” 7 provided additional comments. Comments are provided
below:
FDA is considering all comments and additional comments would only
delay progress.
They have the comments, they just need to ensure industry concerns are
addressed.
It’s taken a long time. FDA should get of the pot.
This will only lengthen the process. We would like to see the final revised
regulations as soon as possible.
The original proposal was 7yrs ago. Any additional comment period would
likely result in an additional number of years before implementation. By
then, the original proposal could be obsolete.
At some point the regs need to get out.
It’s already been 13 years.
The last question in this section asked about areas in which the FDA should request
additional comments. Using the “skip logic” capability of Qualtrics survey software, this survey
question was skipped for the respondents who answered “No” to the previous Question 31. There
were10 responses. The highest selected response was for Animal Rule and Tobacco studies with
5/10 or 50% and the lowest selected response was for protocol with 0/10 or 0% (Figure 32).
85
Figure 32: Selection of Areas for Additional Comment (N=10)
(Q32 – For which of the following areas should the FDA request additional comments?
Select all that apply.)
All four of the respondents for the “other” area also provided additional comments.
Comments are provided below:
None
I chose no for Q31
None
3R’s and animal welfare
4.6 Cost of Implementation
This section consisted of three questions to explore the potential cost of implementing
and maintaining the new revisions. The first question asked respondents who would endure most
of the costs of implantation of the proposed revisions. There were 46 responses. Of these 46
responses, 25 or 54% chose CROs as enduring most of the cost, followed by sponsor company
with 18/46 or 39%, “other” was last with 3/46 or 6%. (Figure 33).
5
4
3 3
2 2
Roles and
Responsibilities
Record
Retention
Equipment/
computer
systems
0
Protocol Multisite
Studies
Animal Rule
and Tobacco
studies
Other
86
Figure 33: Distribution of Enduring Cost of Implementation (N=46)
(Q33 – Who will endure most of the costs of implementation of the proposed revisions?)
Of the three respondents who chose “other” all three provided additional comments.
Comments provided below:
3
CROs and sponsor internal labs
Depends on final version.
The next question in the series was about the cost of the proposed revised GLP
regulations. There were 46 responses. Most respondents (27/46, 58%) agreed that the
implementation cost would impact their company; fewer disagreed (10/46, 21%), or were
undecided (9/46, 19%). Most also agreed that the cost will slow down the implementation
process at the respondent’s company, (18/44, 40%), fewer were undecided (15/46, 32%), or
disagreed (11/46, 23%). Consistent with these results, most respondents disagreed that the cost
of implementation will have no impact on the company (disagree: 27/45, 60%; undecided: 11/45,
24%; agree: 7/45, 15%) and will not slow down the implementation process (disagree: 22/44,
50%; undecided: 14/44, 31%; agree: 8/44, 18%) (Figure 34).
Sponsor company 18
CROs 25
Other 3
87
Figure 34: Cost Impact Distribution (N=46)
(Q34 – Please provide your response to the costs of implementation of the proposed
revised GLP regulations.)
The last question in this series asked about the cost of maintaining the proposed revised
GLP regulations compared to the current regulations. There were 44 responses. The majority
(26/44 or 59%) chose the “higher” cost category; the “same” and “do not know” choices were
almost equal (8/44 or 18% and 9/44 or 20% respectively). The “lower” choice was lowest with
1/44 or 2% (Figure 35).
Figure 35: Distribution of Maintenance Cost (N=44)
(Q35 – Once implementation has been completed, what would be the cost of maintaining
the proposed revised GLP regulations, compared to that of the current GLP regulations?
Please elaborate in the comment fields provided.)
27 27
22
18
The cost to
implement will impact
my company.
The cost to
implement will slow
down the
implementation
process at my
company.
The cost of
implementation will
have no impact on my
company.
The cost of
implementation will
not slow down the
implementation
process at my
company.
Agree Undecided Disagree
9 10 11
7
14
8
15
11
26
8 9
1
Higher Same Lower Do not know
88
There were eight additional comments on the “higher” category. Comments are provided
below:
More regs = higher costs.
New requirements cost time as well (education to staff, SOP updates, SOP creation,
communication alignment, etc).
A new employee will have to be hired.
It’s hard enough to maintain compliance with the original regs…new regs will
make processes even more onerous.
Would require more resources.
Higher, but not too significantly.
Due to any improvements/enhancements that will be required to meet the new
rules.
From a Sponsor perspective, more personnel or additional outsourcing would be
needed to support Sponsor responsibilities that are not defined in the current
version of the regulations.
There were also three additional comments in the “same” category. Comments are
provided below:
No difference to maintain once in place.
It should not be more or less expensive than the present system of control.
Cost of doing regulated business.
There was only one additional comment in the “do not know” category. Comment is
provided below:
Speculate it could be higher but unclear at this time.
4.7 Final Thoughts
Respondents were asked for any final comments regarding the proposed revised GLP
regulations that may not have been captured. Twelve (12) respondents provided comments.
89
(Q36 – Do you have additional comments about this topic that I may not have captured?)
No
The timeline estimation of when the proposed will be adopted. It has been a
long wait. Curious to see when others suspect they will go from proposed
to updated. Also, the time frame in which companies will need to pivot and
adopt the new changes. Management does not always support the
necessary resources needed for GLP as it is not as well understood as GMP
or GCP therefore the support needed for the transition may be slow going.
Alignment with OECD which the FDA were critical in developing can only
benefit the global operation of GLP and the harmonization for global
organisations which are presently hampered by differing requirements in
the US and additional constraints (OECD requirements) on non-US
companies.
The USA should adopt OECD-GLPs. It would be better for business.
None
No
The GLPs are long overdue for an update however, it would be helpful if
some of the updates were more specific and directly addressed newer
technology and systems.
There should have been room for comments on each question as some were
worded in a manner that required an “it depends”, so some answers are
not quite accurate.
Changes in regulation should be carefully considered. Proposed changes
in the regulation clearly demonstrated a lack of understanding of the
research environment and what drives quality as demonstrated by public
comments. Any changes should clearly demonstrate a positive effect on
quality, quality improvement and maintaining a quality culture.
No.
The timeframe to get these out has been excessive. To go about any more
revisions and comments will only make the process more difficult and have
no positive impact. No group will ever completely agree as we have seen in
the past.
The only thing that really needs to be modified are the requirements for
multi-site studies, increased verbiage about electronic data capture and
archiving and increased Sponsor responsibilities. The one thing that is also
positive about the new GLPs is the requirement for management to bring in
a third party to assess QA.
90
Chapter 5. Discussion
5.1 Overview
As discussed in Chapter 2, the current GLP regulations have not been substantially
revised since their inception in 1979. The proposed revisions, first discussed in 2010, were
published in the Federal Register in August 2016. Since the closure of the comment period in
2017, the regulations have not been finalized and no further updates or timelines have been
disclosed. As of the current year of 2024, 14 years since the ANPRM, the industry is operating
in a land of ambiguity – a land where the current regulations are still in effect, but the proposed
new regulations provide a hint of what may or may not be to come. This is coupled with the fact
that there has been no communication, additional literature or documented discussions since the
responses to the NPRM, industry is left in limbo. Many organizations will be affected by
changes in the finalized rule and have a vested interest in those revisions.
This study sought to survey stakeholders in the U.S. pharmaceutical industry on their
views regarding the current GLPs and implementation of the proposed GLP revisions purported
to improve study conduct and the quality and integrity of the data. It also sought to understand
the industry’s view on the transparency and communication of the FDA during the revision
process. The following is a discussion of the methodology including the delimitations and
limitations. The results of the survey are also discussed below as they relate to the five
framework domains of Demographics, Exploration and Adoption, Quality of Communication,
Competence and Cost of Implementation.
5.2 Study Methodology
When reviewing the results of this study, it is essential to consider the methodology
applied. The surveyed population included individuals with professional backgrounds in the
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GLP industry, ensuring the relevance and accuracy of the data collected. An essential step in
the survey design was to screen participants at the beginning to verify their familiarity with GLP
principles. Respondents without sufficient knowledge were sent to the end of the survey and
excluded from participating in further questions. This selection approach led to the exclusion of
one individual who initiated the survey but did not meet the required criteria. This approach
enhanced the quality and reliability of the data by ensuring that only knowledgeable individuals
contributed to the findings. As the survey was anonymous, the accuracy of the responses cannot
be confirmed and are accepted as truthful. Limitations and delimitations of the framework, the
response pool and how the data was captured are presented below.
5.2.1 Delimitations
Delimitations are the administered boundaries of the research, which in this case include
the framework and respondent demographics. These delimitations and how they may have
impacted the results are discussed below.
5.2.1.1 Framework
The research was delimited to a combination of two frameworks, one from Fixsen and
the other from Andaleeb. As the intent of this study was based on industry’s views on the
potential adoption and implementation of the proposed revisions to the GLPs, the utilization of
the field of implementation science was decided upon. As a recognized developer of an accepted
implementation framework, Fixsen’s construct was chosen (Fixsen et al., 2009).
The first stage of Fixsen’s construct is exploration and adoption. This is where the need
for change has been defined and companies begin to educate themselves about the upcoming
potential changes and assess the gaps between the current state and the proposed changes. The
three subsequent stages in Fixsen’s construct revolve around installation and implementation,
92
which, as the current status of the proposed revised GLPs is not yet finalized, and therefore not
yet required to be implemented, the only appropriate stage of the construct was the exploration
and adoption stage.
As this study also intended to assess the industry’s satisfaction with the FDA’s
rulemaking process, there was a need for a secondary framework that would align with this
objective. The approach identified came from the customer service framework, which was
partially utilized and woven into the framework of this study. Andaleeb, identified as a leader in
the customer service framework area, published a paper in 1998 utilizing a set of principles in
determining customer satisfaction in the healthcare delivery industry where satisfaction was
assessed relative to a patient’s experience (Andaleeb, 1998). The framework had five constructs:
quality of communication, competence, quality of facilities, staff demeanor and costs. (Andaleeb,
1998).
To assess industry satisfaction with the FDA’s rulemaking process and the new proposed
rule, only three of these five areas were deemed applicable and thus utilized in this survey. The
selected constructs were the perceived quality of communication, the competence of the agency
and the costs associated with implementing the proposed changes. The remaining two areas, the
quality of the facilities and staff demeanor, did not apply to this study and, hence, were omitted.
In summary, the survey questions were developed based on four domains from the two
frameworks mentioned above, along with an additional demographics category to understand the
background of the respondents. To identify any unrecognized benefits, disadvantages or
pressures, open-ended questions were included throughout the survey, allowing respondents to
provide further input. The combination of these frameworks appeared to be sufficient, based on
the responses received.
93
5.2.1.2 Respondent Demographics
To ensure the validity and reliability of the data collected, the scope of this study was
delimited to industry professionals and consultants with direct experience in GLP and nonclinical
studies. These respondents were either currently involved or had previously worked in areas
directly related to the performance, oversight, or auditing of such studies. By restricting
participation to individuals with this level of expertise, the study aimed to minimize the potential
for misinterpretation of the questions, which could have otherwise impacted the accuracy of the
findings and overall integrity of the results.
In addition, given that the research focused specifically on U.S. GLP regulations, it was
both practical and relevant to limit the scope to individuals working within the U.S. While
respondents may have conducted nonclinical studies or operated laboratories outside of the U.S.,
the primary focus remained on those laboratories that fall under the jurisdiction of the U.S. FDA.
This ensured that the findings directly addressed the regulatory environment governed by the
U.S. laws.
5.2.2 Limitations
Limitations are unforeseen issues within a study that can affect the results. These include
identifying enough industry stakeholders to survey who conduct this type of research, how many
respondents complete the survey and how many of the survey questions to which they responded
and the overall design of the survey. These limited the depth of the results and conclusions and
are discussed below.
5.2.2.1 Response Rate
To ensure the successful execution of this study, it was necessary to engage respondents
actively involved in GLP nonclinical studies within the U.S. To achieve this, the author
94
leveraged a network of 35 industry experts who are directly engaged in GLP, sending
personalized emails that included the survey link to encourage their participation. Additionally,
the author also reached out to several professional organizations including the American College
of Toxicology (ACT), the Society of Toxicology (SOT) and the Society of Quality Assurance
(SQA), requesting their assistance in circulating the survey to their members. To broaden the
reach, the author also posted the link as an open invitation on LinkedIn, aiming to attract further
participation from qualified individuals within the field.
As the survey respondents were working professionals, their willingness to participate
may have been influenced by the relevance of the research topic to their jobs and their
companies’ policies on participation in studies of this nature (Baruch, 1999). Although the
participation rate was relatively low, the survey yielded 132 completed and partially completed
responses. Considering the limited population of potential respondents, this level of engagement
can be regarded as a reasonable representation of the target group.
5.2.2.2 Survey Design
To engage the necessary participants, the author chose a survey-based approach due to its
several advantages, including the potential for a higher response rate compared to other data
collection methods like interviews (Koundinya et.al., 2016). Surveys are often more convenient
for participants, allowing for flexible response times and reaching a larger, more diverse
population. However, concerns about the use of electronic surveys remain, particularly
regarding the response rates which can be influenced by the structure and length of the survey
(Saleh & Bista, 2017). To address this potential issue and enhance the reliability of the data
collected, the author took several measures. Before launching the survey, the author convened a
focus group to review the initial draft of the questionnaire. The focus group played a critical role
95
in refining the questions to ensure the questions were clear and relevant and did not place an
undue burden on the respondents. Additionally, the author limited the number of questions to
35, aiming to balance obtaining comprehensive data and maintaining respondent engagement.
The author also incorporated a variety of question formats, including multiple-choice, Likert
scales, and open-ended questions, to keep the survey dynamic and less monotonous. These
efforts were intended to optimize the response rate and ensure that the data collected would be
robust and meaningful.
The survey collected both qualitative and quantitative data. The open-ended questions
used to collect qualitative data were meant to add additional thoughtfulness to the results and
allow for free space to provide insight into parts of the question that may have needed further
explanation. However, this could have been seen as time-consuming and not all respondents
utilized these spaces, or it could have caused them to skip specific questions or discontinue the
survey.
5.2.2.3 Additional Insight Regarding the Results
This study was conducted eight years after the publishing of the NPRM in the Federal
Register in August 2016 (81 FR 58342). Knowing that the proposed new GLP regulations have
yet to be finalized, the robustness of the data could have been greater if this study had been done
after the finalization of the regulations. If the regulations were finalized, the FDA’s process
would have been complete and industry views would be that of the completed process rather than
the middle of the process not knowing what the completed process looks like. Also, industry
would know what the final regulations state and potentially have been in the process of
implementation and therefore would have definitive, firsthand responses regarding the benefits
96
and disadvantages rather than perceived ones. It is therefore expected that the views of the
respondents presented here could change over time.
The intent of this study is to offer valuable insights into the current perspectives on the
proposed new GLP regulations. This information could support a smoother transition to the new
regulatory requirements and help inform future policymaking decisions. While the author
assumed that all respondents provided honest and accurate responses, the anonymous nature of
the survey precludes the possibility of verifying their accuracy.
5.3 Discussion of Results
This section focuses on how the study’s findings inform the various elements of the
framework used to assess stakeholder perspectives on the current and the proposed new GLP
regulations. Applying a hybrid model that incorporates both the adoption and implementation
framework with selected portions of the customer service framework, the study evaluated
industry views across five domains: Demography, Exploration and Adoption, Quality of
Communication, Competence and Cost of Implementation. The discussion will examine how the
insights gained from the survey contribute to a deeper understanding of these domains, shedding
light on stakeholder opinions regarding the current and proposed new GLPs and the FDA’s
communication during the revision process.
5.3.1 Demographics
Demographic information was important to discern the appropriateness of the
respondents and the type of GLP work in which they are active. Also, since this study was
conducted eight years post-NPRM, it was important to understand if the industry still remembers
the context of the proposed new regulations.
97
Most of the respondents in this survey had over 20 years of experience working in the
GLP field and a medium level of familiarity with the proposed revised GLP regulations. They
came from a mix of organization types with the most in contract research or GLP testing
facilities and consulting firms. The organizations were mostly small companies operating BSL 1
laboratories with less than 100 employees who had been in business for over 15 years. Most of
these companies were based in the U.S. and governed by FDA GLP regulations. Just under half
of the companies followed OECD GLP and did not have laboratories outside of the U.S. Based
on these responses, it is believed that the appropriate demographic population responded to the
survey. This information can help in understanding where the source of the responses came from
in the following sections.
5.3.2 Exploration and Adoption
The rationale behind examining respondents’ perceptions of the proposed new GLP
regulations lies in the need to understand how direct exposure to regulatory oversight influences
attitudes toward changes in compliance standards. Half of the respondents of the survey had
been inspected by the FDA for GLP compliance primarily after 2016, and the other half had not
been inspected at all. These findings could reveal potential differences in how the respondents
perceive the impact of the new regulations. Those with post-2016 FDA inspection experience
likely have a more immediate and practical understanding of the existing GLP framework, which
may shape their expectations of how new regulations could affect their operations. These
respondents may have firsthand knowledge of the compliance challenges or benefits under
current regulations and thus, their perceptions of the proposed changes could be rooted in
practical considerations such as ease of implementation, cost implications, or resource allocation.
Understanding their views helps gauge how well-prepared organizations might be for regulatory
98
shifts, especially those that have recently undergone inspections and are already operating under
scrutiny.
On the other hand, respondents without inspection experience may base their perceptions
more on theoretical or secondhand information and their responses could reflect concerns about
the unknown aspects of regulatory enforcement. New regulations could represent a more
significant shift, potentially requiring the allocation of resources and adjustments to procedures
they have not yet encountered in practice. The absence of direct FDA oversight could influence
their stance on regulatory changes, providing insights into the broader industry’s readiness for
reform.
The decision to analyze the FDA’s GLP inspection history from 2016 onward adds
further depth to the study. These insights help contextualize the respondents’ feedback, offering
a clearer understanding of how current regulatory practices, as shaped by recent inspections,
might influence opinions on proposed regulations. By anchoring the analysis in this specific
period, the study aligns the respondents’ experiences with the most current regulatory
environment, ensuring that the findings are timely and applicable to present-day concerns in the
industry. According to the FDA Nonclinical Labs Inspections List, within the U.S. 251
inspections have been conducted from 2016 through July 2024 (FDA 2024a). Both Voluntary
Action Indicated (VAI) and Official Action Indicated (OAI) are the result of findings of
noncompliance noted during an inspection. From the inspections ending during the period of
2016 through July 1, 2024, there were 16 (6%) resulting in an OAI and 85 (34%) resulting in a
VAI (FDA 2024a). Table 12 shows the number of inspections within the U.S. closed within the
years of 2016 through July 1, 2024.
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Table 12: BIMO Inspections Ended and Actions Taken
(FDA, 2024a)
Year Number of Inspections Ended Number of Inspections with actions
indicated (VAI or OAI)
2016 36 19 (53%)
2017 34 12 (35%)
2018 43 16 (37%)
2019 33 15 (45%)
2020 13 4 (31%)
2021 33 14 (42%)
2022 24 10 (42%)
2023 27 9 (33%)
Through July 1, 2024 8 5 (63%)
The lack of inspection by the FDA and inspections resulting in OAI or VAI could have
influenced some of the respondents’ perceptions as potentially coming from a place of
uncertainty regarding current thinking and adoption of the current GLP regulations. If these
respondents had not had the opportunity to have their current GLP systems inspected to know if
what they had in place was adequate according to the agency, or if they had findings associated
with their current GLP systems, this could then lead to further uncertainty regarding the potential
benefits and potential disadvantages regarding the adoption of the new revised GLP regulations.
When asked to think about the current GLP regulations and the areas that respondents felt
were the most difficult to implement, the responses were test/control article requirements,
personnel/management, SOPs, and equipment. There was an emerging theme among the
categories in that the interpretation of the regulations keeps changing based on inspections. One
respondent stated, “The interpretation of the regs keep changing as the FDA conducts
inspections at different CRO’s and companies. There are a lot of inconsistencies.” Another
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respondent stated, “Varying interpretation among regulators/inspectors regarding expectations
for the oversight role of the Study Director, especially on multi-site studies.” The areas of most
challenge also included the costs and difficulties of validation and adequate training. These
challenges are not surprising because they overlap with areas commonly identified as
problematic when sites have been inspected.
According to BIMO Fiscal Year 2023 Metrics, the most common observations collected
from issued FDA Form 483s involved the failure of the QAU; final reports not including all
circumstances affecting the quality or integrity of the data; the archiving of records; equipment
calibration not adequate; testing facility management failing to assure all personnel clearly
understood their functions; and missing SOPs (FDA 2024b). Further, the challenges align with
additional text comments from respondents regarding areas with which they had difficulties.
These results suggest that the challenging areas are ones that might need to be clarified in the
new revised GLP regulations to prevent further difficulty in implementation.
Overwhelmingly, respondents agreed that the proposed revised GLP regulations should
be adopted but with revisions. The areas that respondents felt needed to be revised in descending
order of importance include GLP quality system, multisite studies, sponsor responsibilities,
animal welfare and test and control article information. Respondents also expressed that the
GLP quality system would also be the most difficult to implement. This was highlighted by one
respondent by stating, “This is a vague requirement.” The results suggest that not only is this
requirement perceived as needing revision, but as being difficult to implement in its current state.
Management requirements were also perceived as being difficult to implement. One respondent
stated, “Unclear responsibilities and lack of point of control.” Another stated, “It is hard to
educate the sponsor that they also have to comply with GLP.”
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One respondent responded to the “other” category made a positive note regarding the
difficulty of implementing these new revised GLPs.
My current company, as with previous companies, have created systems and
SOPs to reflect an amalgamation of FDA, EPA, OECD, and ISO guidelines.
While we do not claim OECD (or ISO) compliance, many Sponsors expect to see
process/verbiage used in the OECDs, for example Principal Investigator, Lead
QA, experimental start date, etc. These have already been adopted and are used
in protocols and final reports. With regards to a Quality System, validated
computer software for data collection/correction, master schedule entries and QA
audit reporting, have been implemented in every company I have worked for. I
see no difficulties in implementing the proposed revisions to the GLP regulations
at my current company. (survey respondent).
This response suggests that some companies are already implementing some of these new
requirements ahead of the release of new regulations, in part due to their adherence to other
quality systems such as ISO and OECD GLP. However, when respondents were asked directly
if alignment of GLP with ISO 9001 would be beneficial, most said “no”. Respondents
commonly identified that maintaining two quality systems and terminology were the highest
areas of burden when trying to align the systems. As stated by two respondents.
I predate GLPs and predate the current testing requirements for medical devices.
My last 30 years has seen my realm of activity evolve to a near even split between
drugs (here you call GLPs) and Devices (ISO). Trying to force fit the two into a
single paradigm requires a lot of compromises that may not be desirable. (survey
respondent)
“9001 is tailored for manufacturing operations and multiple requirements are not
applicable for R&D.” (survey respondent)
One positive response did, however, suggest that a thoughtful alignment between ISO
9001 and GLP could be achieved:
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ISO will implement more GLP terminology which could cause confusion in the
industry, however if differences in quality management systems are considered
and appropriate terminology can be used, this may be beneficial but will take time
to establish procedures to support. (survey respondent)
Respondents felt that resistance from personnel, higher cost and additional
documentation were the top three perceived challenges to implementing the new proposed
regulations. Their views align with previous sentiments, submitted by SQA during the comment
period of the NPRM, regarding the added cost and burden upon the industry (Ault, 2011). For
example, SQA stated that the addition requirement to notify FDA when archived materials are
moved would require additional record-keeping and reporting (Ault, 2011). One respondent
stated, “It won’t work – a system that has been used for over 50 years is being completely
changed as far as the QAU is concerned.”
When asked about possible benefits of implementing the new proposed regulations,
respondents cited improved multisite oversight, increased management oversight and improved
QAU oversight as the three highest benefits. This shows that even though burdens are
anticipated, the revisions are not without value. Over half of the respondents also agreed that
implementing the new regulations would improve data quality over the current GLP regulations.
This is in alignment with the overwhelming response that the new regulations should be revised
and adopted. The benefits here outweigh the burdens.
The modest number of respondents who stated they were involved in Animal Rule
studies, were asked whether these study types should be added to the scope of the revised GLP
regulations. The large majority of respondents said “yes” and stated that all areas listed would
not be particularly challenging to implement. When respondents were asked about tobacco
studies being added to the scope of the revised GLP regulations, the response was also an
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overwhelming “yes”. This aligns with the fact that respondents listed the inclusion of Animal
Rule and tobacco studies as being the top area they would like to be able to comment on again as
discussed in section 5.3.4.
A few other areas of the revised GLP regulations such as animal welfare requirements
and harmonization with OECD on multisite studies, were viewed as positive. Most respondents
stated that the additional animal welfare requirements would improve the quality and integrity of
non-clinical studies, strengthen animal welfare and promote non-animal testing methods. The
responses on harmonization with OECD multisite studies also were in strong agreement that this
would increase the quality of the studies performed.
5.3.3 Quality of Communication
Routes of communication during and after the proposed new GLP regulations were
introduced were assessed based on perceived quality. Question and Answer with the FDA
ranked the highest as being the most helpful. This was followed by training programs for
companies provided by the FDA then followed by new regulations, a working group consisting
of industry and FDA representatives and new guidance documents. The least helpful were
perceived to be the industry working group on the topic and industry literature. The trend here
shows that any official communication route that involves the FDA is perceived as better than
without agency involvement.
Looking at unofficial communication routes by the FDA, all were seen as having some
benefit. These included clarity of communication regarding the proposed changes and timelines,
FDA talks at meetings, responses to questions submitted to the agency and impromptu
information sharing during encounters with FDA personnel. This highlights the fact that
industry, no matter the route, finds that there are benefits in communications with the FDA.
104
However, there was one comment that may highlight the need for additional or more frequent
communication by the FDA.
“What communications regarding proposed changes?” (survey respondent)
In the past few years, there has been little to no communication from the FDA regarding the
status of the proposed revisions. This results in industry living in limbo as they await some form
of communication.
5.3.4 Competence
Responses in this section aligned well with the quality of communication section in that
respondents would like to see more recent communication from the FDA in that it has been too
long since their last. The questions here revolved around the FDA’s process for stakeholder
input and requests for comments. In asking if the solicitation process for input was sufficient,
the majority response was yes. There were, however, additional comments. One respondent
stated, “It would have been but it’s close to 10 years since the feedback.” Another respondent
stated:
Their silence for so many years now is frustrating. I know something like this is a
significant undertaking and does require a great deal of time. However, it has
now been so long that it is frustrating and being unable to go to upper
management/leadership without anything concrete fosters an environment where
QA objectives can be scrutinized even more. (survey respondent)
Another commenter stated, “Yes, in that they got the input, but no in that they have to
completely revise the proposed regs and won’t be having a second tie for input on these new
revisions.”
Most respondents said “yes” to the question regarding whether the FDA should request
additional comments before finalizing the proposed new GLPs. This too aligns with the
perception that it has been too long since the previous draft was released and since the last FDA
105
communications. One respondent stated, “The proposed GLPs have been out for so long that we
need another round of comments.” Another respondent stated, “Publish updated proposal based
on all comments received and reinitiate comment period. I think the proposed regulations are
necessary for consistency with OECD but too many new areas of concern have also been
included in the proposed rule.” Even the respondents who selected “no” had additional
comments that spoke to the length of time that this process is taking. One respondent stated,
“This will only lengthen the process. We would like to see the final revised regulations as soon
as possible.” Another respondent stated, “It’s already been 13 years.” So, in this case both sets
of respondents agree that the process has taken too long and that they want to see something
from the FDA.
The most anticipated communication respondents would like to see from the FDA is
where industry could have the ability to comment again and was wanted for the following
categories. The Animal Rule and Tobacco studies were at the top followed by roles and
responsibilities, equipment/computer systems, multisite studies and record retention.
Interestingly, the areas of Animal Rule studies, roles and responsibilities and multisite studies
were highlighted by the FDA who took more specified considerations and more in-depth
requests for comments from these proposed changes in the call for comments in the NPRM
(Docket FDA-2010-N-0548) (Eitzen, 2017). The fact that Animal Rule and Tobacco studies
were at the top also aligns with concerns raised during the comment period of the proposed new
rule. For example, SQA suggested the Animal Rule studies be conducted under their own
regulations (Eitzen, 2017).
106
5.3.5 Cost of Implementation
Perceived views on the costs of implementing and maintaining the proposed revisions to
the GLPs were also assessed. Most respondents agree that CRO’s, rather than sponsors would
bear most of the direct costs of implementation. This is in contrast to the OMB’s assessment in
that they found that the changes needed for reporting and recordkeeping may increase the costs,
but these costs would mostly be covered by sponsors funding the studies. The annual cost
estimate for the recordkeeping was $27.6 million, again, mainly paid by sponsors (OMB, n.d.).
Perhaps this difference reflects that the OMB assessment did not take operational costs such as
time and resources into account. CRO’s would be responsible for much of the cost associated
with initial implementation, money that they would have to gain back by charging the sponsors
more to run their studies. Thus, sponsors would indirectly have to pay for implementation
through increased fees, aligning with the OMBs conclusions but not for the same reasons.
Regardless, respondents agreed that the cost to implement will impact their company and
will slow down the implementation process. Their conclusions are consistent with comments on
the NPRM. For example, Merck Pharmaceuticals stated in their response letter dated January
21, 2017, that:
We are concerned that, as written the proposed requirements place unnecessary
burdens on industry by introducing redundancies and administrative steps that do
not contribute to data quality or integrity. Further, we suspect that the time and
cost estimates outlined in the docket are underestimated and do not reflect the
true economic impact of the proposed changes. (Mahoney, 2017)
The SQA also stated in a memo to FDA that they believed the proposed regulations not
only would increase costs and create a larger burden on industry but would also in turn create
less consistency between laboratories (Eitzen, 2017).
107
Lastly the perception of the cost of maintaining the proposed revised GLP regulations
was assessed compared to that of the current regulations. The respondents identified that
projected resource needs would be higher than the current cost of maintenance. The theme that
emerged here was that this was due to the increase in burden that the new revised regulations
would cause. One respondent stated, “It’s hard enough to maintain compliance with the original
regs…new regs will make processes even more onerous.” Another respondent commented,
“From a sponsor perspective, more personnel or additional outsourcing would be needed to
support Sponsor responsibilities that are not defined in the current version of the regulations.”
5.4 Final Comments
The purpose of this study was to gain insight into industry views regarding the current
GLPs and implementation of the proposed GLP revisions purported to improve study conduct
and the quality and integrity of the data. It also attempted to understand the industry’s views on
the transparency and communication of the FDA during the revision process. Both endpoints
were obtained.
As there has been no additional literature, documented discussions or other
communications since the responses to the NPRM, insight into the industry’s views is limited.
Respondents mostly agreed that the current GLP regulations need modernization and revision.
While this study points out the perceived burdens and benefits it also revealed several insightful
findings. The following three key themes emerged.
The first was the overwhelming consensus on the need for revisions to the current GLP
regulations. According to Rumsey, as pre-clinical testing and industry R&D processes have
evolved, including computer use and multi-site studies, questions over the interpretation of FDA
GLP have come to light (Rumsey, 2017). The industry was looking to have answered these
108
types of questions in the newly proposed revisions. For example, WuXi AppTec stated in their
Docket No FDA-2010-N-0548 response letter dated 20 January 2017, “WuXi AppTec welcomes
the agencies’ effort to revise and update 21 CFR Par 58, Good Laboratory Practice for
Nonclinical Laboratory Studies.” WuXi AppTec goes on to say:
In general, we agree that revisions to the regulations need to be considered due in
part to industry changes in which nonclinical laboratory studies are carried out
since the issuance of the regulations in 1978. As a result of industry changes, 21
CFR 58 revisions are desirable to clarify and define roles and responsibilities of
all parties involved in the conduct of GLP studies. (Williams, 2017)
The second theme that emerged is the need for increased FDA communication.
Regardless of the delivery route, FDA communication was perceived as better than without FDA
involvement. The need for additional or more frequent communication was highlighted as there
has been little to no communication in the past few years. The NPRM comment period closed in
2017 and there has been no update in the seven years since. Due to the length of time which has
passed, most of the respondents also want a period for additional comments prior to the
finalization of the proposed revisions.
The third theme that emerged is the need for the final rule process to be shorter. This
lengthy process is evident by the series of events that have played out during this revision
process. In December 2010, an ANPRM requesting information and comments from the
industry was published (75 FR 80011, 2010). Then in August 2016, six years after the ANPRM
request, an NPRM was published (81 FR 58342, 2016). The comment period on the NPRM was
closed in January 2017. Survey responses indicated that the solicitation process for input was
sufficient during these early years. However, it has now been eight years since the last request
for comments from the FDA. As one respondent stated, “The proposed GLPs have been out for
109
so long that we need another round of comments.” While there is an understanding that the
process takes time, it may be that now too much time has passed.
Perceived burdens were seen as increased cost and difficulty to implement based on
vague or unclear requirements, resistance by personnel and additional documentation. Perceived
benefits included increased study quality, improved multisite, management and QAU oversight.
Even though there were noted burdens, most respondents saw the need to revise the current GLP
regulations and indicated that the benefits would outweigh the burdens. The areas of GLP
quality system, multisite studies, sponsor responsibilities, animal welfare and test and control
article information were cited as needing revision. Alignment with ISO 9001 was not seen as
being beneficial. In contrast harmonization with OECD GLP, the addition of Animal Rule and
tobacco studies as well as animal welfare requirements were seen as beneficial.
This survey explored industry views, leaving ample opportunity for future studies that
investigate other ANPRM/NPRM processes for proposed new regulations and for the actual
implementation of the new revised GLP regulations once they have been finalized. The results
of this study can also serve to inform process policy going forward and guide revisions of
available material or additional material to be introduced by the FDA.
110
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https://www.google.com/books/edition/Preclinical_and_Clinical_Testing_by_the/QcZFAQAAM
AAJ?hl=en&gbpv=1&dq=Statement+by+Alexander+M.+Schmidt,+Commissioner,+U.S.+Food
+and+Drug+Administration+before+the+U.S.+Senate+Joint+Hearings+before+the+Subcommitt
ee+on+Health+of+the+Committee+on+Labor+and+Public+Welfare+and+the+Subcommittee+on
+Administrative+Practice+and+Procedure+of+the+Committee+on+the+Judiciary&pg=PR4&pri
ntsec=frontcover
Williams, S. (2017) Email to FDA, 20 January 2017, Docket No. FDA-2010-N-0548, NPRM
GLP. WuXi AppTec Inc. Available at https://www.regulations.gov/comment/FDA-2010-N-0548-
0188 (Accessed 10 October 2024).
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Appendices
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Appendix A. 81 FR 58342
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Appendix B. 21 CFR Part 58
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Appendix C. 49 FR 43530
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Appendix D. Survey
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Abstract (if available)
Abstract
This study examined current industry perspectives on the proposed revisions to the GLP regulations and their implementation to provide more insight into these questions. This study also assessed the industry's satisfaction with the FDA's rulemaking process.
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University of Southern California Dissertations and Theses
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Asset Metadata
Creator
Cobb, Kerry
(author)
Core Title
Surveying stakeholder views on the current good laboratory practices (GLP) regulations and their proposed revisions
School
School of Pharmacy
Degree
Doctor of Regulatory Science
Degree Program
Regulatory Science
Degree Conferral Date
2024-12
Publication Date
12/03/2024
Defense Date
12/03/2024
Publisher
Los Angeles, California
(original),
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
GLP,OAI-PMH Harvest,proposed revisions
Format
theses
(aat)
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Pacifici, Enjoo (
committee chair
), Bain, Susan (
committee member
), Cosenza, Mary Ellen (
committee member
), Richmond, Frances (
committee member
)
Creator Email
gskk241@gmail.com,kerrycob@usc.edu
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UC11399E8IZ
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etd-CobbKerry-13668.pdf (filename)
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Document Type
Dissertation
Format
theses (aat)
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Cobb, Kerry
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University of Southern California
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University of Southern California Dissertations and Theses
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The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright.
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Tags
GLP
proposed revisions