Download:
pdf |
pdfDEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Good Laboratory Practice for Nonclinical Laboratory Studies; Proposed Rule
Docket No. FDA-2010-N-0548
Preliminary Regulatory Impact Analysis
Initial Regulatory Flexibility Analysis
Unfunded Mandates Reform Act Analysis
Economics Staff
Office of Planning
Office of Policy and Planning
Office of the Commissioner
August 2016
Table of Contents
I.
Preliminary Regulatory Impact Analysis .............................................................................................. 3
A.
Introduction and Summary................................................................................................................ 3
1.
Introduction ................................................................................................................................... 3
2.
Summary ....................................................................................................................................... 4
B.
Background and Baseline.................................................................................................................. 6
C.
Need for Regulation ........................................................................................................................ 10
D.
The Proposed Rule .......................................................................................................................... 10
E.
Benefits of the Proposed Rule......................................................................................................... 12
F.
Costs of the Proposed Rule ............................................................................................................. 13
3.
Reporting Costs ........................................................................................................................... 13
4.
Recordkeeping Costs .................................................................................................................. 18
5.
One-Time Costs from Reading and Understanding .................................................................... 20
6.
One-Time Costs from Updating SOPs and Writing New SOPs ................................................. 23
7.
One-Time Costs from Training ................................................................................................... 24
8.
Summary of Costs ....................................................................................................................... 24
G.
Analysis of Regulatory Alternatives to the Proposed Rule ............................................................. 26
1.
No Change in Regulation ............................................................................................................ 26
2.
Publish Additional Guidance ...................................................................................................... 27
H.
II.
International Effects ........................................................................................................................ 27
Initial Regulatory Flexibility Analysis ................................................................................................ 28
A.
B.
Who is Affected .......................................................................................................................... 28
Economic Impact on Small Entities ................................................................................................ 31
III.
References ....................................................................................................................................... 34
IV.
Appendix ......................................................................................................................................... 34
2
I.
Preliminary Regulatory Impact Analysis
A. Introduction and Summary
1. Introduction
We have examined the impacts of the proposed rule under Executive Order 12866,
Executive Order 13563, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Public Law 104-4). Executive Orders 12866 and 13563 direct
Agencies to assess all costs and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other advantages; distributive impacts;
and equity). We have developed a comprehensive Economic Analysis of Impacts that assesses
the impacts of the proposed rule. We believe that this proposed rule is not a significant
regulatory action as defined by Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze regulatory options that
would minimize any significant impact of a rule on small entities. Because the proposed
requirements are likely to impose a significant burden on small entities employing fewer than 10
workers in “Dental Equipment and Supplies” (between 1.87 percent and 8.94 percent of average
annual sales), we find that the proposed rule would have a significant economic impact on a
substantial number of small entities, but the impacts are uncertain.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires that Agencies
prepare a written statement, which includes an assessment of anticipated costs and benefits,
before proposing “any rule that includes any Federal mandate that may result in the expenditure
by State, local, and tribal governments, in the aggregate, or by the private sector, of
3
$100,000,000 or more (adjusted annually for inflation) in any one year.” The current threshold
after adjustment for inflation is $146 million, using the most current (2015) Implicit Price
Deflator for the Gross Domestic Product. This proposed rule would not result in an expenditure
in any year that meets or exceeds this amount.
2. Summary
This proposed rule would amend the regulations regarding good laboratory practices
(GLPs) and would require that nonclinical laboratory studies (sometimes referred to as
preclinical studies) follow a complete quality system approach, referred to as a GLP Quality
System, when safety and toxicity studies support or are intended to support applications and
submissions to FDA. The proposed rule would expand the scope to include all products for
which nonclinical laboratory studies are currently conducted that are not explicitly discussed in
the current regulations, specifically tobacco products. The proposed expanded scope also
includes all applications and submissions under the Federal Food, Drug, and Cosmetic Act that
can be supported by the results of nonclinical laboratory studies. In addition, the proposed rule
would introduce and modify definitions, terms, and organizational and personnel roles and
responsibilities consistent with the implementation of the proposed GLP Quality System and the
prevalence of multisite studies. Finally, the proposed rule would incorporate wording consistent
with some of the existing domestic and international guidelines, rules or regulations covering
good laboratory practices such as those established by the Organisation for Economic Cooperation and Development (OECD).
Costs of the rule, when final, would include annual and one-time costs. Annual costs
would include the additional reporting and recordkeeping responsibilities required under the
proposed GLP Quality System. One-time costs include reading and understanding the rule,
4
updating existing Standard Operating Procedures (SOPs), writing new SOPs, and training.
Combined, all costs annualized over a ten-year period at a 7-percent discount rate are estimated
to range between $34.4 million and $69.3 million, with an average annualized cost of $51.9
million. By contrast, with a 3 percent discount rate, annualized cost would range from $34.2
million to $68.9 million, with an average annualized cost of $51.5 million.
Conducting nonclinical laboratory studies under the proposed GLP Quality System is
expected to improve the reliability and quality of the data that support applications and
submissions to us, including those applications and submissions that lead to the use of new
medical products in first-in-human clinical studies. In addition, the proposed system is
conducive to improving compliance and accountability by all involved in the conduct of
nonclinical laboratory studies. The costs and benefits are summarized in Table 1 below.
Table 1.--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
Category
Primary
Estimate
Low
Estimate
Annualized
Monetized
$millions/year
Annualized
Quantified
Qualitative
Benefits
Annualized
Monetized
$millions/year
Costs
Transfers
Units
Discount
Rate
7%
Period
Covered
10 years
2014
3%
10 years
2014
2014
7%
3%
10 years
10 years
7%
10 years
$68.9 2014
3%
10 years
2014
2014
7%
3%
10 years
10 years
2014
7%
10 years
High
Estimate
Year
Dollars
2014
The proposed rule would
clarify GLP standards to
facilitate a more consistent
approach and provide greater
international consistency. As a
result, we anticipate
improvements in the integrity
and quality of data submitted
for FDA review decisions.
$51.9
$34.4
$69.3 2014
$51.5
$34.2
Annualized
Quantified
Qualitative
Federal
5
Notes
Category
Effects
Primary
Estimate
Low
Estimate
High
Estimate
Year
Dollars
2014
To:
Units
Discount
Rate
3%
Period
Covered
10 years
Notes
Annualized
Monetized
From:
$millions/year
Other
2014
7%
10 years
Annualized
2014
3%
10 years
Monetized
From:
To:
$millions/year
State, Local or Tribal Government: None estimated.
Small Business: The proposed requirements would likely impose a significant burden on small entities
employing fewer than 10 workers in “Dental Equipment and Supplies” (between 1.87 and 8.94 percent
of average annual sales). However, we do not have data on how many of these dental-equipment small
entities perform nonclinical laboratory studies to support, or intended to support, an application or
submission regulated by us; only such entities would be affected by the rule.
Wages: None estimated.
B. Background and Baseline
Nonclinical laboratory studies, often referred to as preclinical studies when conducted
before first-in-human clinical studies, provide safety or toxicity information or both that is
essential for the development of FDA-regulated products and help determine the safety of new
food ingredients. For drugs administered to animals whose products will be consumed by
humans, such studies are critical for determining safe levels of residual drug product. For
tobacco products, nonclinical laboratory studies may provide evidence regarding the relative
toxicities of new or modified risk tobacco products. Our regulation of the conduct of nonclinical
laboratory studies is important to help ensure the quality and integrity of data derived from those
studies, the protection of human subjects, and that marketing decisions are based on accurate and
reliable data. To help ensure data quality and integrity, nonclinical laboratory studies must
comply with the good laboratory practice (GLP) regulations prescribed in Title 21 Code of
Federal Regulations, part 58 (21 CFR part 58). The conduct of these studies involves a variety
of persons, including sponsors, testing facilities, study directors, contributing scientists, principal
investigators, and contracted persons that are also affected by the proposed rule.
6
Current FDA regulations describing good laboratory practice (GLP) requirements
(21 CFR part 58) were developed when nonclinical laboratory studies were less complex.
However, nonclinical laboratory studies have grown larger in size (i.e., involve a greater number
of persons) and may involve multiple persons in a number of different locations--both foreign
and domestic. This added complexity can result in inadequate management of critical elements
of nonclinical laboratory studies. During GLP inspections we have found evidence of repeated
noncompliance or deficiencies, including organizational or personnel deficiencies. We use GLPinspection results as a measure of the degree of GLP non-compliance.
We classify results from inspections according to three categories: (1) if there are no
issues found, the inspection receives a No Action Indicated classification; (2) problems found
during an inspection that do not require regulatory action receive a Voluntary Action Indicated;
and (3) more importantly, if we uncover substantial non-compliance with GLP regulations, the
inspection is assigned an Official Action Indicated (OAI) classification.1 Column 3 of Table 2
shows that for all inspections classified between 2007 and 2012 the percentages of inspections
resulting in an OAI range from a minimum of 2 percent to a maximum of 12 percent.
Table 2.--GLP Inspections and Their Outcomes
1 Further guidance on this terminology can be found at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/ucm073059.h
tm.
7
Fiscal Year
2007
2008
2009
2010
2011
2012
Number of
Classified
Inspections
55
43
49
81
41
40
Percent of Classified
Inspections with
Official Action
Indicated (OAI)
7%
4%
12%
4%
10%
2%
Source: Bioresearch Monitoring (BIMO) Metrics,
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm261409.htm
Bioresearch Monitoring (BIMO) program data show that most of the deficiencies found
during GLP inspections are associated with: organizational or personnel inadequacies;
inadequate, incomplete, or lack of study reports or study records; study article or equipment
inadequacies; inadequate procedures followed when study deviations occur; inadequate or lack
of standard operating procedures or protocol; and animal care inadequacies. Table 3 below
shows the number of citations issued during inspections for fiscal years 2006-2012.
Organizational and personnel inadequacies include cases such as failure of a study director,
quality assurance unit, or testing facility management to fulfill their roles or functions as required
by the current regulation. The second most common deficiency found is associated with
problems with data, study records or study reports that were not adequately archived, recorded,
reviewed, maintained, or completed. Our investigators also found deficiencies with respect to
material essential to the study such as test or control articles, equipment, mixtures or reagents.
The top three most cited deficiencies account for most of the citations.
8
Table 3.--Deficiencies Found During GLP Inspections
Citation associated with
2006 2007 2008 2009 2010 2011 2012
Organizational or personnel
inadequacies
48
36
30
46
38
50
54
Study reports or study records
Test article, equipment, mixtures, or
reagents
SOPs
Study conduct
Protocol
Animal care
29
20
19
35
19
14
15
25
12
9
16
7
29
13
16
2
5
9
7
10
5
5
15
8
16
6
5
11
11
11
4
2
12
11
7
1
2
11
12
5
3
1
Source: TURBO Inspectional Observation Datasets of Bioresearch Monitoring (BIMO) GLP Inspections,
Fiscal Years 2006-2012, http://www.fda.gov/ICECI/EnforcementActions/ucm250720.htm.
Comments to the December 10, 2010 Advanced Notice of Proposed Rulemaking
(ANPRM 2010) (Docket No. FDA-2010-N-0548) supported the need to revise and clarify roles
and responsibilities of those involved in the conduct of nonclinical laboratory studies, including
management, the quality assurance unit, the sponsor, the study director, the collaborating
scientists, and the other entities involved in the conduct of a nonclinical laboratory study.
Several comments called for FDA GLP regulations to be aligned with other existing regulations
or guidelines such as Environmental Protection Agency (EPA) GLPs (Ref. 1), the Organisation
for Economic Co-operation and Development (OECD) Principles of GLPs (Ref. 2), or the
Animal Welfare Act. Many comments requested that we provide further clarification with
respect to documentation and retention of data, study reports and study records. Comments from
stakeholders recognized the importance of having a GLP quality system. However, some
comments suggested that the ISO 9001, in addition to being too prescriptive, was not adequate
for the conduct of nonclinical laboratory studies. Instead, comments recommended that we
require a flexible system such as the one required by OECD Principles of GLPs or to model it
after 21 CFR part 820 (manufacturing quality system requirements for medical devices). The
9
comments concluded that additional oversight by FDA on animal welfare could result in
duplicative efforts. Finally, commenters indicated that allowing us to review findings on quality
assurance inspections could compromise candid disclosure and undermine the intended role of
the quality assurance unit.
C. Need for Regulation
Based on outdated practices, our existing GLP regulations fail to reflect the current
conduct of nonclinical laboratory studies, especially for multisite studies. This can create
confusion about how we expect people to conduct these studies. Some provisions written prior
to the widespread use of electronic media require persons conducting nonclinical laboratory
studies to maintain paper records, requirements that hamper the efficient use of resources. Our
current GLP regulations create a potential institutional failure that inhibits a modern quality
system approach to conduct these studies. Modernizing the GLP regulations and providing a
flexible framework to promote use of a complete quality system approach would inform persons
conducting nonclinical laboratory studies of our expectations and reduce uncertainty. With a
flexible framework, we allow laboratories to implement a GLP Quality System to efficiently use
their resources. We expect that studies conducted under a complete quality system would
generate consistently higher quality data, improving the data integrity of studies used to support
regulatory decisions about product safety.
D. The Proposed Rule
Incorporating stakeholder feedback and our experience, the proposed rule would require
the implementation of the proposed GLP Quality System’s full quality system approach. First,
the proposed rule would clarify and define new terms, roles, and responsibilities for all persons
involved in the conduct of nonclinical laboratory studies to accommodate current practice, i.e.
10
address multisite studies, and to be more consistent with other existing domestic and
international regulations and guidelines. This also involves proposed requirements for additional
information to be included in existing standard operating procedures (SOPs) as well as new
SOPs needed to implement the proposed GLP Quality System. It also proposes implementing a
‘checks and balances’ system to further ensure integrity of the data; GLP compliance; and proper
recording and retention of study materials, documents, and reports. Second, it proposes that all
entities involved in the conduct of a nonclinical laboratory study such as a sponsor, testing
facility, contributing scientist, the quality assurance unit (QAU), and contracted person are
explicitly defined as are their roles and responsibilities. As part of this, all persons who conduct
a phase of the study would be subject to inspection and disqualification.
Third, the proposed rule would expand the scope of current regulations to include all nonclinical laboratory studies for safety or toxicity or both that support an application or submission
to us. This includes applications involving tobacco products and other products such as
abbreviated new animal drug applications, applications for conditional approval of new animal
drugs for minor use or minor species, authorizations to market edible products from experimental
animals, Humanitarian Device Exemptions (HDEs), and premarket submissions (510(k)s). Thus,
by proposing to expand regulatory oversight, the proposed rule would address gaps in current
GLP regulations.
Further consistency of FDA’s GLP requirements with EPA’s GLP regulations and the
OECD Principles of GLP can help reduce expenditures and required resources for those entities
that already have processes in place to meet the requirements of either or both of them. Clarifying
roles and responsibilities for those involved in the conduct of nonclinical laboratory studies can
improve the integrity and quality of the data submitted in support of applications and submissions
11
to us. A more consistent global approach can facilitate the conduct of nonclinical laboratory
studies and help to enhance compliance.
E. Benefits of the Proposed Rule
Given the complexity of the nonclinical laboratory studies enterprise and lack of data, we
cannot quantify or monetize benefits arising from this rule. We seek comments or data to
support (quantify or monetize) the benefits of this rule. Lacking data to monetize the potential
benefits, we provide a summary of comments received from stakeholders (FDA Docket 2010-N0548) to describe what some of the benefits of the proposed rule could entail. Review of the
comments indicates that there is significant support for revising the current regulation. The most
common reasons given to support revisions to GLP regulation (21 CFR part 58) included: the
inadequacy of the current regulations, the need for clarification of roles and responsibilities of all
entities involved in the conduct of clinical laboratory studies, and the alignment of GLP
regulations with other international regulations. Some comments also suggested that to some
entities, revisions to GLP regulations would reflect current practice.
Many comments suggested that we revise the provisions pertaining to organizational
structure or personnel roles, international consistency, study records, study data, and study
material. Such revisions would modernize our regulations to better match current business
practices and remove some regulatory obstacles that could hamper efficient use of resources
(e.g., requiring paper records rather than accepting electronic records).
Beside potential gains in efficiency, the proposed rule could provide additional benefits
from the implementation of the proposed GLP Quality System. A more consistent alignment of
our regulations with other existing international and domestic GLP regulations and guidance can
further reduce duplicative efforts or allocation of resources. This in turn could reduce
12
development costs and improve compliance. We believe that implementing the proposed GLP
Quality System will help ensure uniformity, consistency, reliability, quality, reproducibility, and
integrity in all aspects of a nonclinical laboratory study, which will result in improvements in the
quality and integrity of data submitted in support of applications and submissions to us.
Nonclinical laboratory study data form the basis for our characterization of potential
hazards and risks that humans could be exposed to during an investigational study or can help us
understand risks that emerge after years of marketing an approved product. For example,
nonclinical laboratory studies help determine the safety of new food ingredients. Nonclinical
laboratory studies are also critical for determining safe levels of investigational drugs that may
be used in human subjects participating in clinical studies. Nonclinical laboratory studies also
provide certain information on the safety and effectiveness of medical devices that would not be
possible, or ethical, to test in humans during the development stage, e.g., heart valves. And, for
tobacco products, nonclinical laboratory studies help in providing evidence of the relative
toxicity of new or modified risk tobacco products.
We request detailed comment on the potential benefits of the proposed rule.
F. Costs of the Proposed Rule
The proposed requirements would result in annual costs from reporting and
recordkeeping. In addition, we estimate one-time costs from reading and understanding,
updating SOP and writing new SOPs, and training. These costs are in turn discussed in the
subsections that follow.
3. Reporting Costs
The proposed rule proposes additional reporting responsibilities from various entities
involved in the conduct of a nonclinical laboratory study to enhance the information that is
13
essential to implement the proposed GLP Quality System, e.g., providing information on test,
control, and reference article characterization, reporting results of process-based inspections, and
adequate reporting of study deviations and study reports. Table 4A below briefly describes the
additional reporting requirements, and the proposed entity responsible for ensuring the
requirement is fulfilled.
Table 4A.--Additional Reporting Responsibilities Proposed by the Rule
Main Entity
Additional Reporting Responsibility
Responsible*
Sponsor
Quality Assurance Unit
(QAU)
R01. Provide test, control, and reference article
characterization and risk information
R02. Provide nonclinical laboratory study report in
support of applications and submissions
R03. Expanded content of QAU statement in final
study report
R04. Management report of actions taken when a
process-based inspection reveals problems
Management with
Executive Responsibility
R05. Management report of personnel deviations from
protocol
R06. Expanded contents of final study report
Study Director
R07. Compliance statement by study director
appended to final study report
R08. Summary report of close-out for discontinued
studies
R09. Reports by independent contributing scientist(s)
to study director or principal investigator
Contributing Scientists R10. Study deviation reports from principal
or Principal Investigators investigator to study director
R11. Signed and dated compliance statement, final
study reports and amendments, if applicable, from
principal investigator to study director
Note: * Task may involve other assistance such as clerical.
14
With input from the Society for Quality Assurance (SQA) and other experts in the field,
we estimated the number of entities (responders), the annual reporting frequency, and total labor
hours associated with each of the additional proposed requirements. In estimating the value of
labor resources, we assume 25 percent of the total estimated labor time is allocated to clerical
assistance. We seek comments or data to support other assumptions on this issue.
Because the composition of the entities affected cover manufacturers across all product
areas regulated by FDA, we use the median hourly wage rate for industry sectors 31, 32, and 33
as reported by the Bureau of Labor Statistics for 2014 (Ref. 3) to value labor hours. Reporting
responsibilities for the sponsor or other entities with a managerial role are valued using
“Management Occupations,” (Standard Occupation Code (SOC), 110000) at $52.80 per hour.
Labor hours for contributing scientists or investigators are valued using an average of the wage
rate for the following occupations “Statisticians” (SOC 152041, hourly wage of $45.71),
“Chemists and Material Scientists” (SOC 192030, hourly wage rate of $35.82), “Veterinarians”
(SOC 291131, hourly wage rate of $34.26), “Biochemists and Biophysicists” (SOC 191021,
hourly wage rate of $40.92), “Environmental Scientists and Specialists including Health” (SOC
192041, hourly wage rate of $41.83), “Biological Scientists” (SOC 191020, hourly wage rate of
$37.44), “Animal Scientists” (SOC 191011, hourly wage rate of $34.46). The average wage rate
among these occupations is $39.90. Clerical assistance is valued using SOC 434071 (“File
Clerks”) reported at $14.42 per hour. Before calculating the estimated labor cost we multiply the
reported wage rate by 2—a commonly used multiplier—to adjust the median hourly wage rate
for benefits and overhead.
Estimated total cost for each of the additional proposed responsibilities is determined by
multiplying the number of entities affected by the annual reporting frequency per entity affected
15
and the unit labor cost (see Table 4B). Unit cost of labor for each reporting responsibility is
calculated as the labor hours per entity involved in the specific reporting task times the wage
rate. For instance, total cost of $0.57 million for reporting responsibility code R01 (“Provide
test, control, and reference article characterization and risk information”) is calculated as
follows: 1,316 respondents x 5 average annual responses per respondent x (0.75 hours x $105.60
per hour + 0.25 hours x $28.84 per hour). The reporting costs for the remaining reporting
responsibilities, R02-R12, are calculated in a similar fashion. Adding the estimated costs across
all entities affected provides an estimated annual cost of the proposed rule of $5.8 million. We
note that even though Table 4B provides costs disaggregated by entity responsible; these costs
will be mainly paid by the sponsor funding the nonclinical laboratory study. We request
comments with data regarding the average annual reporting per entity as some entities may vary
from this expected average.
16
Table 4B.--Estimated Reporting Costs of the Proposed Rule
Main Entity
Responsible*
Sponsor
Additional
Reporting
Responsibility
Number
of
Entities
Affected
Average
Annual
Reporting
1,316
5
1
0.75
10
1
15
300
60.25
10
Unit Cost
($)
Total Cost
($millions)
0.25
$86.41
$0.57
11.25
3.75
$1,296.15
$0.01
0.25
0.19
0.06
$21.60
$0.39
2
5
3.75
1.25
$432.05
$0.01
300
10
0.5
0.38
0.13
$43.21
$0.13
300
60.25
2
1.50
0.50
$172.82
$3.12
300
60.25
0.5
0.38
0.13
$43.21
$0.78
300
2
2
1.50
0.50
$172.82
$0.10
30
1
5
3.75
1.25
$335.28
$0.01
R01
R02
Quality
Assurance Unit
(QAU)
Labor Hours (per response)
Total
Hours
per
Main
Respons
Entit
Clerical
e
y
Assistant
R03
R04
Management
with Executive
Responsibility
R05
R06
R07
R08
Study Director
R09
R10
Independent
200
10
1
0.75
0.25
$67.06
$0.13
Contributing
Scientist or
R11
Principal
Investigator
200
5
8
6.00
2.00
$536.45
$0.54
Total
$5.8
Note: * Hourly median wage rate for sponsor, QAU, and management with executive responsibility is $105.60, $79.80
for contributing scientists or principal investigators, and $28.84 for clerical assistants. Total may not add up due to
rounding. See Table 4A for a description of each reporting code. The number of affected entities and additional burden
come from the Paperwork Reduction Act estimates in the preamble.
4. Recordkeeping Costs
The proposed rule proposes additional recordkeeping responsibilities from multiple
entities involved in the conduct of a nonclinical laboratory study to enhance the information that
is essential for appropriate conduct of nonclinical laboratory studies, e.g., documenting protocol
and SOPs approval, documenting training and inspectional findings. Table 4C below briefly
describes the additional proposed recordkeeping requirements, and the proposed entity
responsible for ensuring each of the additional requirements is fulfilled.
Table 4C.--Additional Recordkeeping Responsibilities Proposed by Rule
Main Entity Responsible*
Additional Documentation Responsibility
K01. Protocol approval, including all amendments
Sponsor
Management with executive
responsibility
Quality Assurance Unit
(QAU)
Study Director
K02. Animal welfare determination
K03. Accreditation status of person conducting the animal testing
K04. Test, control, and reference article parameters
K05. Archival locations
K06. Qualifications of contracted persons
K07. Training and experience on GLP
K08. Training and experience on animal care
K09. All persons are qualified for multisite studies
K10. Periodic review of GLP Quality System
K11. Periodic review of QAU
K12. Appointment of management representative
K13. All test sites have master schedule
K14. Appointment of person to manage master schedule
K15. Selection of lead QAU for multisite studies
K16. Process-based inspections
K17. Audits of final reports of contributing scientists
K18. Audits of principal investigator reports
K19. Audits of final study reports for multisite studies
K20. Review of protocols and amendments
K21. Review of SOPs and amendments as they pertain to specific
studies
K22. Multisite need for PIs
K23. Document communications
K24. Compliance with protocol
Independent Contributing
Scientist
K25. QAU review of protocol and applicable SOPs
K26. Management provided adequate resources
K27. Computerized systems validated
K28. Review by animal study review board
K29. Multisite personnel qualified
K30. Test system as required
K31. GLP compliance
K32. Test article accountability when containers disposed of
K33. Education, training, and experience
K34. Archive location
K35. Appropriate animal care (when applicable)
K36. Protocol and protocol amendment acceptance
Principal Investigator
K37. Study deviations
K38. Archive location
Note: * Task may involve other assistance such as clerical.
To estimate recordkeeping costs we use the same wage rates discussed in section E1
above. However, we assume that documentation and recordkeeping activities involve 75 percent
of the total labor hours allocated to clerical assistants and 25 percent to the main entity
responsible for the documentation. Thus, after adjusting for benefits and overhead, the hourly
wage rate for entities with a managerial role (“Management Occupations,” SOC 110000) is
$105.60 and $28.84 for clerks (“File Clerks,” SOC 434071).
Estimated total cost for each of the additional recordkeeping responsibilities is
determined by multiplying the number of entities affected by the annual recordkeeping frequency
per entity affected and the unit labor cost (for brevity we provide this information in Appendix
Table A1). Unit cost of labor for each recordkeeping responsibility is calculated as the labor
hours per entity involved in the specific task times the wage rate. For instance, total cost of
$10.53 million for responsibility K01, “Protocol approval, including all amendments”, is
calculated as follows: 2,193 respondents x 100 responses per respondent x (0.25 hours x $105.60
per hour + 0.75 hours x $28.84 per hour). The recordkeeping costs for the remaining
19
responsibilities, K02-K38, are calculated following the same approach. We expect that the
average number records for recordkeeping of protocol approval, including all amendments, may
vary across, and within, industries and seek comments supported by data.
Table 4D below provides a summary of the recordkeeping costs by the main entity
responsible. Total estimated annual cost is $27.6 million. Again, even though the proposed
recordkeeping responsibilities would be required from entities other than the sponsor, all costs
are assumed to be ultimately borne by the sponsor funding the nonclinical laboratory study.
Table 4D.--Estimated Annual Recordkeeping Cost
Main Entity Responsible*
Cost Item Codes
K01-K06
Sponsor
Management with executive
responsibility
Quality Assurance Unit (QAU)
Study Director
Independent Contributing Scientist
Principal Investigator
Total
K07-K15
K16-K21
K22-K32
K33-K35
K36-K38
Estimated Cost
($million)
$13.75
$1.93
$6.36
$5.41
$0.00
$0.14
$27.60
Note: See Appendix Table A1 for further details on costs per item.
5. One-Time Costs from Reading and Understanding
We estimate the one-time costs to read and understand the proposed rule would be
between $1.49 million and $2.98 million, or $2.24 million on average. To calculate this cost, we
first estimate the time to read and understand the proposed rule (Table 4E). Then, we estimate
the cost for entities that would face lower complexity from reading the proposed rule and for
entities that would face higher complexity (Table 4F).
20
Table 4E.--Time to Read and Understand the Proposed Rule (per Entity)
Low
High
Lower Bound
Complexity
Complexity
Words of preamble
36,000
36,000
Words read per minute
250
200
Hours to read
2.4
3.0
People to read
1
2
Total hours to read
2.4
6.0
Total hours to understand
2.4
6.0
Total hours to read and understand
4.8
12.0
Low
High
Upper Bound
Complexity
Complexity
Words of preamble
36,000
36,000
Words read per minute
250
200
Hours to read
2.4
3.0
People to read
2
4
Total hours to read
4.8
12.0
Total hours to understand
4.8
12.0
Total hours to read and understand
9.6
24.0
Note: The number of words is an approximation and includes title and other words that some entities
would potentially skip. Therefore, such count is an upper bound of the reading burden.
In Table 4E we calculate lower and upper estimates of time to read and understand the
proposed rule under a low-complexity scenario for sponsors of nonclinical laboratory studies
who would face fewer provisions. Our estimates under a high-complexity scenario apply to
entities that would have to read and understand more provisions in the rule. Each calculation,
under either scenario, multiplies the estimated words in the preamble by the reading speed and
by the number of people to read and understand the rule. We use the resulting estimates in Table
4F to calculate the monetary cost.
21
Table 4F.--Cost to Read and Understand the Proposed Rule ($ Dollars)
Lower Complexity
Low
High
Average
Number of firms
2,193
2,193
Hours to read and understand
4.8
9.6
Adjusted hourly wage
$105.6
$105.6
Cost per firm
$506.9
$1,013.8
$2,223,
176 $1,667,382
Cost to read and understand the rule $1,111,588
Annualized over 10 years 3%
$195,468
Annualized over 10 years 7%
$237,398
Higher Complexity
Number of firms
Hours to read and understand
Adjusted hourly wage
Cost per firm
Cost to read and understand the rule
Annualized over 10 years 3%
Annualized over 10 years 7%
Low
300
12.0
$105.6
$1,267.2
$380,160
Total costs to read and understand
High
300
24.0
$105.6
$2,534.4
$760,320
$1,491,748 $2,983,496
Average
$570,240
$66,850
$81,189
$2,237,622
Note: The number of entities is from the Paper Reduction Act analysis in the preamble of this
proposed rule.
In Table 4F, we calculate the cost to read and understand the proposed rule for two groups
of entities. The first group at the top of the table is for sponsors of nonclinical laboratory studies;
the second group at the bottom half of the table represents estimates for testing facilities of
nonclinical laboratory studies. For example, for the first group, multiplying the number of
entities (2,193) by our estimates of hours to read and understand (4.8 hours, from Table 4E) by
hourly wage adjusted for benefits and overhead ($105.6), results in $1.1 million as the lower
bound. After estimating lower and upper estimates for each group of entities, we then add costs
for the two groups to calculate total costs at the bottom of the table, which range from $1.49
22
million to $2.98 million, or $2.24 million on average. In addition to total costs, we also present
costs per firm and annualized costs over a 10-year period.
6. One-Time Costs from Updating SOPs and Writing New SOPs
We estimate the one-time costs to update existing SOPs and to write new SOPs combined
would range between $5.1 million to nearly $12 million, or around $8.6 million on average. For
example, Table 4G shows that to calculate the cost of updating SOPs, we multiply the number of
SOPs per entity (12) by the time estimate to update an SOP (4 hours) by the adjusted hourly
wage ($86.4) and by the number of entities (300), thus resulting in a lower bound estimate of
$1.2 million. We estimate the rest of the estimates in the same way. The 300 firms represent
independent testing laboratories that firms regulated by any of our centers may contract out to
perform nonclinical laboratory studies on their behalf.
Table 4G.--Cost to Update Existing SOPs and to Write New SOPs ($ Dollars)
Update Existing SOPs
Number of SOPs to update (per
entity)
Time to update existing SOPs
(hours)
Adjusted hourly wage
Cost per firm
Number firms
Total cost to update SOPs
Low
Write New SOPs
Number of SOPs to write (per
entity)
Hours to write new SOPs (hours)
Adjusted hourly wage
Cost per firm
Number firms
Total cost to write new SOPs
Low
Total one-time cost to update
existing SOPs and to write new
High
Average
12
12
4
$86.4
$4,147.68
300
$1,244,304
11
$86.4
$11,406.12
300
$3,421,836
High
10
15
$86.4
$12,961.5
300
$3,888,450
$5,132,754
23
Average
10
33
$86.4
$28,515.3
300
$8,554,590
$11,976,426 $8,554,590
SOPs
Annualized over 10 years 3%
Annualized over 10 years 7%
$1,002,859
$1,217,981
Note: Part 58.81 describes the SOP provisions, and based on such provisions we estimate testing facilities would
update 12 SOPs each and write 10 additional SOPs. We use a 2007 ERG report (Evaluation of Recordkeeping Costs
for Food Manufacturers) to account for the number of hours that would be required to fulfill each SOP provision.
The adjusted hourly wage assumes that managerial staff would participate in 75% of the process and that the
remaining 25% of the process would be completed by clerical staff. Thus, the adjusted hourly wage is: 0.75 x $105.6
+ 0.25 x $28.82. This adjusted wage also reflects adjustments for overhead.
7. One-Time Costs from Training
We estimate the one-time costs for training would be between $0.3 million and $2.9
million, or $1.6 million on average. To calculate this cost, we consider that for the low estimate
one person would be doing the training and one person would be trained. By contrast, for the
high estimate we consider that also one person would be doing the training and potentially three
people would receive such training. We then multiply the number of people involved in each
case by the number of hours and by the adjusted (for overhead and benefits) wage value and by
the number of entities.
Table 4H.--Cost for Training ($ dollars)
Initial Training
Low
High
Number of employees in training
(per entity)
2
4
Time to train (hours)
5
23
Adjusted hourly wage
$105.6
$105.6
Cost per firm
$1,056.00
$9,715.20
Number firms
300
300
Total cost to update SOPs
$316,800
$2,914,560
Annualized over 10 years 3%
Annualized over 10 years 7%
Average
$1,615,680
$189,407
$230,036
Note: We use a 2007 ERG report (Evaluation of Recordkeeping Costs for Food Manufacturers) to
account for the number of hours that would be required for training.
8. Summary of Costs
The estimated reporting, recordkeeping, reading and understanding, SOP, and training
costs are summarized in Table 4I below. The first half of this table shows the one-time costs,
24
which annualized at 7-percent over a 10-year period would range from $1 million to $2.5
million, or $1.8 million on average. In the second half of the table, costs are annual, and we do
not need to annualize such estimates. These annual costs of reporting and recordkeeping
combined would range from $33.4 million to $66.8 million and average $50.1 million.
Combined, the annualized total costs, at 7% over a ten-year period, would range from $34.4
million to $69.3 million and would average $51.9 million. Using a 3-percent discounting rate,
total annualized costs would range from $34.2 million to $68.9 million and would average $51.5
million.
If approximately 2,193 sponsors would be affected by the proposed rule, the average
(rounded off) annualized cost per sponsor would be between $15,678 ($34.4 million divided
2,193 sponsors) and $31,617 ($69.3 million divided by 2,193 sponsors) with a 7 percent discount
rate, or between $15,599 ($34.2 million divided by 2,193 sponsors) and $31,412 ($68.9 million
divided by 2,193 sponsors) with a 3 percent discount rate. This simple calculation assumes that
sponsors ultimately bear the cost that would arise from the proposed rule. Although the number
of sponsors comes from the Paperwork Reduction Act estimate, included in the preamble of this
proposed rule, we seek comments or data to support other estimates presented here or elsewhere
in this analysis.
Table 4I.--Total Costs of the Proposed Rule ($ Millions)
Type of cost
Frequency
Low
High
Read and understand
one-time
$1.5
$3.0
SOP update and write
one-time
$5.1
$12.0
Training
one-time
$0.3
$2.9
Total one-time
$6.9
$17.9
Total one-time annualized 7%
$1.0
$2.5
Total one-time annualized 3%
$0.8
$2.1
Reporting
Recordkeeping
Annual
Annual
25
$5.8
$27.6
$11.6
$55.2
Average
$2.2
$8.6
$1.6
$12.4
$1.8
$1.5
$8.7
$41.4
Total annual
$33.4
$66.8
$50.1
Total Annualized 7%
Total Annualized 3%
$34.4
$34.2
$69.3
$68.9
$51.9
$51.5
Note: In the first half of the table costs are annualized over a ten year period. For the second half,
costs are annual, and we do not need to annualize such estimates. Totals may not add up due to
rounding.
Under the proposed regulation, any person conducting one or more phases of a
nonclinical laboratory study would be subject to inspection and disqualification. The implied
assumption made throughout this analysis is that there will be 100 percent compliance, and as
such inspection and disqualification costs were not included in our estimates. We also assume
that resources to conduct additional compliance and enforcement are held constant—either there
is no change in our budget to these activities, or there is no reallocation of existing resources
from other areas. Relaxing these assumptions might increase the costs of the proposed rule for
industry. We may have inadvertently excluded some potential costs of the proposed rule and
welcome comments from affected laboratories. We also request detailed comment on our cost
estimate from academic and any other affected entities conducting nonclinical laboratory studies
intended to support an application or submission.
G. Analysis of Regulatory Alternatives to the Proposed Rule
1. No Change in Regulation
The simplest alternative would be to leave the existing GLP regulation unchanged.
Under the current regulation, failure to specifically include all persons conducting a phase of a
multisite study would remain unchanged and gaps in the current quality system would remain
unaddressed. Without addressing such gaps, the quality and integrity of the data used to support
an application or submission to us might be suboptimal. Additionally, any inefficient use of
26
resources to comply with regulations that differ from international standards or current practices
would continue.
2. Publish Additional Guidance
While guidance exists with respect to GLP regulation (Ref. 4), without regulation that
explicitly delineates the roles and responsibilities of the organizational structure and personnel,
study misconduct may continue along the observed increasing trend. FDA’s GLP guidance
document represents our recommendations with regard to the conduct of GLP studies, but it does
not establish legally enforceable responsibilities. Therefore, under this alternative, if the
recommendations in the guidance are not followed, the proposed benefits from improved
international consistency and improved data integrity and quality will not be realized.
H. International Effects
Foreign entities that are proposed to be subject to the proposed rule would incur the same
costs associated with the preparation and submission of the proposed requirements as incurred by
firms operating in the United States. The proposed rule would be unlikely to alter the current
mix of foreign and domestic manufacturing for the affected products. Nevertheless, we request
comment on the impact of the proposed rule on foreign laboratories.
27
II.
Initial Regulatory Flexibility Analysis
The Regulatory Flexibility Act requires agencies to prepare an initial regulatory
flexibility analysis if a proposed rule would have a significant effect on a substantial number of
small businesses, non-profit organizations, local jurisdictions or other entities. This analysis,
together with other relevant sections of this document, serves as the initial regulatory flexibility
analysis required by the Regulatory Flexibility Act.
We find that there would be a substantial impact on firms employing fewer than 10
workers in “Dental Equipment and Supplies.” We estimate an impact between 1.87 percent and
8.9 percent of average annual sales. Therefore, we anticipate that this rule may have a
significant economic impact on some small entities, and invite comments from stakeholders on
this conclusion. We also seek comment, particularly from small entities, about the proposed
effective date of 1 year after the date of publication of any final rule that may issue to help us
determine if such time frame is appropriate.2
A. Who is Affected
There are various types of entities that conduct nonclinical laboratory studies intended to
support an application or submission. The nature of such entities may vary from general
academic laboratories to specialized industry laboratories. Although some entities performing
such nonclinical laboratory studies may be considered small according to the Small Business
Administration (SBA), costs are likely paid by the sponsors funding the nonclinical laboratory
studies which may be larger according to annual revenue.
The SBA uses different definitions of small entity for different industries. Table 5A
below summarizes the size standards to determine a small business entity based on the SBA
2
See the proposed rule, section VI. – Proposed Implementation Plan.
28
standards and the North American Industrial Classification System (NAICS) for the industries
covered by the proposed rule (Proposed Rule Economics Ref. 5). Based on SBA size standards,
except for blood and organ banks whose size is determined based on revenues, most firms
covered by the proposed rule would be considered small if they employ fewer than 500
employees. Firms in the tobacco industry would be considered small if they employ fewer than
1,000 employees. Firms in the pharmaceutical industry are considered small if they employ
fewer than 750 employees. Blood and organ banks would be considered small if their annual
revenue is less than $10 million. Table 5A below provides a summary of the size standards as
determined by the SBA.
We may have inadvertently excluded some potential entities such as academic
laboratories because the NAICS classification does not allow disaggregation of such entities and
because such entities likely perform other research beyond nonclinical laboratory studies. We
request detailed comment on how the proposed rule would affect academic and any other entities
conducting nonclinical laboratory studies intended to support an application or submission.
Table 5A.--Small Business Size Standards for Industries Covered by the Proposed Rule
NAICS Code
Size
Size standards
or
Standards
(Number of
Subsector
Description
( million$)
Employees)
Food Manufacturing (includes animal
311
500 to 1,000
food)
3122
Tobacco Manufacturing
1,000
Pharmaceutical preparation
325412
750
manufacturing
325413
In-vitro diagnostic substance
500
Biological Product (except Diagnostic)
325414
500
Manufacturing
334510
Electromedical and electrotherapeutic
500
334516
Analytical laboratory instruments
500
334517
Irradiation apparatus
500
339112
Surgical and medical instruments
500
339113
Surgical appliance and supplies
500
339114
Dental equipment and supplies
500
29
339115
621991
Ophthalmic goods
Blood and Organ Banks
500
$10.00
Currently available data from the 2007 Economic Census (Ref. 6) show that at least 92
percent of the establishments in pharmaceutical, medical devices, foods, and biologics (except
blood and blood organs) industries would be considered small by SBA standards.3 Our
Registration and Listing data indicate that 15 (12.7 percent) of the registered tobacco
manufacturers are considered small. Using revenue measures as determined by the SBA
standards we estimate that 72 percent of blood and organ banks would be considered small (see
table 5B).
Table 5B.--Estimated Number of Firms or Establishments Considered Small
NAICS
Code or
Subsector
Description
Total Number
of
Establishments
Establishments
Considered
Small*
Estimated
Percent of
Establishments
or Firms
Considered
Small**
311
Food Manufacturing
(includes animal food)***
3122
Tobacco Manufacturing****
325412
Pharmaceutical preparation
manufacturing***
325413
In-vitro diagnostic substance
991
259
916-969
245
325414
Biological Product (except
Diagnostic) Manufacturing
350
335
95.7%
334510
Electromedical and
electrotherapeutic
671
638
95.1%
334516
Analytical laboratory
instruments
334517
Irradiation apparatus
636
181
620
175
97.5%
96.7%
25,616 25,019 – 25,443
193
25
3
97.7 - 99.3%
12.71%
92.4 - 97.8%
94.6%
Although the SBA standard indicates that a firm in NAICS 325412 would be considered small if it employs fewer
than 750 employees, due to data limitations our estimate is based on the average number of establishments with 500
and 1000 employees.
30
339115
Surgical and medical
instruments
Surgical appliance and
supplies
Dental equipment and
supplies
Ophthalmic goods
621991
Blood and Organ Banks
339112
339113
339114
1,340
1,293
96.5%
2,219
2,189
98.6%
756
622
753
614
99.6%
98.7%
1,267
908
72%
Note: *Due to the construction of the Economic Census data we are unable to disaggregate the data for
establishments with fewer than 750 employees. ** NAICS 621991 includes 1267 establishments associated with 365
firms. To calculate the average annual sales we divide annual revenue by the total establishments in various
employment size categories; a firm is considered small if its average sales are under $10 million. *** For NAICS
code 325412 and subsector 311, the lower bound is based on the number of establishments with fewer than 500
employees, and the upper bound is based on the number of establishments with fewer than 1000 employees. ****
Number of establishments for tobacco products is based on FDA registration and listing information, revenue data
are from the 2007 Economic Census.
B. Economic Impact on Small Entities
The implementation of the proposed GLP Quality System will result in additional costs
incurred by entities involved in the conduct of nonclinical laboratory studies, including the
sponsor, testing facility, and any contracted persons. However, although costs are incurred by
these various entities, the additional costs are ultimately paid by the sponsors funding the
nonclinical laboratory studies. Thus, reducing or increasing the costs to any of these entities
participating in the conduct of a nonclinical laboratory study will result in costs or savings
realized by the sponsor. In the cost section, we estimate that the average annualized cost per
sponsor is between $15,679 and $31,617 with a 7 percent discount rate. Using U.S. Census
Bureau data on the average annual revenue for each industry or sector, we estimate the average
annualized cost per sponsor as a percent of their average revenue for each of the affected
industries (Table 5C). For example, the low estimate impact for small establishments in sector
311 is 0.098%, calculated as average annualized cost ($15,679) divided by average annual
revenue ($15,938,000). Similarly, the high estimate impact for small establishments in sector 311
31
is 0.213%, calculated as $31, 617 divided by $15,938,000. All other calculations in the table
follow the same steps using the respective average annual revenue but using the same costs
estimates per sponsor.
Table 5C.--Estimated Economic Impact of the Proposed Rule on Small Entities
Small Establishment
NAICS
or
Sector
311
3122*
325412
325413
325414
334510
334516
334517
339112
339113
339114
339115
621991
Average
Revenue
($1,000)
$15,938
$11,318
$60,962
$25,639
$20,634
$17,559
$13,448
$16,523
$12,456
$7,720
$5,182
$4,828
$5,273
Large Establishment
Unit Cost as a Percent of Average
Revenue
Low
High
Average
0.098%
0.198%
0.148%
0.138%
0.279%
0.209%
0.026%
0.052%
0.039%
0.061%
0.123%
0.092%
0.076%
0.153%
0.114%
0.089%
0.180%
0.134%
0.116%
0.235%
0.176%
0.094%
0.191%
0.143%
0.125%
0.254%
0.190%
0.202%
0.410%
0.306%
0.301%
0.610%
0.456%
0.323%
0.655%
0.489%
0.296%
0.600%
0.448%
Average
Revenue
($1,000)
$319,898
$3,916,971
$1,160,470
$437,588
$992,395
$405,399
$277,881
$468,385
$293,519
$574,904
$241,505
$331,194
$11,492
Unit Cost as a Percent of Average
Revenue
Low
High
Average
0.005%
0.010%
0.007%
0.000%
0.001%
0.001%
0.001%
0.003%
0.002%
0.004%
0.007%
0.005%
0.002%
0.003%
0.002%
0.004%
0.008%
0.006%
0.006%
0.011%
0.008%
0.003%
0.007%
0.005%
0.005%
0.011%
0.008%
0.003%
0.005%
0.004%
0.006%
0.013%
0.010%
0.005%
0.010%
0.007%
0.136%
0.275%
0.205%
Note: *The Economic Census 2007 does not report data for establishments with fewer than 750 employees, therefore for all
establishments, except those in NAICS code 621991, we define a business entity as small if it employs fewer than 500
employees. ** Except for NAICS 621991, average revenue is defined as the total value of shipments divided by the total
number of establishments. For NAICS 621991, average revenue is total revenue divided by total number of establishments.
*** Due to confidentiality, the Economic Census 2007 does not report the value of shipments for all firms in NAICS code
3122; thus, the average revenue for both small and large establishments is underestimated. To calculate the average annual
sales we divide annual revenue by the total establishments in various employment size categories; an establishment is
considered small if its average sales are under $10 million. Table 5A describes each NAICS category.
Based on the available data, we estimate that the average annualized cost per sponsor
would represent a small portion of a typical sponsor’s average annual revenue. Table 5C shows
that the estimated cost would represent less than 1 percent of average annual sales for small
establishments. This suggests that the proposed rule would not have a significant effect on a
substantial number of small entities. We request detailed comment on our cost estimate from
32
academic and any other affected entities conducting nonclinical laboratory studies intended to
support an application or submission.
We also examine whether there could be a disproportionate effect among some very
small entities.4 Table 5D shows that for entities in the “Dental Equipment and Supplies”
industry (NAICS 339114), the proposed rule would have a greater impact on small entities
employing fewer than 10 employees than on small entities employing more than 10 employees.
The economic burden ranges between 1.87 percent and 8.94 percent of average annual sales for
the very small entities with less than 10 employees, compared to 0.04 percent or less for entities
employing between 100 and 499 workers. Moreover, the Census data indicate that small entities
hiring fewer than 10 workers represent approximately 72 percent ((426+120)/756) of all
establishments classified in this category. However, some very small entities included in the
Census data may not be sponsors affected by the proposed rule, and some of the smallest
sponsors may incur lower costs than the estimated average costs for all sponsors. Consequently,
we request comment from very small sponsors about the expected burden of the proposed rule.
Table 5D.--Economic Impact on Establishments on Dental Equipment and Supplies
(NAICS 339114)
Employees
0-4
5-9
10-19
20-49
50-99
100-249
250-499
4
Average Value
of Shipments
Number of
($1,000)
Establishments
$353
426
$834
120
$1,753
75
$5,467
72
$17,888
28
$78,583
25
$94,425
7
Unit Cost as a Percent of Average
Revenue
Low
4.41%
1.87%
0.89%
0.29%
0.09%
0.02%
0.02%
High
8.94%
3.79%
1.80%
0.58%
0.18%
0.04%
0.03%
Average
6.68%
2.83%
1.35%
0.43%
0.13%
0.03%
0.03%
Small Business Administration, “A Guide for Government Agencies: How to Comply with the Regulatory Flexibility
Act,” June 2010. http://www.sba.gov/sites/default/files/rfaguide.pdf, accessed November 6, 2015.
33
Note: Totals may not add up due to rounding.
III.
References
1. U.S. Environmental Protection Agency (EPA), “Good Laboratory Practice Standards,” :
http://www2.epa.gov/compliance/good-laboratory-practices-standard-operatingprocedures, accessed November 2015.
2. Organisation for Economic Co-operation and Development (OECD),
http://www.oecd.org/chemicalsafety/testing/goodlaboratorypracticeglp.htm, accessed
November 2015.
3. U.S. Bureau of Labor Statistics. “May 2014 National Occupational Employment and
Wage Estimates,” May 2014 Occupational Employment Statistics,
http://data.bls.gov/oes/, accessed November 2015.
4. U.S. Food and Drug Administration. “Guidance for Industry. Good Laboratory Practices.
Questions and Answers,” July 2007,
http://www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/UC
M133748.pdf, accessed November 2015.
5. U.S. Small Business Administration. “Table of Small Business Size Standards Matched
to North American Industry Classification System Codes,” March 26, 2012.
http://www.sba.gov/sites/default/files/files/Size_Standards_Table.pdf, accessed
November 2015.
6. U.S. Census Bureau, “Industry Statistics for Subsectors and Industries by Employment
Size: 2007 Economic Census,” American FactFinder, data downloaded December 11,
2012, http://factfinder2.census.gov/, accessed November 2015.
7. Eastern Research Group, Inc., “Evaluation of Recordkeeping Costs for Food
Manufacturers,” pp. 62, 2007.
IV.
Appendix
34
Appendix Table A1. Additional Recordkeeping Responsibilities Proposed by Rule
Main Entity
Responsible*
Additional Documentation Responsibility
Unit
Cost
Total
Cost
($mil)
0.75
$48.03
$10.53
0.50
1.50
$96.06
$0.63
0.5
0.13
0.38
$24.02
$0.16
5
0.5
0.13
0.38
$24.02
$0.16
2,193
62
0.3
0.06
0.19
$12.01
$1.64
K06. Qualifications of contracted persons
1,316
5
2.0
0.50
1.50
$96.06
$0.63
K07. Training and experience on GLP
K08. Training and experience on animal
care
K09. All persons are qualified for
multisite studies
K10. Periodic review of GLP Quality
System
K11. Periodic review of QAU
K12. Appointment of management
representative
K13. All test sites have master schedule
K14. Appointment of person to manage
master schedule
K15. Selection of lead QAU for multisite
studies
K16. Process-based inspections
K17. Audits of final reports of
contributing scientists
K18. Audits of principal investigator
reports
300
5
0.3
0.06
0.19
$12.01
$0.02
300
500
0.3
0.06
0.19
$12.01
$1.80
300
0.25
0.5
0.13
0.38
$24.02
$0.00
300
1
0.5
0.13
0.38
$24.02
$0.00
300
0.1
0.3
0.06
0.19
$12.01
$0.00
300
15
0.3
0.06
0.19
$12.01
$0.05
300
0
1.0
0.25
0.75
$48.03
$0.00
300
5
0.5
0.13
0.38
$24.02
$0.04
300
5
0.3
0.06
0.19
$12.01
$0.02
150
5
0.3
0.06
0.19
$12.01
$0.01
300
600
0.5
0.13
0.38
$24.02
$4.32
300
120
0.5
0.13
0.38
$24.02
$0.86
K01. Protocol approval, including all
amendments
K02. Animal welfare determination
K03. Accreditation of person conducting
the animal testing
K04. Test, control, and reference article
parameters
K05. Archival locations
Sponsor
Management with
executive
responsibility
Quality Assurance
Unit (QAU)
Labor Hours (per response)
Total
Hours
per
Main
Clerical
Response
Entity
Assistant
Number of
Entities
Affected
Average
Annual
Records
2,193
100
1.0
0.25
1,316
5
2.0
1,316
5
1,316
K19. Audits of final study reports for
multisite studies
K20. Review of protocols and
amendments
K21. Review of SOPs and amendments
as they pertain to specific studies
K22. Multisite need for PIs
Study Director
Independent
Contributing Scientist
Principal Investigator
300
60
0.5
0.13
0.38
$24.02
$0.43
300
17
1.5
0.38
1.13
$72.05
$0.37
300
17
1.5
0.38
1.13
$72.05
$0.37
300
180
1.0
0.25
0.75
$48.03
$3.07
K23. Document communications
300
180
0.3
0.06
0.19
$12.01
$0.77
K24. Compliance with protocol
300
60
1.0
0.25
0.75
$48.03
$0.87
K25. QAU review of protocol & SOPs
K26. Management provided adequate
resources
K27. Computerized systems validated
300
17
0.3
0.06
0.19
$12.01
$0.06
300
5
0.5
0.13
0.38
$24.02
$0.04
300
5
0.3
0.06
0.19
$12.01
$0.02
K28. Review by animal review board
300
17
0.3
0.06
0.19
$12.01
$0.06
K29. Multisite personnel qualified
300
15
1.0
0.25
0.75
$48.03
$0.22
K30. Test system as required
300
5
0.3
0.06
0.19
$12.01
$0.02
K31. GLP compliance
K32. Test article accountability when
containers disposed of
K33. Education, training, and experience
300
60
1.0
0.25
0.75
$48.03
$0.87
300
6
0.3
0.06
0.19
$12.01
$0.02
30
1
0.3
0.06
0.19
$10.39
$0.00
K34. Archive location
K35. Appropriate animal care (when
applicable)
K36. Protocol and protocol amendment
acceptance
K37. Study deviations
30
1
0.3
0.06
0.19
$10.39
$0.00
2
1
0.5
0.13
0.38
$20.79
$0.00
200
5
0.3
0.06
0.19
$10.39
$0.01
200
10
0.5
0.13
0.38
$20.79
$0.04
200
40
0.3
0.06
0.19
$10.39
$0.08
K38. Archive location
Total
$27.6
Note: * Task may involve other assistance such as clerical. Hourly median wage rate for sponsor, QAU, and management with executive responsibility is
$105.60, $79.80 for contributing scientists or principal investigators, and $28.84 for clerical assistants. Total may not add up due to rounding.
36
| File Type | application/pdf |
| File Title | Good Laboratory Practice for Nonclinical Laboratory Studies; Proposed Rule |
| Subject | economic, impact, RIA, good laboratory practice, nonclinical, laboratory |
| Author | Food and Drug Administration |
| File Modified | 2017-02-02 |
| File Created | 2016-08-25 |