Contains Nonbinding Recommendations

Guidance for
Industry and FDA Staff
General Considerations for
Animal Studies for
Cardiovascular Devices
Document issued on: July 29, 2010

For questions regarding this document, contact CAPT Victoria Hampshire, VMD, Office of
Device Evaluation, at 301-796-6395 or victoria.hampshire@fda.hhs.gov.

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Devices and Radiological Health
Office of Device Evaluation
Division of Cardiovascular Devices

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Preface
Public Comment
You may submit written comments and suggestions at any time for Agency consideration to
the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane,
Room 1061, (HFA-305), Rockville, MD, 20852. Submit electronic comments to
www.regulations.gov.

When submitting comments, please refer to the exact title of this guidance document.
Comments may not be acted upon by the Agency until the document is next revised or
updated.

Additional Copies
Additional copies are available from the Internet. You may also send an e-mail request to
dsmica@fda.hhs.gov to receive an electronic copy of the guidance or send a fax request to
301-827-8149 to receive a hard copy. Please use the document number 1717 to identify the
guidance you are requesting.

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TABLE OF CONTENTS

I. Introduction .................................................................................................................... 6

II. Scope .............................................................................................................................. 7

III. Overview ........................................................................................................................ 7

IV. Elements of the Animal Study........................................................................................ 8

A. Rationale for Selecting Animal Models...................................................................... 8

B. Study Assurances ........................................................................................................ 9

C. Study Objectives ......................................................................................................... 9

1. Performance and Handling.................................................................................... 10

2. Device Safety ........................................................................................................ 10

a. Mortality and Morbidity .................................................................................... 10

b. Vascular Safety.................................................................................................. 10

c. Downstream and Systemic Effects .................................................................... 11

D. Study Schedule.......................................................................................................... 11

E. Characterization of Test and Control Articles .......................................................... 12

F. Accessory Devices and Equipment........................................................................... 12

G. Test System............................................................................................................... 12

V. Personnel ...................................................................................................................... 13

VI. Facilities........................................................................................................................ 14

A. Environment.............................................................................................................. 14

B. Animal Groupings..................................................................................................... 14

C. Primary and Secondary Enclosures .......................................................................... 15

D. Transport Systems..................................................................................................... 15

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VII. Study Methods and Conduct......................................................................................... 15

A. Research Controls ..................................................................................................... 15

B. Study Equipment....................................................................................................... 16

C. Animal Identification ................................................................................................ 17

D. Animal Quarantine and Conditioning....................................................................... 17

E. Animal Allocation to Experimental Grouping.......................................................... 17

F. Food, Water and Basic Husbandry ........................................................................... 18

G. Periods of Observation.............................................................................................. 19

1. Acute Studies......................................................................................................... 19

2. Chronic Studies ..................................................................................................... 20

a. Post-Operative Period........................................................................................ 20

b. Interim Periods of Observation.......................................................................... 20

c. Terminal Study Period....................................................................................... 20

d. Necropsy and Post-Mortem Evaluation............................................................. 21

H. Post-Mortem Imaging and Assessment Methods ..................................................... 21

1. Explant Radiography............................................................................................. 21

2. Scanning Electron Microscopy (SEM) ................................................................. 21

3. Histomorphometric Analysis................................................................................. 22

4. Local and Downstream Tissue Assessment .......................................................... 22

VIII.Records and Reports .................................................................................................... 23

IX. Preparation of Regulatory Submissions ....................................................................... 23

Appendix A: List of Common Acronyms For Animal Studies ........................................... 25

Appendix B: Sample Decision Tree for Animal Studies in the Cardiovascular System ..... 26

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Appendix C: Recommended Animal Study Research Controls to Consider....................... 28

Appendix D: Sample Organization of Animal Study Test Reports..................................... 30

Appendix E: Tabulated Summary of Relevant Federal Regulations………………………34

Bibliography of Manuals and Publications.......................................................................... 35

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Guidance for Industry and FDA Staff

General Considerations for Animal
Studies for Cardiovascular Devices
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking
on this topic. It does not create or confer any rights for or on any person and does not
operate to bind FDA or the public. An alternative approach may be used if such
approach satisfies the requirements of the applicable statues and regulations. If you
want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the
appropriate number listed on the front page of this guidance.

I. Introduction

FDA has developed this guidance document to assist industry in designing evaluation
strategies for, and reporting the results of, animal studies involving cardiovascular devices,
including intra-cardiac devices and devices used in the coronary and peripheral vasculature.
The animal studies utilized for the assessment of these devices typically provide initial
evidence of device safety, their potential performance when used in a living system, and
the biologic response that a living system may mount towards the device. We recommend
that members of industry and FDA staff who perform or review evaluations of animal
studies for cardiovascular devices use this guidance. In this document, the terms “you” and
“your” refer to members of industry, also known as “sponsors” or “applicants”. The terms
“we,” “us,” “our,” and “Agency” refer to FDA.

The intent of this guidance is to provide a reference of best practices for the approach,
conduct, and presentation of animal study data intended to demonstrate that the device
under study is sufficiently safe for early human experience, while accounting for modern
animal care and use strategies. The guidance makes multiple references to pre-existing
regulatory requirements involving animal care and use.1-5 Of note, FDA maintains a
memorandum of understanding (MOU) with the U.S. Department of Agriculture (USDA)
and the National Institutes of Health (NIH) that addresses common areas of regulatory
practice under which animal studies are to be performed.38

We recommend that you use this guidance to develop and present animal study protocols,
methods, and reports that support the safety and performance of cardiovascular devices.
We intend to use this guidance to review animal study protocols, methods, data, and reports
provided in regulatory submissions to demonstrate the safety and performance of
cardiovascular devices.

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FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and
should be viewed only as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word “should” in Agency guidances means that
something is suggested or recommended, but not required.
 

II. Scope
 
This guidance applies to devices intended for use in the human cardiovascular system.
Cardiovascular devices encompass an array of product classifications, and many such
devices are defined in 21 CFR Subchapter H, Part 870.1 This classification consists of
medical devices intended for intra-cardiac or extra-cardiac use, or for use in the coronary
and peripheral circulations. The scope includes the carotid and renal vasculature, but
excludes the neuro-vasculature.

This guidance is intended specifically to apply to in vivo nonclinical laboratory studies as

defined in 21 CFR §58.3(d). A list of common acronyms encountered in relation to these
studies is provided in Appendix A. The recommendations in this document are also
consistent with those already published under Title 9 of the US Code and its applicable
definitions, regulations, standards, rules of practice, and policies. 2,4,5

III. Overview

FDA recommends that you consider the following general principles when developing
animal study strategies for cardiovascular devices:

 You should follow Good Laboratory Practices (GLP) for all animal studies
involving cardiovascular devices that are to be submitted to the Agency.

 The animal model selected for a cardiovascular study should be generally accepted
for the study of the device type. That is, there should be a reasonable amount of
scientific evidence that the animal model has utility for the study of the product
class.

 FDA’s primary purpose in asking for an animal study for a particular device is to
demonstrate sufficient safety including performance and handling. A secondary
objective is to study the efficacy of the device, if applicable. Sometimes the
performance of a particular device is intricately linked to its safety, such as for
products that provide circulatory support.

 The in vivo setting generally provides FDA with an initial assessment of how the
device interacts with biologic systems and also how the biologic system may affect
the device, such as via device corrosion and structural deformities.

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 You should observe the best practices of refinement, reduction, replacement, and
current standards of humane veterinary care and use. This may also involve
consideration of available validated alternatives.37-45
 
Recommendations regarding specific elements of animal studies are provided in the
following sections.

IV. Elements of the Animal Study

FDA recommends that your regulatory submissions include a discussion of each of the
following key animal study features:

 introduction, including a rationale for the selection of the particular animal model;

 the study assurances;

 the purpose and objectives of each test protocol;

 the study schedule;

 the methods and procedures utilized in the study;

 the characterization of the test articles and test systems;

 the in vivo study results;

 any ex vivo test article characterization;

 any ex vivo tissue characterization; and

 the relevant study conclusions, including any limitations imparted by the choice of
the animal model and any amendments and deviations from the original test
protocol.

Specific recommendations for how to optimize the development and reporting of some of
these elements are provided below.

A. Rationale for Selecting Animal Models

FDA recommends that you provide your rationale for the selection of particular
animal models for your animal study. A sample decision analysis flowchart for this
determination is provided in Appendix B. FDA believes that the animal and its
related environmental and physiologic attributes should provide a test system that
offers a best attempt at simulating the clinical setting. The rationale for the conduct
of an animal study should clearly state which of the elements of your risk analysis

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will be addressed and why the particular animal model was selected. If there are
limitations to the animal model such that the risks of the device are best addressed
by bench or cadaver testing, these relationships should be described. Your rationale
should also describe inherent challenges to the test system, such as:

 the similarities and differences between the test system and humans in the
metabolism of drugs or the use of ancillary devices that represent the
standard of care for the procedures utilized in device implantation;

 the size, including the diameter and length, of the device and delivery
systems, as compared to the same characteristics of the device version
intended for human use;

 the location of device insertion and the tracking pathway or, if surgically
placed, the anatomic point of surgical entry and the surgical technique
utilized in the animal versus the human;

 the tortuosity of the vascular bed of interest, and why any size limitations
exist as barriers (exclusive of cost) to obtaining the most size-appropriate
model; and

 if the device is intended for use in or near the heart, such as a prosthetic
heart valve or an endovascular aortic aneurysm graft, the selection of the
profile and diameter of the device, and the distance to key cardiac structures
such as the coronary ostia and the chordae tendinae.

B. Study Assurances
 
FDA requires that animal studies comply with animal care and research conduct as
detailed in 21 CFR Parts 58.90 and 58.130. Because managerial independence of
the Quality Assurance Unit (QAU) is required by FDA regulations (21 CFR 58.35),
we expect the final study report to be the report resulting from an independent
review of GLP. If it is not clearly stated in the Quality Assurance Statement (QAS)
the test report should clarify how the QAU is operationally independent from the
study managers. The statement should also include dates of inspection of each
aspect of the study schedule.

FDA recognizes that, for various reasons, use of a GLP facility may not be possible,
such as when a highly specialized skill set of investigators is only available at a
particular non-GLP facility. In these situations, FDA recommends that you provide
a complete rationale for the selection of the test site, and that you follow the highest
levels of oversight, record-keeping, and reporting. FDA also recommends that you
hire an independent auditor so that impartial quality assurance is provided.

C. Study Objectives

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FDA recommends that animal studies for cardiovascular devices be designed with
the objective of studying the risks that are predicted from the design of the device,
any known risks of the product class, and any new risks that may have emerged in
prior investigations such as bench testing or in feasibility studies.

Recommendations for evaluating specific types of risks are provided below.

1. Performance and Handling

FDA recommends that you consider combining performance and handling test
protocols with chronic study protocols. One potential way to accomplish this
goal is to develop case report forms for the implant phase of the study as a
mechanism for capturing handling, deployment, and implantation information.
As part of the study protocol, you should identify all steps required to deliver or
implant the device, and develop acceptance criteria for each of the steps. FDA
recommends that you apply an objective or subjective rating scale to each
acceptance criterion. If the device is delivered with ancillary equipment, the
acceptance criteria should include elements evaluating system compatibility.
Rating criteria should encompass steps between the preparation of the device
through device placement, and also withdrawal and redeployment, if
appropriate. If the device is surgically placed, all steps from entry through the
body wall through the final device handling steps should be described.

2. Device Safety

a. Mortality and Morbidity

FDA recommends that you fully explain all observed instances of animal
illness and death, and that any statements made regarding whether such
events are device-related be thoroughly described. Retrospective
testimonials or statements made by study directors, their designates, or their
consultants that explain veterinary clinical outcomes should be supported by
appropriate evidence, records, and reports. If the cause of death or illness
could be indirectly attributed to the device, you should discuss the etiology
of the condition. FDA recommends that you follow modern methods of
animal health surveillance for the purpose of detailing wellness or
morbidity, including the development of key assessments for systemic
effects of device use. These assessments includepostoperative, interim, and
terminal clinical pathology, such as but not limited to serum creatinine; liver
enzymes, (e.g., alkaline phosphatase); and electrolytes, (e.g., sodium, potassium
and calcium); and hemograms, including white and red blood cell indices.

b. Vascular Safety

Cardiovascular devices can cause mechanical or biologic stresses when used

in the vasculature. If your device will be used in or tracked through the

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coronary or peripheral vasculature, FDA recommends that you identify key

biologic response variables at regional sites, at locations adjacent to the
implant site, and along all paths to and from the point of implantation to
develop active means of surveying the impact of your device on the
vasculature. You may wish to work with pathology experts as part of this
approach. Some common biological evaluation parameters include:

 type and quantity of inflammatory components, such as neutrophils,

eosinophils, lymphocytes, giant cells, and macrophages;

 the cellularity of the intima, media, and adventitia;

 the presence of mineralization or ossification; and

 injurious events and biological responses such as disruption of the

internal or external elastic lamina, perforation, dissection,
hemorrhage, fibrin formation, and neointimal proliferation.

c. Downstream and Systemic Effects

FDA recommends that you evaluate whether or not devices placed in the
heart and vasculature can have effects remote from the site of placement. If
you believe that your device has the potential for this type of risk, you
should ensure that your study includes objectives to evaluate downstream
tissue for evidence of potential emboli that might be part of the device and
delivery system, or thrombi that might originate at the site of the device and
progress downstream. Should these findings occur, you should develop a
plan for assessing the quantity of tissue affected and whether there are any
resulting functional disturbances.

D. Study Schedule

FDA recommends that you develop a schedule of key interventions and endpoints
for your study, based on your knowledge of the known risks and predicated
outcomes of the device. These endpoints typically include:

 full characterization, implantation, and intermittent examination of device

performance and/or animal response;

 explantation of the device;

 full analysis of any explanted tissue;

 preparation of the tissue; and

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 preparation and sign-off of the final written reports.

FDA recommends that the QAU be aware of these key scheduling objectives so that
interim study monitoring and inspections can be arranged. Because cardiovascular
devices may involve some degree of invasiveness and predictable variability in
animal survival, FDA believes that any anticipated change in the duration of study
may necessitate adjustment of these parameters, depending on the interim data. For
example, if adverse outcomes are detected at earlier time points than expected, you
should consider enhancing the timetable for observation and device explantation so
that useful terminal data are not lost.5 FDA believes that the responsible use of
animals optimizes the use of all animal tissue and that tissue that is not freshly
studied is prone to erroneous interpretation.

E. Characterization of Test and Control Articles

FDA recommends that you fully characterize and account for all test and control
articles used in the study. Since investigators may often develop several iterations
of the test article prior to clinical study initiation, FDA recommends that pivotal
animal studies utilize test articles representing the final clinical design. If the final
design was not used, FDA recommends that you provide a rationale for why the
final clinical design presents no new risks to the patient compared to the design
studied in animals. In addition, FDA recommends that test and control articles be
packaged, sterilized, and shipped to the research site in the same manner as would
clinical product. Finally, FDA recommends that you develop and follow a method
for tracking the test and control devices from their manufacture or procurement to
final use.

F. Accessory Devices and Equipment

Some test articles, such as vascular stents, are typically used in conjunction with
specific or commercially-available accessory devices or components, such as guide
catheters or guidewires. Such accessories are sometimes described as a part of the
test system when their use is necessary to use the test article properly. FDA
recommends that you explain whether any accessory devices used in the animal
study are completely separate from the test article, whether they will be marketed
together with the test article, and whether the final labeling for the device will
include instructions for accessory device selection or use.

G. Test System

FDA recommends that you provide a sufficiently detailed description of the test
system so that FDA can make a reasonable assessment of all physical and
environmental contributions to the study outcome. 21 CFR 58.3(i) defines test
system as, “any animal, plant, microorganism, or sub-parts thereof to which the test
or control article is administered or added for study. Test system also includes

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appropriate groups or components of the system not treated with the test or control
articles. For the purpose of this guidance, FDA considers key components of a test
system to include the environment, including temperature, lighting, and physical
structure; nutritional status; homeostatic controls, including electrolytes, blood
glucose, maintenance of asepsis, and control of bleeding; ancillary diagnostic tools;
and materials and methods used to define or describe the interaction between test or
control article and the animal.

V. Personnel

FDA recommends that each test report contain a section that lists key study personnel.
FDA believes that this information is relevant to regulatory review because all applicable
regulations require that study personnel are appropriately trained and experienced to
properly carry out their duties. 2, 3, 5, 13,15 In addition, FDA believes that the training and
expertise of animal study personnel are especially important for cardiovascular devices
because many cardiovascular procedures require invasive techniques and a high level of
technical proficiency. Because the risks associated with cardiovascular devices may be
associated with subclinical or discrete subjective and objective findings, FDA recommends
that the animal study team include skilled clinical veterinary staff in order to detect and
resolve adverse outcomes, make decisions about the necessity to intervene, intervene
accordingly, or deviate from protocol in the interest of humane care, preserve valuable
tissue, and to assist in the determination of device associations with any adverse finding.

An animal study to support a cardiovascular device usually begins after a risk analysis,
bench testing, and other information, including scientific presentations, publications, or
non-anecdotal experiences, have identified the expected risks associated with the device.
FDA recommends that the animal study involve investigators with a combination of
expertise, including human clinical, veterinary clinical, and veterinary pathologic fields. In
keeping with best practices stated in 21 CFR Part 58 and other federal regulations and
policies, we also recommend that you record the qualifications and experience of all
personnel engaged in the conduct of animal studies and that any assessment of the
competencies of key personnel be based on a rationale for why the individuals are suited
for the type of studies being conducted. 2, 4

In addition to assembling a cadre of competent oversight personnel (including the study

director, QAU, and attending veterinary and interventional staff), FDA recommends that
you select the number of qualified personnel and their resources (including equipment,
lateral and subordinate personnel, records and reports, and standard operating procedures)
such that treatments and test sampling can be obtained at appropriate time points and to
ensure that there is active surveillance at these periods for risks known or predicted in
previous animal or bench testing, or possibly from previous experience with products in the
same class of devices. Finally, FDA recommends that you employ veterinary professionals
with adequate training and experience to evaluate the facilities, personnel, and
methodology that you may wish to contract from other business entities, such as contract
animal research or holding facilities.

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VI. Facilities

A. Environment

FDA recommends that you follow previously established regulations and principles
of humane animal care, including assurances to state, national, and international
authorities that a state of animal wellness is maintained during research as a well-
controlled test system.2-6, 17-20

While the selection of an appropriate animal model is left to the sponsor, FDA has
observed that dogs comprise the bulk of research involving cardiac pacing and
models in which heart failure is necessary. FDA has also observed that small
ruminants serve as a model for prosthetic heart valves and artificial circulatory
support devices, and that small swine represent the majority of other cardiovascular
research animals. As a result of these preferences, the recommendations on animal
study facilities in the following paragraphs focus on these particular models.

FDA recommends that you consult prior publications for recommendations and
regulations involving the housing and well-being of dogs5-7, swine and small
ruminants8-11. The referenced regulations and guides address minimum housing and
husbandry standards and social and environmental enrichment requirements, and
encourage the development of standard operating procedures that address timely
and adequate veterinary medial care. FDA believes that following these procedures
and allowing animals sufficient access to resources such as food and water
receptacles, toys, and clean and species-typical resting surfaces, and providing them
with opportunities for postural adjustments, adequate play and exercise, and
comfort and familiarity with handlers can reduce background stress, thus potentially
minimizing experimental confounding factors that could adversely affect the
interpretation of your study results.

In keeping with the standard of care, FDA recommends that the floors, walls, and
ceilings of animal holding structures be non-porous in order to permit easy
sanitization of surfaces. FDA recommends that there be adequate lighting and light
controls to permit periods of normal daylight and opportunities for rest. FDA also
recommends the utilization of facilities with appropriate environmental controls for
temperature and humidity in order to prevent temperature stress and minimize
respiratory infections.5

B. Animal Groupings

While 21 CFR Part 58.43 recommends isolation of intra-species test systems, other
national policies encourage animal play and contact in groupings in order to meet
standards of social enrichment. Regardless of whether your test system consists of
one group or multiple groups of animals within a study, FDA recommends that the
environmental conditions not interfere with the assessment of the device, and that
all animals have access to the same resources. If your protocol allows conspecific
housing, FDA recommends that you consider the effects of inter-animal

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socialization and tolerance once animals are housed in groups, and that you provide
adequate resources such as food, water, and toys in order to prevent bullying and
territorial stress.

C. Primary and Secondary Enclosures

Because many cardiovascular procedures necessitate frequent observations during

certain predicted sub-acute periods, FDA recommends that your facilities include
access to small recovery rooms or enclosures that can provide intensive care
treatments such as oxygen, swivel systems for intravenous medications, remote
ECG monitoring, and temperature and/or humidity adjustment. FDA also
recommends that you consider whether your protocol should include periods of
animal holding in high-level experimental facilities, with subsequent transport to
more agricultural facilities following post-procedural stabilization.

D. Transport Systems

To minimize the stress animals such as small swine, ungulates, and dogs can
experience during transport, FDA recommends that you consider the use of
transport cages with raised flooring, soft cushioning rest devices, carboys, hay nets,
or other enrichment and food/water devices to make transportation less stressful.12
Transport vehicles should afford the animals environmentally-controlled heating
and air conditioning in order to further minimize shipping stress.2, 5,

VII. Study Methods and Conduct

FDA recommends that the methods and materials utilized for the use of cardiovascular
devices in research animals be similar to those utilized in modern veterinary and human
hospitals. Monitoring and intervention strategies should be based on the previous
experience of key veterinary and scientific professionals. Once the failure modes and
effects that can be addressed in an animal study have been identified, you should develop
an animal study protocol that addresses each of the identified risks and that prescribes the
frequency and type of monitoring, interventions, and outcome assessments. Because
animal systems are imperfect and may often detect new safety concerns, the study
documentation should describe when protocol deviations typically can occur or have
occurred, and how these new safety concerns have been or will be addressed.

A. Research Controls
Evaluation of device safety prior to human investigational use is based largely on
animal studies that provide valid scientific evidence (21 CFR§860.7), and whether
or not a facility has adequate standard operating procedures to ensure the quality
and integrity of the data (21 CFR§58.81). FDA makes a distinction between the
research controls discussed in this documentand a control article. We consider
adequate animal research controls to include but not be limited to anything given to
or affecting the test animal in the course of an experiment that would impact the

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comparison between the test and control animals. Controls that may impart change
to the test animals may be devices other than the test article, or they may consist of
background factors such as environmental factors, concomitant medications, or co-
morbidities. For the purpose of assessing the effect of the test device on the animal
and of the animal on the device, FDA considers research controls to not only
include materials, but also minimization of confounding factors resulting from
unequal or erroneous methods and practices, as these factors can hinder the ability
of the investigator to clearly associate adverse or positive outcomes with the device
and or its effects.

With this consideration in mind, FDA recommends the use of personnel,

consumable equipment, and practices that enable test article-associated outcomes to
be clearly understood. Within the context of animal studies, FDA recommends that
you consider the use of the following controls:

 provision of physiologic homeostasis, such as adequate thermoregulation,

electrolyte, and blood glucose and caloric balance;

 procedures that minimize infection;

 a program to maximize animal wellness through the provision of species-

specific social nutritional adequacy and environmental enrichment;

 procedures that standardize the methods for the collection, handling, and
shipment of tissue specimens; and

 personnel and practices that demonstrate ample levels of training and

experience.

A sample reference of key controls for animal research studies is included as

Appendix C.

B. Study Equipment

Given that a cardiovascular device animal study is typically sophisticated in its

components, and in recognition of the shift from the use of sponsor-owned to
contract study facilities 15, FDA recommends that you encourage early and frequent
interaction between personnel involved in the planning of the animal study and
those who will actually perform the study. FDA believes this dialogue is especially
important to ensure that the study facilities have the proper ancillary equipment and
supplies for the study.

One common complexity in animal studies for cardiovascular devices is that

animals tend to benefit from multiple drug combinations to attain adequate
anesthetic depth and control of pain and distress, vascular spasm, infection, and
thrombosis. In addition, imaging equipment and personnel may be as advanced as

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those found in human interventional suites. Because of this relatively high level of
support, FDA recommends that study sponsors, their consultants, and the study
director carefully assess the care, maintenance, and knowledge of any contract
equipment associated with the conduct of the study.

C. Animal Identification

FDA recommends that animal identification, age, weight, sex, and baseline health
be fully characterized.1-3, If animals are re-identified for a particular study, you
should include a table of information pertaining to animal identification, allocation
to study sub-groups, and the fate or disposition of each animal. For example, if
animals are purchased with a USDA identification number but then subsequently
identified with an institutional identification number and then further described by a
group number, this information should be clearly understood and equally well
presented to FDA so that a chain of custody of any individual test or control
recipient is possible.

D. Animal Quarantine and Conditioning

FDA recommends that you follow the FDA and USDA regulations prescribing that
animal facilities adopt and implement standard operating procedures that permit for
adequate periods of quarantine and acclimation, as well as a program of
socialization.1,5, Because cardiovascular studies can be invasive and entail
predictable levels of pain or distress, background levels of disease and
psychological stress should be controlled as much as possible. Farm animals are
particularly prone to intestinal parasites, which commonly present sub-clinically but
can cause clinical syndromes under the stress of surgery and during recovery. To
minimize this confounding factor, FDA recommends that you initiate early and
frequent dialogue with the attending veterinarian about ways to detect and eliminate
clinical and sub-clinical disease to ensure optimal animal wellness. We recommend
that you follow the Animal Welfare Act, PHS policy, and their applicable
regulations and statutes, as these guidelines and regulations have resulted in
important changes in the use of environmental and socialization protocols that are
routinely implemented to control background stress. FDA believes that following
these regulations enhances the opportunity and intensity of observations and can
potentially result in other useful findings for the investigators. 1-5

E. Animal Allocation to Experimental Grouping

When considering the number of animals and the amount of data that can support
the safety and performance of a cardiovascular device, FDA recommends balancing
the veterinary principles of reduction/replacement/refinement as well as regulatory
least burdensome principles, with the goal of using the minimum number of animals
necessary to demonstrate adequate safety and performance. FDA believes that this
determination can best be made after bench testing is complete and the device
iterations are finalized, although we recognize that this is not always feasible. FDA

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recommends that the number of animals also be based on the difficulty of the model
and whether one or more test article and/or control can be reasonably studied in a
single animal. For example, FDA believes that deployment and handling studies
can often be performed multiple times in the same test subject, or incorporated into
a chronic safety study. By contrast, studies involving high-risk implants such as
prosthetic heart valves can involve such a high degree of expertise and some
expected morbidity that a relatively large number of animals may be appropriate, in
order to allow the Agency to reasonably interpret device safety. For novel devices
or animal models that are expected to be challenging, FDA recommends that you
complete key bench tests and conduct a full risk analysis before developing an
animal study strategy, so that your studies can include the most comprehensive
assessment of device safety and performance. If you wish to discuss your animal
study strategy with FDA prior to study initiation, you should provide this
information, as it can assist FDA in balancing responsible animal use and least
burdensome principles with a best effort to discover appropriate in vivo safety.
Designing and conducting animal studies prior to obtaining full knowledge of in
vitro performance or device-related risks may result in the need for additional
animal studies if new risks or failure modes are subsequently identified or elevated.

F. Food, Water and Basic Husbandry

FDA recommends that study animals be free of disease and that you provide
adequate resources to prevent conditions such as aggression, disparate growth rates,
and different patterns of sustenance and healing, and account for species-typical
states of wellness. As part of this approach, you should consider previously
documented nutrient requirements of commonly utilized animal species for
cardiovascular device research.20-23

FDA believes that weight loss, which can occur when incisions are made through
multiple tissue layers, or when recovery from a procedure is slow, can be
challenging to interpret, especially when accompanied by low serum albumin
levels. Thus, in order to separate weight loss as a sign of device-associated disease,
FDA recommends that you follow 21 CFR§58.90, which requires regular inspection
of food and water for contaminants as well as proper nutritional ingredients, and
that research facilities have standard operating procedures for the feeding and
hydration of animals and for the evaluation of body condition.1 As part of animal
evaluation, you should consider adopting a body scoring paradigm, a number of
which have already been developed for a number of species.33-36 You should ensure
that individuals monitor animals to document specifics regarding appetite, thirst,
and food and water intake, particularly when animals are pen-housed. Bullying and
resource coveting are commonly associated with weight loss due to inadvertent
caloric or fluid intake, and if not actively surveyed, an animal or group of animals
may present with unexpected weight loss near the conclusion of a study when
intervention is not possible. FDA recommends that sponsors expressly
communicate with subordinate and contract personnel the type and quantity of food
that will be offered, and also to pre specify that cage sizes and the location and
quantity of food receptacles should be ample in pen-housed situations. You should

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 Contains Nonbinding Recommendations

also consider following other research standards that more specifically prescribe
housing limitations.5

G. Periods of Observation

In keeping with the provisions for adequate veterinary care that are common to all
applicable national regulations, standards, policies, and procedures, 1-5,11, 16 FDA
recommends that you monitor study animals at a frequency and intensity that
adequately assesses for known risks posed by the device, and that you work with
attending veterinary staff at the study facility to develop these monitoring
parameters. FDA believes that such monitoring is appropriate not only for humane
reasons, but also because well-monitored animals best help FDA to sort common
spontaneously occurring conditions from conditions that might be attributed to the
device. To best characterize the device effects on the animal, FDA recommends
that the process should be active and specific, rather than passive and general.
Important attributes to consider for evaluation include, but are not limited to:

 respiratory rate pattern and depth;

 blood pressure;

 heart sounds and pulse character;

 mucus membrane color at rest and under exertion;

 attitude;

 mentation;

 gait; and

 presence or absence of abdominal, bladder, or bowel distension.

To best assist FDA’s assessment of test article safety, FDA recommends that you
follow current standards of record-keeping in veterinary medicine, such as the
subjective/objective assessment and plan (SOAP) format. Additionally, these
records should be readily available to all key support personnel in order to optimize
data entry.

Specific recommendations for animal study monitoring are provided below.

1. Acute Studies

If the study is acute and the device-associated trends are expected to be

transient during the period of acute observation and harvest, FDA
recommends that you track and record co-variables such as cardiac rhythm,

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 Contains Nonbinding Recommendations

respiratory rate, and blood pressure on operative records so that FDA can
evaluate safety concerns associated with major periods of implant. The
timing of insertion or deployment of the device and/or contrast or other
device-associated materials of use should be noted on the anesthetic and/or
operative records.

2. Chronic Studies

a. Post-Operative Period

In FDA’s experience, the post-implant or post-surgical period for most

cardiovascular studies is frequently one of intensive monitoring. FDA
recommends that you follow the current standard of care for laboratory
research animals by ensuring that investigators manage normal body
temperature, minimize pain and infection, and provide adequate fluids
and electrolytes. 5, 25-32 You should capture physiological information
similar in quality to that obtained in human intensive care and recovery
areas, so that any early success and failures deaths can be well described
clinically as well as by necropsy information if, for example, it is
necessary to euthanize an animal for humane considerations. In
addition, you should control stress variables by establishing a standard
assessment paradigm for the monitoring of pain and body temperature,
and directing the administration of additional warmth and pain killers
based on interim outcomes.

b. Interim Periods of Observation

During periods where animals have recovered from initial surgical

procedures but are to be monitored for device-associated risks, FDA
recommends that you monitor them at least twice daily at feeding times
so that they may be observed when active. We recommend that you
collect animal weight information on a weekly basis to establish any
weight loss as early as possible. You should consider inclusion of body
scoring to monitor conditions such as ascites of cardiogenic origin,
especially when cardiac output is a parameter of interest in the study, as
these animals may be losing body mass while still preserving weight as
fluid.

If your study involves the collection of clinical chemistry data or more

advanced diagnostics, FDA recommends that you develop standard
operating procedures that prescribe a method of chemical restraint that
does not interfere with the device. In FDA’s experience, some animals,
such as dogs and sheep, may be conditioned to be compliant for these
activities, while swine rarely are.

c. Terminal Study Period

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 Contains Nonbinding Recommendations

FDA recommends that the study protocol include details of the terminal
study and include all methodology for the collection and processing of
tissue. This section of the protocol should include the following
information:

 methods for end-period examination;

 whether or not in-life radiographic analysis of blood flow or

device positioning is needed;

 methods for establishing end weight; and

 anticoagulation, euthanasia, and tissue harvest methods, so that

we can determine whether all observations made during necropsy
and tissue preparation are related or unrelated to the method of
euthanasia or harvest.   

d. Necropsy and Post-Mortem Evaluation

FDA recommends that you include a comprehensive systematic

necropsy in your study, as the resulting information can help FDA to
determine whether observed adverse events are device-related. You
should support any statements regarding whether any adverse outcomes
are device-related with appropriate evidence from the necropsy report
and from in-life observations.

H. Post-Mortem Imaging and Assessment Methods

1. Explant Radiography

Prior to preparing devices for histomorphometric analysis, you should

consider whether an analysis of the structural integrity of the device would
assist in the determination of device safety. For devices that are implanted
in coronary arteries or intra-cardiac locations such as coronary artery stents
or prosthetic heart valves, you should consider the use of device radiography
in explanted whole hearts.

2. Scanning Electron Microscopy (SEM)

FDA recommends the use of SEM for characterizing the surface behavior of
devices implanted in animals and also for the characterization of
endothelialization of coronary and peripheral stents. We recommend that
your regulatory submissions include representation of best- and worst-case
outcomes, so that FDA can better appreciate the range of outcomes of your
study.

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 Contains Nonbinding Recommendations

3. Histomorphometric Analysis

Because proper interpretation of acute and chronic biologic responses is

critical to FDA’s evaluation of safety, especially in the absence of clinical
data, FDA recommends that you seek the expertise of board-certified
veterinary or clinical pathologists when developing and executing methods
for preparing explanted cardiovascular tissues for histomorphometric
analysis. We also recommend that you identify appropriate expertise to
develop pre-specified objective methods for scoring and analyzing
observations of injury and inflammation of vascular and peri-vascular tissue.
We recommend that you consider the inclusion of the following assessments
in your evaluation:

 endothelialization;

 mural injury;

 inflammation;

 vascularization;

 intimal fibrin;

 intimal and medial smooth muscle cell proliferation;

 adventitial fibrosis; and

 the integrity of the internal and external elastic laminae.

FDA recommends that you report the tools and methods used to extract the
tissue and the methods of fixation, cutting, and staining. The reports should
also include diagrams indicating the location of sectioned vessels or cardiac
structures, the sectioning methods, and the magnification of each section
image. When discussing the study results, you should include well-marked
high resolution color images, each indicating the animal number, study
group, tissue section, magnification, and other important identifiers.

4. Local and Downstream Tissue Assessment

FDA believes that most cardiovascular devices, including both implant and
delivery system components, have the ability to embolize particulates or
microthrombi from devices structural elements or coatings, resulting in
adverse observations such as downstream pressure necrosis and
inflammation. If your risk analysis identifies this potential risk for your
device, FDA recommends that your pathologic study include systematic
descriptive evaluation of downstream tissue. If foreign bodies are observed,

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 Contains Nonbinding Recommendations

you should provide a discussion of the amount of surface area affected as

well as the methods utilized to calculate this affected area. As part of your
evaluation strategy, you should consider whether retrograde embolization is
also possible. For example, venous congestion may occur with devices
placed in the coronary sinus, and renal congestion may occur due to
thrombus generated from inferior vena cava filter implantation.

VIII. Records and Reports

FDA recommends that you prepare the records and reports for your animal studies such
that FDA can most efficiently evaluate device safety and performance. You should include
the animal recordings and key study attributes as appendices to the study protocol, and
organize their format and content with the goals of explaining all study outcomes and
minimizing ambiguity in how contract and subordinate research personnel interpret their
responsibilities. FDA recommends that the protocol also contain information about how
the records will be organized and stored, who will make entries for each attribute, and
when interim inspection of the records will be performed. We also recommend time and
date stamping for study observations, so that the inter-observational differences between
study subjects may be established as part of the conformity to the test protocol.

IX. Preparation of Regulatory Submissions

When preparing regulatory submissions, including IDE, 510(k), and PMA submissions,
FDA recommends that you include all information collected as part of your animal studies.
FDA also recommends that your submission include a summary that provides an overview
of all the animal studies you conducted. This summary should discuss the number of
studies conducted, and include the following information for each of the studies:

 the rationale for the model selected;

 the similarity of the selected model compared to humans;

 the general animal study methodology you used;

 whether there were quality systems in place during the study; and

 how the quality systems maintained independence and impartiality in the inspection
of the data and the reporting of the results.

In addition, you should include your rationale for your transition from feasibility studies to
pivotal studies, or from one pivotal study to the next, as this information assists FDA in
understanding how you comprehensively assessed device safety and performance across
multiple studies. You should also describe any design changes to the device that were
implemented after completion of all animal studies.

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 Contains Nonbinding Recommendations

FDA recommends that you also provide a tabular representation of key parameters for each
study, including the following information:

 the study groups;

 the number of animals in each group;

 identification of animals corresponding to test group allocation;

 study duration;

 the device design iteration used; and

 a summary of study outcomes.

In addition, you should provide an attachment for each animal study that includes study
details, including individual scientific reports, accompanying test protocols, and raw data.
These attachments should also identify key study personnel and facilities, describe the
overall results of the study, and discuss how the results met the objectives of the study and
demonstrated that the device is safe for human use. To aid with the presentation of this
information, FDA recommends that your overall animal study summary identify and
present the individual test reports in a tabular format, and provide the locations of relevant
appendices and attachments within the submission.

When compiling more than one study into a group of attachments, FDA recommends that
you do so in the order in which the studies were performed so that FDA can follow the
device history and in vivo performance from the first to the last study and evaluate the
means by which you assessed device safety and performance and arrived at your final
conclusions. A sample organizational template for relevant content of the animal study
section of regulatory submissions is provided in Appendix D. Finally, FDA recommends
that your submission include the animal study information in an electronic bookmarked file
or similar format, as such a format can assist FDA with the animal study review.

In addition to these considerations, FDA recommends that you review any available FDA
guidance documents specific to your device type for more detailed animal study
recommendations.

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 Contains Nonbinding Recommendations

Appendix A: List of Common Acronyms Related to Animal Studies

AAALAC: International Association for Assessment and Accreditation of

Laboratory Animal Care

ACVIM: American College of Veterinary Internal Medicine

ACVECC: American College of Veterinary Emergency and Critical Care

ACLAM: American College of Laboratory Animal Medicine

APHIS: USDA Animal and Plant Health Inspection Service

CDRH: Center for Devices and Radiological Health

CLIA: Clinical Laboratory Improvements Act

CFR: Code of Federal Regulations

FDA: United States Food and Drug Administration

GLP: Good Laboratory Practices

IACUC: Institutional Animal Care and Use Committee

PHS: Public Health Service

QAS: Quality Assurance Statement

QAU: Quality Assurance Unit

SOAP: Subjective/Objective Assessment and Plan

USDA: United States Department of Agriculture

US: United States

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 Contains Nonbinding Recommendations

Appendix B: Sample Decision Tree for Animal Studies

in the Cardiovascular System

1. Have you completed a risk analysis that considered all sources of relevant
information, including your own knowledge of risks and failure modes that you
believe exist with your device, risks commonly attributed to this general device type,
and post-market information for similar marketed devices? Postmarket information
can be obtained from the published literature or the CDRH Medical Device Report
(MDR) database (http://www.fda.gov/cdrh/mdr/)

a. If yes, go to step 2.

b. If no, we recommend that you complete the risk analysis and then go to step
2.

2. Have all of the evaluable risks been tested on the benchtop using the final design
iteration?

a. If yes, go to Step 3.

b. If no, we recommend completion of bench testing with the final design

before proceeding to step 3, although such an approach may not always be
possible.

3. Is there an established animal model for the type of device you are testing (i.e., one
that has been described in the literature or used to support the clearance or approval
of a similar device for the same indications for use?

a. If yes, go to Step 4.

b. If no, have you assessed the anatomy and physiology of commonly utilized
laboratory animal species (such as small hoofed stock, dogs, and primates)
for size and procedural approach features?

i. If yes, and you can identify an animal model that would work, go to Step
4.

ii. If yes, and you identify significant challenges that prohibit the use of a
reasonable animal model for all or some of the animal studies
recommended by the risk analysis, FDA recommends that you contact
the Agency for a discussion of these challenges and alternative
approaches for collecting evidence to demonstrate satisfactory device
safety and performance prior to clinical use. Please note that FDA
believes such situations to be unusual. As part of this discussion, you
should include any available evidence that animal studies would not be

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 Contains Nonbinding Recommendations

feasible, propose alternative solutions, including any available

simulations, cadaveric studies, and clinical information collected outside
the Unites States. Please also note that FDA generally does not consider
high cost as sufficient justification for not conducting animal studies.

iii. If no, FDA recommends that you consult an experienced laboratory

animal veterinarian to determine the availability and utility of common
laboratory species before proceeding to Step 4 or Step 3.b.ii.

4. Are there any particular features of the device that would result in study endpoints
that differ from those previously used in studies for other devices of the same type
for the same proposed indications, or are there new indications that suggest the use
of different or additional evaluation time points or methods?

a. If yes, you should identify the new endpoints and time points, and proceed
to Step 5.

b. If no, FDA recommends that you use the time points reported for similar
devices, and proceed to Step 5.

5. Is there anything known about the device that would indicate high variability
of animal responses, due to factors such as investigator training and familiarity with
the device or inherent challenges in the placement or tolerance of the device?

a. If you have investigated this issue and have determined that there is not a
significant learning curve or predicted animal response variability, proceed
to Step 6.

b. If evidence exists from either in vivo or in vitro studies that a significant

learning curve exists that would significantly increase animal response
variability, FDA recommends conducting feasibility animal studies to
evaluate this issue prior to conducting pivotal animal studies and before
proceeding to Step 6.

6. If, after consideration of all these issues, you would like FDA feedback on your
proposed animal study strategy, FDA recommends that you submit a Pre-IDE that
includes a proposal for your pivotal GLP animal studies. This proposal should
detail all methods of assessment for identified risks that may be observed
dynamically in life and with gross and histopathology, and include any specific
questions for which you would like FDA input. More information regarding the
pre-IDE process is available at
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarket
YourDevice/InvestigationalDeviceExemptionIDE/ucm046164.htm#pre_ide.

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 Contains Nonbinding Recommendations

Appendix C: Recommended Animal Study

Research Controls to Consider

 A determination of satisfactory source animal health, based on veterinary examinations

 Methods that permit a knowledge of food and water purity and nutritional adequacy for
the species under study, such as:

o regularly scheduled interim weight measurements

o provision of adequate number of feeders in pen-housed animals

o standard operating procedures to screen for food and water contaminants

o consultation with attending veterinary staff regarding provision of special feeds or

special nutritional supplements during periods when you may expect finicky eating
behavior, such as peri-procedural

 Use of an acclimation period after the source animals arrive at the test facility, such as 7
to10 days

 Appropriate baseline assessments of animal health and behavior

 Proper aseptic surgical technique, and monitoring and intervention to control

unintended infections

 Practices and procedures that ensure the animal facility staff are providing adequate
sanitation and air conditioning to prevent unintended injury and infection

 Practices to ensure that training in the planned experimental methods have exceeded the
device learning curve, such that there is low to non-existent inter-procedural variability

 Practices ensuring that all experimental equipment is calibrated and maintained

according to accepted standard operating procedures

 Practices ensuring that there is adequate personnel and staffing to ensure that animals
are appropriately monitored throughout the duration of study and at the appropriate
intensity and duration that would reasonably detect the predicted failure modes as well
as any common experimental outcomes

 Appropriate monitoring and timely postoperative monitoring and intervention to detect,

control, and report common cardiovascular outcomes such as spasms, arrhythmias,
pain, and distress

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 Contains Nonbinding Recommendations

 Practices ensuring that transportation and shipping stress is minimized when moving
peri-procedural animals to remote holding sites

 Practices and procedures that enable animals in group settings to consume adequate
amounts of water and food and to minimize inter-species injury

 Practices that encourage adequate and timely intervention to obtain necropsies when
animals die unexpectedly

 Practices that encourage proper handling, storage, and preparation of tissue for
chemical analysis and histological processing

 Practices ensuring that the test system, test article, control article, and all specimens or
data collected from the test system are properly identified and that their identity is not
confused

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 Contains Nonbinding Recommendations

Appendix D: Sample Organization of Animal Study Test Reports

1. Report number

a. Institutional protocol number

b. Study number(s)

c. Test protocol number(s)

2. Title of the report

3. Contact information

a. Sponsor

b. Sponsor representative

c. Test facility name(s)

d. Study director

e. Quality Assurance director

4. Final report signature page

a. Study Director’s signature

b. Quality Assurance signature

c. Copy of Institutional Animal Care and Use Committee (IACUC) protocol,

signed by the IACUC chairperson and attending veterinarian

5. Executive summary

a. Overview of animal study

i. Objective of the study

ii. Acceptance criteria

iii. Rationale for selection or exclusion of animals, including supporting

discussion and rationale if the proposed animal model could not be
used

iv. Characterization of test and control articles

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 Contains Nonbinding Recommendations

a) Design iteration of device used

b) Referenced serial or model numbers

v. Brief discussion of methods used, including insertion, approach,

incision, monitoring, intervention, imaging, necropsy, and histology as
appropriate

vi. Brief overview of results

a) Morbidity/mortality

(i) Gross necropsy information

(ii) In situ photography

(iii) Descriptive findings

b) Biologic response to the device

(i) Inflammation

(ii) Endothelialization

(iii) Injury

(iv) Fibrin and/or thrombin formation

c) Impact of animal on device

(i) Device structural integrity

(ii) Device functional integrity

d) Deployment/surgical success, positioning, and overall handling

e) System compatibility, if routinely used with other

cardiovascular devices

f) Imaging characteristics

vii. Conclusions

a) Conformity with controls

b) Success in meeting acceptance criteria

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 Contains Nonbinding Recommendations

c) Identification of related studies that were conducted or are

scheduled to be completed that explain any outstanding issues

6. Secondary attachments (raw data and individual test reports)

a. Vendor reports

b. Baseline and interim health examinations

c. Surgery and anesthesia reports

d. Imaging reports

e. Clinical chemistry results

f. Electromechanical results

g. Explant radiography images

h. In situ photography images

i. Principal investigator report

j. Signed descriptive pathology report, with accompanying images

k. Signed descriptive histopathology report, with accompanying images and raw

data

l. Signed interventionalist or surgeon’s reports on device performance, with

accompanying case report forms

m. Signed attending veterinary statement

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 Contains Nonbinding Recommendations

Appendix E: Tabulated Summary of Relevant Federal Regulations

 
Applicable Guidance
Topic Regulatory Citation
Section
Section III and Section
GLP Animal Care 21 CFR 58.90
IV, Part B
Protocol 21 CFR 58.130 Section III
Section IV, Parts B
Quality Assurance Unit 21 CFR 58.35
and D, and Section V
Test and Control
21 CFR 58.105 and 58.107. Section IV, Part E
Articles
Section IV, Parts A, F
Test System 21 CFR58.3(i)
and G
Federal Animal
9 CFR Chapter 1, Part 3 Standards §
Biomedical Research Section VI, Part A
3.1
Standards
The care, exercise, and housing of
dogs are described in 9 CFR Chapter
1, Part 3 Standards.
Housing, animal management, and
species-specific space requirements
Housing and Well-Being are generally prescribed as
Section VI, Part A
of Dogs performance standards in the NRC
publication Guide for the Care and
Use of Laboratory Research Animals
which is the recommended reference
to which metrics are applied by
AAALAC and the PHS.
9 CFR Chapter 1, Part 3 Standards §
Sanitization and
3.11, 3.31 and in The Guide for the Section VI, Part A
Husbandry
Care and Use of Laboratory Animals.6
Environmental Control 9 CFR Chapter 1, Part 3 Standards
Section VI, Part D
of Transportation §3.5.
Identification of animals is discussed
in 21 CFR, 58.90, and with respect to
Animal Identification
dogs and cats used in research, within Section VII, Part C
Systems
9 CFR, Chapter 1, Part 2 Regulations
§2.9.
Animal Quarantine and 21 CFR 58.9 and in the NRC Guide Section VII, Part D
Conditioning for the Care and Use of Animals6, and E

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 Contains Nonbinding Recommendations

Page 58. The European Convention

for the Protection of Vertebrate
Animals Used for Experimental and
Other Scientific Purposes41 provides
similar guidance to Western European
member state facilities.
Title 9, Chapter 1, Part 3 Standards
Social and
§3.7 and 3.8, and in the NRC Guide
Environmental Research Section VII, Part E
for the Care and Use of Laboratory
Standards
Animals6, page 37.
 

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 Contains Nonbinding Recommendations

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on Sheep Nutrition. Nutrient Requirements of Sheep. 6th rev. ed. (1985).
Washington, D.C. National Academy Press. Retrieved from:
http://www.nap.edu/openbook.php?record_id=614&page=R1

24. Veterinary Medical Records; in Pennsylvania State Board of Veterinary Medicine

Newsletter Winter 2002, Page 8.
http://www.dos.state.pa.us/bpoa/LIB/bpoa/20/10/vetnews02.pdf

25. Battaglia, A M. Small Animal Emergency and Critical Care. Ithica,

NY: W.B. Saunders.

26. Flecknell P.A. (1996) Laboratory Animal Anesthesia, San Diego, CA:
Academic Press Inc,

27. Flecknell P.A, Waterman-Pearson A. ( 2000). Pain Management in Animals.

London: Harcourt Publishers Ltd.

28. Hellyer P.W. (2002). Pain Management. In Wingfield W.E and Raffe,
MR (Eds). The Veterinary ICU Book. Jackson Hole, WY: Teton NewMedia.

29. Lee L, Leslie K, Kayak E, Myles PS. (2004). Intraoperative Patient Warming
Using Radiant Warming or Forced-Air Warming During Long Operations. Anaesth
Intensive Care, 32(3),358-61.

30. Peterson N.C. (2004). Assessment of Pain Scoring. Contemp Top Lab
Anim Sci,43(1):74-76

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 Contains Nonbinding Recommendations

31. Rudloff E, Kirby R. (1998). Fluid Therapy: Crystalloids and Colloids.

In Dibaratola, S.P. (Ed). Vet Clin North Am Small Anim Pract. 28(2),297-328.

32. Stasiak K.L, Maul D, French E, Hellyer P.W, VandeWoude S. (2003).

Species-specific assessment of pain in laboratory animals. Contemp Top Lab Anim
Sci.,42(4):13-20.

33. Keown, J. F. (2005). How to Body Condition Score Dairy Animals. The
University of Nebraska Extension-Lincoln Institute of Agriculture and Natural
Resources. Retrieved from:
http://www.ianrpubs.unl.edu/epublic/live/g1583/build/g1583.pdf.
sion Date 11/1/08 Accession Date 11/31/08
34. Ohio State University College of Veterinary Medicine on-line learning system:
How to Assess Body Score in Dogs and Cats. Retrieved from:
http://vet.osu.edu/1851.htm

35. Michel, K.D., Sorenmo, K., Shofer, F.S. (2004). Evaluation of Body Condition
and Weight Loss in Dogs Presented to a Veterinary Oncology Service. J Vet Intern
Med, 13(5),692-5.

36. Carr, John. 1998. Garth Pig Stockmanship Standards. Iowa, 5M Enterprises, LTD
Sheffield, UK. Website with condition images. Retrievable from:
http://www.thepigsite.com/stockstds/23/body-condition-scoring. Accession date
11/14/08

37. The European Convention for the Protection of Vertebrate Animals used for
Experimental and Other Scientific Purposes is a useful web resource for european
regulations and standards relating to animal care and use in member states.
(http://conventions.coe.int/treaty/Commun/QueVoulezVous.asp?NT=123&CM=0&C
L=ENG.)

38. The FDA maintains an intergovernmental Memorandum of Understanding (MOU)

between NIH, FDA, USDA regarding common areas of regulatory interest in animal
care and use. (http://grants.nih.gov/grants/olaw/references/finalmou.htm)

39. The Interagency Coordinating committee on the Validationof Alternative Methods

(ICCVAM) provides many websites for decisions related to animal care and use,
refinements, reductions, and replacement of animal models and validated models.
(http://iccvam.niehs.nih.gov/about/accept.htm.)

40. The European Convention on the Validation of Alternative Methods is a useful web
link to validated European alternative animal models. (http://ecvam.jrc.it/)

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 Contains Nonbinding Recommendations

41. The Japanese Convention on the Validation of Alternative Methods is a resource for
those animal models and animal welfare items of interest from Japan.
(http://jacvam.jp/en/)

42. The Johns Hopkins Center for Alternatives (CAT) is a comprehensive web resource
for all subjects related to global animal care and use, animal welfare, and animal
alternatives. (http://caat.jhsph.edu/)

43. The National Center for 3Rs is a comprehensive web link for animal care and use and
animal refinement and replacement questions. (http://www.nc3rs.org.uk/)

44. AltTox Forum (sponsored by Proctor and Gamble and The Humane Society of the
United States provides information about validated animal alternatives.
(http://www.alttox.org/)

45. Tox Net is an an NIH-sponsored website of available literature on alternatives.

(http://toxnet.nlm.nih.gov/altbib.html)

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