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1 General Considerations for Animal

2 Studies for Medical Devices
3 Draft Guidance for
4 Industry and Food and Drug
5 Administration Staff
6
7 DRAFT GUIDANCE
8
9 This guidance document is being distributed for comment purposes only.
10
11 Document issued on: October 14, 2015.
12
13 You should submit comments and suggestions regarding this draft document within 90 days of
14 publication in the Federal Register of the notice announcing the availability of the draft guidance.
15 Submit electronic comments to [Link] Submit written comments to the
16 Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
17 rm. 1061, Rockville, MD 20852. Identify all comments with the docket number listed in the
18 notice of availability that publishes in the Federal Register.
19
20 For questions regarding this document, contact Judith A. Davis, Office of Device Evaluation, 301-
21 796-6636, [Link]@[Link].
22
23 When final, this guidance will supersede “Guidance for Industry and FDA
24 Staff: General Considerations for Animal Studies for Cardiovascular
25 Devices” issued July 29, 2010.
26
27
28
29
30
31
32 U.S. Department of Health and Human Services
33 Food and Drug Administration
34 Center for Devices and Radiological Health
35 Office of Device Evaluation
36 Office of Compliance
37
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39 Preface
40
41 Additional Copies
42 Additional copies are available from the Internet. You may also send an e-mail request to
43 CDRH-Guidance@[Link] to receive an electronic copy of the guidance. Please use the
44 document number 1802 to identify the guidance you are requesting.
45
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46 Table of Contents
47 I. Introduction .................................................................................................................... 1
48 II. Scope .............................................................................................................................. 2
49 III. Overview ........................................................................................................................ 2
50 IV. Study Planning and Protocol .......................................................................................... 3
51 V. Elements of the Animal Study ........................................................................................ 4
52 A. Rationale for Selecting Animal Models ...................................................................... 5
53 B. Study Assurances ........................................................................................................ 5
54 C. Study Objectives ......................................................................................................... 6
55 1. Performance and Handling ...................................................................................... 6
56 2. Device Safety .......................................................................................................... 6
57 a. Physiological Response ....................................................................................... 6
58 b. Unexpected Morbidity and Mortality .................................................................. 7
59 c. Downstream and Systemic Effects ...................................................................... 7
60 D. Study Schedule............................................................................................................ 7
61 E. Test and Control Articles ............................................................................................ 8
62 F. Accessory Devices and Equipment ............................................................................. 8
63 G. Test System ................................................................................................................. 9
64 VI. Personnel ........................................................................................................................ 9
65 VII. Facilities........................................................................................................................ 10
66 A. Environment .............................................................................................................. 10
67 B. Animal Groupings ..................................................................................................... 10
68 C. Primary and Secondary Enclosures .......................................................................... 10
69 D. Transport Systems ..................................................................................................... 11
70 VIII. Study Methods and Conduct ....................................................................................... 11
71 A. Research Controls ..................................................................................................... 11
72 B. Study Equipment ....................................................................................................... 12
73 C. Animal Identification ................................................................................................ 12
74 D. Animal Quarantine and Conditioning ....................................................................... 12
75 E. Animal Allocation to Experimental Grouping.......................................................... 12
76 F. Food, Water, and Basic Husbandry .......................................................................... 13
77 G. Periods of Observation .............................................................................................. 14
78 1. Intraoperative Monitoring ..................................................................................... 14
79 2. Acute Studies......................................................................................................... 15
80 3. Chronic Studies ..................................................................................................... 15
81 a. Post-Operative Period ........................................................................................ 15
82 b. Interim Periods of Observation.......................................................................... 15
83 c. Terminal Study Period ....................................................................................... 15
84 d. Necropsy and Post-Mortem Evaluation ............................................................. 16
85 H. Post-Mortem Imaging and Assessment Methods ..................................................... 16
86 1. Explant Imaging (i.e., radiography, microCT) ...................................................... 16
87 2. Scanning Electron Microscopy (SEM) ................................................................. 16
88 3. Histomorphometric Analysis ................................................................................ 16
89 4. Local and Downstream Tissue Assessment .......................................................... 17
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90 IX. Records and Reports ..................................................................................................... 17

91 X. Preparation of Regulatory Submissions ....................................................................... 18
92 Appendix A: List of Common Acronyms Related to Animal Studies................................. 20
93 Appendix B: Sample Decision Tree for Medical Device Animal Studies........................... 21
94 Appendix C: Recommended Animal Study Research Controls to Consider....................... 23
95 Appendix D: Sample Organization of Animal Study Test Report Components to Facilitiate
96 Review ................................................................................................................................. 26
97 Appendix E: Tabulated Summary of Relevant Federal Regulations and Guides ................ 30
98 Appendix F: Additional Resources on Animal Care and Research ..................................... 31
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100 General Considerations for Animal

101
102
Studies for Medical Devices
103

104 Draft Guidance for Industry and Food

105 and Drug Administration Staff
106

107 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
108 Administration (FDA or Agency) on this topic. It does not establish any rights for any person
109 and is not binding on FDA or the public. You can use an alternative approach if it satisfies
110 the requirements of the applicable statutes and regulations. To discuss an alternative
111 approach, contact the FDA staff responsible for this guidance as listed on the title page.

112 I. Introduction
113 FDA has developed this guidance document to assist industry in designing evaluation strategies
114 for, and reporting the results of, animal studies for medical devices. The animal studies utilized
115 for the assessment of these devices typically provide initial evidence of device safety, their
116 potential performance when used in a living system, and the biologic response that a living
117 system may mount towards the device. This guidance provides recommendations for members
118 of industry who perform, and FDA staff who review evaluations of, animal studies for medical
119 devices. In this document, the terms “you” and “your” refer to members of industry, also known
120 as “sponsors” or “applicants.” The terms “we,” “us,” “our,” and “Agency” refer to FDA.
121
122 The intent of this guidance is to provide a reference of best practices for the approach to and
123 conduct of animal studies, and the presentation of animal study data intended to demonstrate that
124 the device under study is sufficiently safe for early human experience [e.g., to support an
125 investigational device exemption (IDE) application] or to demonstrate device safety in support of
126 a marketing application, while incorporating modern animal care and use strategies. We
127 recommend that you use this guidance to develop and present animal study protocols, methods,
128 and reports that support the safety and performance 1 of medical devices. When considering the
129 number of animals and the amount of data that can support the safety and performance of a
130 medical device, FDA recommends balancing the ethical principles of
131 reduction/replacement/refinement as well as regulatory least burdensome principles, with the
132 goal of using the minimum number of animals necessary to generate valid scientific data to
133 demonstrate reasonable safety and performance.
1
While the handling/performance of a medical device may be demonstrated in an animal model, additional data in a human
model may be necessary to assess outcomes demonstrating device effectiveness.
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134
135 Although this document is not intended to address the regulations and policies of other agencies,
136 or other laboratory animal guides, we note that there are other relevant regulations and policies
137 involving animal care and use that are administered by other agencies, some of which are
138 referenced in this guidance. 1- 4 A summary of relevant federal regulations is provided in
139 Appendix E, and additional resources on animal care and research are provided in Appendix F.
140 Of note, FDA maintains a memorandum of understanding (MOU) with the U.S. Department of
141 Agriculture (USDA) and the National Institutes of Health (NIH) that addresses common areas of
142 regulatory interest concerning animal care and use. 5
143
144 This draft guidance, when finalized, will supersede the July 2010 guidance entitled “Guidance
145 for Industry and FDA Staff: General Considerations for Animal Studies for Cardiovascular
146 Devices.”
147
148 FDA's guidance documents, including this guidance, do not establish legally enforceable
149 responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
150 be viewed only as recommendations, unless specific regulatory or statutory requirements are
151 cited. The use of the word should in Agency guidances means that something is suggested or
152 recommended, but not required.

153 II. Scope

154 This guidance applies to medical devices intended for use in humans, as defined in section
155 201(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The recommendations in this
156 guidance apply to animal studies submitted in support of an IDE application, premarket approval
157 (PMA) application, premarket notification (510(k)), humanitarian device exemption (HDE)
158 application, or a request for de novo classification.
159
160 This guidance is intended specifically to apply to in vivo nonclinical laboratory studies as defined
161 in 21 CFR 58.3(d). A list of common acronyms encountered in relation to these studies is
162 provided in Appendix A.

163 III. Overview

164 FDA recommends that you consider the following general principles when developing animal
165 study protocols for medical devices:
166
167 • For animal studies that are to be submitted to the Agency to support the safety of a
168 medical device, Good Laboratory Practice (GLP) applies (21 CFR Part 58). If your
169 animal study was not conducted in compliance with Part 58, your statement provided in
170 your submission explaining the reasons why the study was not in compliance with GLP
171 regulations should also describe in detail all deviations from the regulations. The
172 statement should include information that will help FDA reconstruct the study, explain
173 any confounding variables, and demonstrate that authentic and complete test data have
174 been collected and reported.

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175
176 • The animal model selected should be generally accepted for the study of the device
177 type. 6 -12 There should be a reasonable amount of scientific evidence that the animal
178 model has utility for the study of the device type. In some cases there may not be an
179 established or accepted animal model for a specific device type. We recognize that the
180 utility of animal testing may be limited in these situations, and it may be most appropriate
181 to proceed with limited clinical evaluation in humans, if scientifically justified. In other
182 cases, an alternative animal model may be used and appropriately justified.
183
184 • FDA’s primary purpose in recommending an animal study is for the applicant to provide
185 evidence of safety, including performance and handling. Note that in many cases, the
186 performance of a particular device is intricately linked to its safety, such as for products
187 that provide circulatory support.
188
189 • A secondary objective for conducting the animal study can be to evaluate the efficacy of
190 the device or to demonstrate proof of principle.
191
192 • The in vivo setting generally provides an initial assessment of how the device interacts
193 with biologic systems and also how the biologic system may affect the device, such as via
194 device corrosion and structural deformities.
195
196 FDA is available to review your rationale for and design of an animal study as part of a Pre-
197 Submission.13 Additionally, it is important to consider the following points when designing your
198 study: adequacy of controls, timing and route of intervention, and methods to minimize bias (e.g.
199 blinding, randomization, use of controls, sample size based on expected magnitude of the
200 biological response, reporting missing data, and clearly stated statistical considerations). If you
201 are uncertain regarding elements of the animal study that are important to the Agency, please
202 initiate contact with your respective review division for clarification.
203
204 You should observe the best practices of refinement, reduction, replacement, and current
205 standards of humane veterinary care and use. This may also involve consideration of available
206 validated alternatives. 14- 20
207
208 Recommendations regarding specific elements of animal studies and other considerations are
209 provided in the following sections.

210 IV. Study Planning and Protocol

211 FDA believes that an animal study that is carefully planned and executed is more likely to
212 provide useful data in support of a device premarket submission. In this regard, the study should
213 be planned by individual(s) with appropriate credentials and experience, and must be directed by
214 a designated study director with appropriate credentials and experience in accordance with 21
215 CFR 58.33. The study director should be located in close proximity to the actual study location
216 so that s/he can provide oversight for the technical conduct of the study. The study director is
217 also responsible for the interpretation, analysis, documentation and reporting of the study results

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218 (21 CFR 58.33). In some cases, additional investigators or contributing scientists may need to be
219 designated for different aspects of the study, e.g., in-life portion and ex vivo imaging.
220
221 Because the primary purpose of the study is to evaluate safety and performance, we recommend
222 you consider your risk analysis (i.e., the identified risks associated with your device through
223 bench testing, and other information, such as scientific presentations, literature review, etc.) and
224 design the study objectives to enable study of all identified risks of your device as well as any
225 known risks of the device type.
226
227 The study must be guided by an a priori study protocol that is approved by the sponsor and
228 signed and dated by the study director (21 CFR 58.120). The protocol must contain the elements
229 outlined in 21 CFR 58.120 and should contain study instructions as dictated by the particular
230 circumstances. Any changes or revisions to the final approved protocol, and the reason for the
231 change, must be documented, dated and signed by the study director (21 CFR 58.120). The
232 protocol and any revisions must be available for Agency review and are subject to inspection (21
233 CFR 58.15).
234
235 FDA recommends that an Institutional Animal Care and Use Committee (IACUC) review and
236 approve all elements of the a priori protocol that address animal care and use prior to the
237 initiation of the study and any major protocol amendment that affects animal care or use before
238 the change is implemented (such review and approval may be required for some studies1). The
239 IACUC will provide guidance as to the process and format for providing that information to the
240 Committee.
241
242 The number of animals and experimental groupings should be designed after pilot and bench
243 testing provide some idea of reliability and outcome. A thoughtful attempt at utilizing the least
244 number of animals that will provide meaningful interpretation is paramount and includes such
245 measures as attention to the appropriate experimental control, consideration of potential
246 experimental confounders, and an idea of best observation intervals (See Appendix C).

247 V. Elements of the Animal Study

248 We recommend that your regulatory submissions include a discussion of each of the following
249 key animal study features, in addition to the requirements outlined in 21 CFR 58.185:
250
251 • introduction, including a rationale for the selection of the particular animal model;
252
253 • the study assurances (e.g., USDA registration, AAALACi accreditation, NIH Office of
254 Laboratory Animal Welfare [OLAW] Assurance Statement number);
255
256 • the purpose of each test protocol;
257
258 • the study schedule;
259
260 • any ex vivo tissue characterization; and
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261
262 • any limitations imparted by the choice of the animal model and any amendments and
263 deviations from the original test protocol.
264
265 Specific recommendations for how to optimize the development and reporting of some of these
266 elements, as well as some of the elements required under 21 CFR 58.185, are provided below.

267 A. Rationale for Selecting Animal Models

268 FDA recommends that you provide your rationale for the selection of particular animal
269 models for your animal study. A sample decision analysis flowchart for this
270 determination is provided in Appendix B. The animal and its related environmental and
271 physiologic attributes should provide a test system that offers a best attempt at simulating
272 the clinical setting. The rationale for the conduct of an animal study should clearly state
273 which of the elements of your risk analysis will be addressed and why the particular
274 animal model was selected. If there are limitations to the animal model such that certain
275 risks of the device are best addressed by bench or cadaver testing, these relationships
276 should be described. Your rationale should also describe inherent challenges to the test
277 system, such as:
278
279 • the similarities and differences between the test system and humans in the
280 metabolism of drugs or the use of ancillary devices that represent the standard of
281 care for the procedures utilized in device implantation;
282
283 • the dimensions of the device and delivery systems, as compared to the same
284 characteristics of the device version intended for human use;
285
286 • the location of device insertion and the tracking pathway or, if surgically placed,
287 the anatomic point of surgical entry and the surgical technique utilized in the
288 animal versus the human; and
289
290 • size limitations that exist as barriers (exclusive of cost) to use of the most size-
291 appropriate and anatomically appropriate model.

292 B. Study Assurances

293 Animal studies that are intended to support the safety of a medical device must comply
294 with the GLP requirements detailed in 21 CFR Part 58. As part of these requirements,
295 under 21 CFR 58.35, the Quality Assurance Unit (QAU) must be separate from and
296 independent of the personnel engaged in the direction and conduct of the study. The final
297 study report must contain the signed Quality Assurance Statement (QAS) (21 CFR 58.35
298 and 58.185), which should also be dated. The statement must also include dates of each
299 inspection (21 CFR 58.35).
300
301 FDA recognizes that, for various reasons, use of a GLP facility may not be possible, such
302 as when a highly specialized skill set of investigators is only available at a particular non-
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303 GLP facility. In these situations, FDA recommends that you provide a complete rationale
304 for the selection of the test site and that you follow the highest levels of oversight, record-
305 keeping, and reporting. The rationale should include the differences from GLP and
306 include an explanation as to why those GLP deviations do not affect the integrity of the
307 data. If the reason for non-compliance with GLP is the lack of a QAU, FDA
308 recommends that you employ an independent auditor so that impartial quality assurance
309 is provided. For example, the quality assurance auditor should monitor the study conduct
310 against the study protocol and facility standard operating procedures. The standard
311 operating procedures should be similar in scope and detail as those typically used for
312 GLP studies.
313
314 Finally, in situations where a study report and/or its appendices are lacking key data and
315 information, if the study site has assurances such as USDA registration, AAALACi
316 accreditation, and/or an approved Animal Welfare Assurance Statement with NIH, the scope and
317 level of detail found in the test facilities’ standard operating procedures may provide sufficient
318 evidence to confirm the validity of statements in the final study report.

319 C. Study Objectives

320 FDA recommends that animal studies for medical devices be designed with the objective
321 of studying the risks that are predicted from the design of the device, any known risks of
322 the device type, and any new risks that may have emerged in prior investigations, such as
323 bench testing or animal feasibility/pilot studies.
324
325 Recommendations for evaluating specific types of risks are provided below.

326 1. Performance and Handling

327 FDA recommends that your animal study protocol simulate the clinical setting as
328 much as possible. You should identify all steps required to deliver, implant, or use
329 the device, and develop acceptance criteria for each of the steps. FDA recommends
330 that you apply a semi-objective rating scale (e.g., Likert scale) to each acceptance
331 criterion. If the device is delivered or used with ancillary equipment, the acceptance
332 criteria should include elements evaluating system compatibility. Rating criteria
333 should encompass steps between the preparation of the device through device
334 placement or use, and also withdrawal and redeployment, if appropriate. If the device
335 is surgically placed, all steps from entry through the body wall through the final
336 device handling should be described.

337 2. Device Safety

338 a. Physiological Response
339 Medical devices can cause mechanical or biologic stresses. FDA recommends
340 that you identify key biologic response variables at regional sites, at locations
341 adjacent to the implant site (if applicable), and along all paths to and from the
342 point of implantation or use to develop active means of surveying the impact of
343 your device on the body. FDA strongly recommends that you work with a
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344 pathology expert such as a veterinarian boarded by the American College of

345 Veterinary Pathology to develop the study protocol.

346 b. Unexpected Morbidity and Mortality

347 You should fully explain all observed instances of animal illness and death. The
348 supporting rationale for any statements made regarding whether such events are
349 or are not device-related should be thoroughly described. Retrospective
350 testimonials or statements made by study directors, their designees, or their
351 consultants that explain veterinary clinical outcomes should be supported by
352 appropriate evidence, records, and reports. If the cause of death or illness could
353 be indirectly attributed to the device, you should discuss the etiology of the
354 condition. FDA recommends that you follow modern methods of animal health
355 surveillance by having qualified veterinarians use problem-oriented veterinary
356 medical records (POVMR) 21 for the purpose of detailing wellness or morbidity,
357 including the development of key assessments for systemic effects of device use.
358 These assessments include postoperative, interim, and terminal clinical pathology,
359 including but not limited to: serum chemistry, hematology, and coagulation
360 profiles with laboratory reference range values; imaging reports; and case report
361 forms for specialized evaluations (e.g., electrophysiological, behavioral, and
362 neurological assessments).

363 c. Downstream and Systemic Effects

364 FDA recommends that you evaluate whether or not the device can have effects
365 remote from the site of placement or use. If you believe that your device has the
366 potential for this type of risk, you should ensure that your study includes
367 objectives to evaluate other tissue beds (such as downstream tissue for blood-
368 contacting devices or other relevant end organ tissue) for evidence of potential
369 systemic problem(s) that might be part of the device and delivery system. Should
370 these findings occur, you should develop a plan for assessing the quantity of
371 tissue affected and whether there are any resulting functional disturbances.

372 D. Study Schedule

373 FDA recommends that you develop a schedule of key interventions and time points for
374 your study based on your knowledge of the known risks and predicted outcomes of use of
375 the device. These timepoints typically include:
376
377 • full characterization, implantation, and intermittent examination of device
378 performance and/or animal response;
379
380 • explantation of the device (if an implant);
381
382 • full analysis of any explanted tissue;
383

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384 • preparation of the tissue; and

385
386 • preparation and sign-off of the final written reports.
387
388 We recommend that the QAU be aware of these key scheduling objectives so that interim
389 study monitoring and inspections can be arranged. Because medical devices may involve
390 some degree of invasiveness and predictable variability in animal survival, any
391 anticipated change in the duration of study may necessitate adjustment of these
392 parameters, depending on the interim data. For example, if adverse outcomes are
393 detected at earlier time points than expected, you should consider enhancing the timetable
394 for observation and device explantation so that useful terminal data are not lost. Also, we
395 believe that the responsible use of animals optimizes the use of all animal tissue, and
396 therefore recommend that complete gross and microscopic organ and tissue evaluations
397 be performed on all animals and that tissue be freshly studied to avoid the potential for
398 erroneous interpretation.

399 E. Test and Control Articles

400 Under 21 CFR 58.105 and 58.107, you are required to fully characterize and account for
401 all test and control articles used in the study. Since sponsors may often develop several
402 iterations of the test article prior to clinical study initiation, we recommend that pivotal
403 animal studies utilize test articles representing the final clinical design. If the final design
404 was not used, you should provide a rationale for why the final clinical design presents no
405 new risks to the patient compared to the design studied in animals. FDA also
406 recommends that test and control articles be packaged, sterilized, and shipped to the
407 research site in the same manner as would clinical product. You should develop and
408 follow a method for tracking the test and control devices from their manufacture or
409 procurement to final use.

410 F. Accessory Devices and Equipment

411 Some test articles, such as vascular stents, are typically used in conjunction with specific
412 or commercially-available accessory devices or components, such as guide catheters or
413 guidewires. Such accessories are sometimes described as a part of the test system when
414 their use is necessary to use the test article properly. We recommend that in such a case,
415 you state if:
416
417 • any accessory devices used in the animal study are to be provided completely
418 separate from the test article (i.e., commercially available), or if accessory devices
419 will be marketed together with the test article (i.e., a kit); and
420
421 • whether the final labeling for the device will include instructions for accessory
422 device selection or use.

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423 G. Test System

424 The final study report must include a description of the test system (21 CFR 58.185). 21
425 CFR 58.3(i) defines test system as, “any animal, plant, microorganism, or subparts
426 thereof to which the test or control article is administered or added for study.”
427 Additionally, FDA recommends that you provide a description of the following factors,
428 as applicable, that may affect or influence the test system so that we can make a
429 reasonable assessment of their contributions to the study outcome: the environment,
430 including temperature, lighting, and physical structure; nutritional status; homeostatic
431 controls, including electrolytes, blood glucose, maintenance of asepsis, and control of
432 bleeding; ancillary diagnostic tools; and materials and methods used to define or describe
433 the interaction between test or control article and the animal.

434 VI. Personnel

435 Each test report must contain a section that lists key study personnel (21 CFR 58.185(a)(10)).
436 We believe that this information is relevant to regulatory review because 21 CFR 58.29(a)
437 requires that study personnel are appropriately trained and experienced to properly carry out their
438 duties. This regulation underscores the importance of the training and expertise of animal study
439 personnel. FDA recommends that the animal study team include skilled clinical veterinary staff
440 in order to detect and resolve adverse outcomes; make decisions about the necessity to intervene,
441 intervene accordingly, or deviate from the protocol in the interest of humane care; preserve
442 valuable tissue; and assist in the determination of device associations with any adverse finding.
443 Animal models may frequently impart the need for unique surgical approaches, anatomical
444 limitations, and important features of wound closure that best argue for trained veterinary
445 surgical expertise as part of the research team.
446
447 FDA recommends that the animal study involve investigators with a combination of expertise,
448 including human clinical, veterinary clinical, and veterinary pathologic fields. In keeping with
449 the requirements in 21 CFR 58.29(b), you must maintain a current summary of the training and
450 experience and job description of all personnel engaged in, or supervising the conduct of, animal
451 studies. FDA recommends that any assessment of the competencies of key personnel be based
452 on a rationale for why the individuals are suited for the type of studies being conducted.
453
454 FDA notes that appropriate training and experience of study personnel are also addressed in
455 other relevant guides, and other agency regulations and policies.1,1,4
456
457 In addition to assembling a team of competent oversight personnel (including the study director,
458 QAU, and attending veterinary and interventional staff), FDA recommends that you select the
459 number of qualified personnel and their resources (including equipment, lateral and subordinate
460 personnel, records and reports, and standard operating procedures) such that monitoring,
461 treatments, and test sampling can be obtained at appropriate time points and to ensure that there
462 is active surveillance at these periods for risks known or predicted in previous animal or bench
463 testing, or possibly from previous experience with similar products. Finally, we recommend that
464 you employ veterinary professionals with adequate training and experience to perform animal

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465 welfare audits of facilities, personnel, and methodology for those business entities that you may
466 wish to contract from, such as contract animal research or holding facilities.

467 VII. Facilities

468 A. Environment
469 We recommend that you consult published guidelines involving the housing and well-
470 being of animal research models. 22- 26 The referenced guidelines address
471 recommendations for minimum housing, husbandry standards, social and environmental
472 enrichment, and the development of standard operating procedures that address timely
473 and adequate veterinary medical care. FDA believes that following these guidelines and
474 allowing animals sufficient access to resources such as food and water receptacles,
475 enrichment devices (toys), clean and species-typical resting surfaces, provisions for
476 postural adjustments, and adequate play and exercise are important. Comfort and
477 familiarity with handlers can reduce background stress, thus potentially minimizing
478 experimental confounding factors that could adversely affect the interpretation of your
479 study results.
480
481 In keeping with the standard of care, we recommend that the floors, walls, and ceilings of
482 animal holding structures be non-porous in order to permit easy sanitization of surfaces.
483 We recommend that there be adequate lighting and light controls to permit periods of
484 normal daylight and opportunities for rest. We also recommend the utilization of
485 facilities with appropriate environmental controls for temperature and humidity in order
486 to prevent temperature stress and minimize respiratory infections.4
487
488 Additionally, we note that laboratory animal guides have been developed, and other
489 agencies have established regulations and principles of humane animal care, including
490 assurances to state, national, and international authorities that a state of animal wellness
491 is maintained during research as a well-controlled test system.1-3

492 B. Animal Groupings

493 FDA regulation 21 CFR 58.43 requires testing facilities to have a sufficient number of
494 animal rooms or areas, as needed, to assure proper separation of species or test systems.
495 However, outside of the post-operative monitoring period, we recommend housing social
496 animals in conspecific groups. FDA cautions that the environmental conditions not
497 interfere with the assessment of the study and that all animals have access to adequate
498 resources such as food, water, and toys in order to prevent bullying and territorial stress.

499 C. Primary and Secondary Enclosures

500 Because many Class III devices and implants associated with surgical procedures
501 necessitate frequent observations during certain predicted sub-acute periods, FDA
502 recommends that your facilities include access to small recovery rooms or enclosures that
503 can provide intensive care treatments such as oxygen, swivel systems for intravenous

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504 medications, remote ECG monitoring, and temperature and/or humidity adjustment. We
505 also recommend that you consider whether your protocol should include periods of
506 animal holding in high-level experimental facilities, with subsequent transport to more
507 agricultural facilities following post-procedural stabilization.

508 D. Transport Systems

509 To minimize the stress animals can experience during transport, FDA recommends that
510 you consider the use of transport cages with raised flooring, soft cushioning rest devices,
511 carboys, hay nets, or other enrichment and food/water devices.26, 27 Transport vehicles
512 should afford animals environmentally-controlled heating and air conditioning in order to
513 further minimize shipping stress.1,4 FDA notes that proper care in transport of animals is
514 also addressed in other agency regulations.1

515 VIII. Study Methods and Conduct

516 FDA recommends that the methods and materials utilized for the assessment of medical devices
517 in research animals be similar to those utilized in modern veterinary and human hospitals.
518 Monitoring and intervention strategies should be based on the previous experience of key
519 veterinary and scientific professionals. Once the failure modes and effects that can be addressed
520 in an animal study have been identified, you should develop an animal study protocol that
521 addresses each of the identified risks and that prescribes the frequency and type of monitoring,
522 interventions, and outcome assessments.

523 A. Research Controls

524 Evaluation of device safety is often based on animal studies that provide valid scientific
525 evidence (21 CFR 860.7(d)), and whether or not a facility has adequate standard
526 operating procedures to ensure the quality and integrity of the data (21 CFR 58.81). FDA
527 recommends that animal studies include adequate controls to minimize experimental
528 variability and error. Such research controls include, but are not limited to, the
529 minimization of anything given to or affecting the test animal in the course of an
530 experiment that would impact the comparison between the test animals (i.e., animals
531 receiving the test article) and control animals (i.e., animals receiving the control article).
532 Variables that may impart change to the test animals may be devices other than the test
533 article, or they may consist of background factors such as environmental factors,
534 concomitant medications, or co-morbidities. You should minimize these confounding
535 factors because they may hinder the ability of the investigator and FDA to clearly
536 associate adverse or positive outcomes with the device and/or its effects.
537
538 With this consideration in mind, we recommend the use of personnel, consumable
539 equipment, and practices that enable test article-associated outcomes to be clearly
540 understood. A reference of key controls recommended for animal research studies is
541 included in Appendix C.

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542 B. Study Equipment

543 Given that a medical device animal study is typically sophisticated in its components, and
544 in recognition of the shift from the use of sponsor-owned to contract study facilities, FDA
545 recommends that study sponsors, their consultants, and the study director carefully assess
546 the care, maintenance, and knowledge about the contract equipment used in the study.
547 We encourage early and frequent interaction between personnel involved in the planning
548 of the animal study and those who will actually perform the study. We believe this
549 dialogue is especially important to ensure that the study facilities have the proper
550 ancillary equipment, supplies, and resources for the study. For example, imaging
551 equipment and personnel may need to be as advanced as those found in human
552 interventional suites or operating rooms to properly emulate the clinical situation.

553 C. Animal Identification

554 You should include a table of information pertaining to animal identification, allocation
555 to study sub-groups, type of procedure performed, and the fate or disposition of each
556 animal. For example, if animals are purchased with a USDA identification number but
557 then subsequently identified with an institutional identification number and then further
558 described by a group number, this information should be clearly understood and equally
559 well presented to FDA so that a chain of custody of any individual test or control animal
560 is possible.

561 D. Animal Quarantine and Conditioning

562 FDA recommends that you implement standard operating procedures that permit for
563 adequate periods of quarantine and acclimation, as well as a program of socialization.4
564 Background levels of disease and psychological stress should be controlled as much as
565 possible. Farm animals are particularly prone to intestinal parasites, which commonly
566 present sub-clinically but can cause clinical syndromes under the stress of surgery and
567 during recovery. To minimize this confounding factor, we recommend that you initiate
568 early and frequent dialogue with the attending veterinarian about ways to detect and
569 eliminate clinical and sub-clinical disease to ensure optimal animal wellness. We note
570 that the laws and policies of other agencies, e.g., the Animal Welfare Act (7 U.S.C.
571 §§ 2131-2159) and Public Health Service (PHS) “Policy on Humane Care and Use of
572 Laboratory Animals,” have resulted in important changes in the use of environmental and
573 socialization protocols that are routinely implemented to control background stress.1-2 We
574 believe that following these laws and policies enhances the opportunity for and intensity
575 of observations and can potentially result in other useful findings for the investigators.

576 E. Animal Allocation to Experimental Grouping

577 FDA recommends including a control group within the animal study design, or an
578 explanation why a control group was not included. Additionally, when considering the
579 number of animals needed to generate sufficient data that can support the safety and
580 performance of a medical device, it is important to utilize sufficient animal numbers to
581 obtain predictive outcomes. We believe that this determination can best be made after
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582 bench testing is complete and the device iterations are finalized. We strongly recommend
583 that you conduct definitive animal studies on the market ready device except as required
584 to scale, if needed, to implant in the animal model. The number of animals in the study
585 should be based on sound scientific justification with consideration for the difficulty of
586 the model and whether one or more test article(s) and/or control article(s) can be
587 reasonably studied in a single animal. For example, FDA believes that deployment and
588 handling studies can often be performed multiple times in the same test subject, or
589 incorporated into a chronic safety study. By contrast, studies involving high-risk
590 implants such as prosthetic joints can involve a high degree of expertise and some
591 expected morbidity, such that a relatively large number of animals may be appropriate in
592 order to establish device safety. Based on our experience, typical animal studies in a
593 higher species (e.g., sheep, goat, nonhuman primate) generally have 3-9 animals per
594 group/time point. However, in all cases a scientific justification should be provided in
595 the protocol for the numbers used. We encourage you to discuss proposed animal studies,
596 including the number of animals to be involved, prior to implementation through the Pre-
597 Submission process.13

598 F. Food, Water, and Basic Husbandry

599 FDA recommends that sponsors expressly communicate with subordinate and contract
600 personnel the type and quantity of food that will be offered, and also to pre-specify that
601 cage sizes, and the location and quantity of food receptacles should be ample in pen-
602 housed situations. You should also consider following other research standards that more
603 specifically prescribe housing limitations.4
604
605 We find weight loss challenging to interpret, making it difficult to attribute whether
606 weight loss is or is not device related. As such, you should ensure that individuals
607 monitor animals to document specifics regarding appetite, food and water intake, and
608 micturition and bowel movements, particularly when animals are pen-housed. Bullying
609 and resource coveting are commonly associated with weight loss due to inadvertent
610 reduced caloric or fluid intake.
611
612 Animals (i.e., small ruminants) enrolled in chronic studies are often transferred to a more
613 typical agricultural setting where animals are allowed to graze on open pasture and/or are
614 fed hay as a component of their diet. The sponsor/test facility should ensure that the
615 pasture is free of potentially poisonous plants, parasite ova and other potential
616 contaminants, and that the condition (soil, grass) of the pasture meets the animal’s
617 nutritional requirements, including minerals. Some species may be sensitive to
618 imbalances in organic metals in the soil (e.g., sheep are sensitive to copper and
619 molybdenum imbalances) which may inadvertently lead to toxicities (copper toxicity in
620 sheep). Growth-enhancing additives, such as monensin, are another common source of
621 inadvertent toxicity due to errors in ration preparation or feeding a ration for one species
622 to another. Feed and water used for the animals must be analyzed periodically to ensure
623 that contaminants known to be capable of interfering with the study and reasonably
624 expected to be present in such feed or water are not present at levels above those
625 specified in the protocol (21 CFR 58.90(g)). The sponsor/test facility should be
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626 cognizant of these potential problems and judicious in writing standard operating
627 procedures that address periodic tests of water and feed for potential contaminants, the
628 pasture soil and crop for nutritional balance, training employees on the importance of
629 reading ration labels, feeding species-specific rations, etc. Local farm extension services
630 provide invaluable assistance for this purpose.

631 G. Periods of Observation

632 FDA recommends that standards of veterinary care be followed.1-3,7,28- 31 For example,
633 study animals should be monitored at a frequency and intensity that adequately assess for
634 known risks posed by the device, and you should work with attending veterinary staff at
635 the study facility to develop these monitoring parameters. We believe that such
636 monitoring is appropriate not only for humane reasons, but also because well-monitored
637 animals help us sort common spontaneously occurring conditions from conditions that
638 might be attributed to the device. To best characterize the device effects on the animal,
639 FDA recommends that the process be active and specific, rather than passive and general.
640 Important attributes to consider for evaluation include, but are not limited to:
641
642 • respiratory rate, pattern, and depth;
643
644 • blood pressure;
645
646 • heart sounds and pulse character;
647
648 • mucus membrane color at rest and under exertion;
649
650 • attitude;
651
652 • mentation;
653
654 • gait; and
655
656 • presence or absence of abdominal, bladder, or bowel distension.
657
658 To best assist FDA’s assessment of test article safety, we recommend that you follow
659 current standards of record-keeping in veterinary medicine, such as the
660 subjective/objective assessment and plan (SOAP) format. Additionally, these records
661 should be readily available to all key support personnel in order to optimize data entry.
662
663 Specific recommendations for animal study monitoring are provided below.

664 1. Intraoperative Monitoring

665 Good surgical technique alone is not sufficient to ensure a successful outcome for
666 complex procedures required for medical device implants. Intraoperative and

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667 postoperative monitoring of heart rate, electrocardiogram, blood pressure, and

668 blood gases are essential contributors to a positive outcome.

669 2. Acute Studies

670 If the study is acute and the device-associated trends are expected to be transient
671 during the period of acute observation and harvest, we recommend that you track
672 and record vital signs such as cardiac rhythm, respiratory rate, pulse oximetery,
673 and blood pressure on operative records. This information should be correlated
674 with the timing of insertion, implantation, deployment, or use of the device,
675 contrast agent, or other device-associated materials, and noted on the anesthetic
676 and/or operative records.

677 3. Chronic Studies

678 a. Post-Operative Period
679 FDA recommends that you follow the current standard of care for laboratory
680 research animals by ensuring that investigators manage normal body
681 temperature, minimize pain and infection, and provide adequate fluids and
682 electrolytes.4,30- 34 You should capture physiological information similar in
683 quality to that obtained in human care and recovery areas. In addition, you
684 should control stress variables by establishing a standard assessment paradigm
685 for the monitoring of pain and body temperature, and directing the
686 administration of additional warmth and pain killers based on interim
687 outcomes.

688 b. Interim Periods of Observation

689 During periods where animals have recovered from initial surgical procedures
690 but are to be monitored for device-associated risks, FDA recommends that
691 you monitor them at least twice daily at feeding times so that they may be
692 observed when active. We also recommend that you consult your veterinarian
693 and develop a weight monitoring plan. You should consider inclusion of body
694 scoring as an adjunct to your periodic observations of the animal.7,35- 38
695
696 If your study involves the collection of clinical chemistry data or more
697 advanced diagnostics, we recommend that you develop standard operating
698 procedures that prescribe, when needed, a method of chemical restraint that
699 does not interfere with the device. In our experience, some animals, such as
700 dogs and sheep, may be conditioned to be compliant for these activities, while
701 swine rarely are.

702 c. Terminal Study Period

703 FDA recommends that the study protocol include details of the terminal study
704 and include all methodology for the examination, collection and processing of
705 tissue. This section of the protocol should include the following information:
706

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707 • methods for end-period examination;

708
709 • (if applicable) a statement that in-life radiographic analysis and/or
710 imaging will be completed; and
711
712 • methods for establishing end weight and/or body score.

713 d. Necropsy and Post-Mortem Evaluation

714 Adverse events may present clinically or subclinically; therefore, we
715 recommend that you include a comprehensive systematic necropsy in your
716 study, including tissue collection and preservation for possible processing for
717 histopathology examination as the resulting information can help FDA to
718 determine whether observed adverse events are device-related. FDA
719 generally recommends that you describe the rationale and process for how
720 sectioning of organs is performed and the training and experience of the
721 prosector in order to assure an objective process in the sampling of gross
722 tissue for microscopic evaluation. You should support any statements
723 regarding whether any adverse outcomes are device-related with appropriate
724 evidence from the necropsy or histopathology report and from in-life
725 observations. In the event of an unscheduled death, you should be able to
726 provide evidence that supports your statement regarding cause of death.

727 H. Post-Mortem Imaging and Assessment Methods

728 1. Explant Imaging (i.e., radiography, microCT)
729 Prior to preparing devices for histomorphometric analysis, you should consider
730 whether an analysis of the structural integrity of the device would assist in the
731 determination of device safety.

732 2. Scanning Electron Microscopy (SEM)

733 FDA recommends the use of Scanning Electron Microscopy to fully characterize
734 the implant device surface after explant of the device from animals.

735 3. Histomorphometric Analysis

736 Because proper interpretation of acute and chronic biologic responses is critical to
737 FDA’s evaluation of safety, especially in the absence of clinical data, we
738 recommend that you seek the expertise of board-certified veterinary or clinical
739 pathologists when developing and executing methods for preparing tissues for
740 histomorphometric analysis. We also recommend that you identify appropriate
741 expertise to develop pre-specified objective methods for scoring and analyzing
742 observations of injury and inflammation of all tissue. Specific assessments such
743 as inflammation, vascularization, calcification, proteoglycan/collagen, and
744 fibrin/thrombus, etc. should be considered in your evaluation.
745

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746 FDA recommends that you report any non-standard tools and methods used to
747 collect the tissues that contain the device as well as the methods of fixation,
748 cutting, and staining. The reports should also include diagrams indicating the
749 location of implants. The sectioning methods, including tissue and device
750 orientation, should be detailed. When discussing the study results, you should
751 include well-marked high resolution color images, each indicating the animal
752 number, study group, tissue section, magnification, stain, and other important
753 identifiers. Some sponsors find the use of pathology keys that further detail their
754 grading system useful. Other important identifiers are experimental animal
755 number and cohort as well as a scale on the photomicrograph.

756 4. Local and Downstream Tissue Assessment

757 FDA believes that most devices, including both implant and delivery system
758 components, have the ability to embolize particulates or microthrombi from
759 devices’ structural elements or coatings, resulting in adverse observations such as
760 pressure necrosis and inflammation in surrounding tissue or upstream/downstream
761 tissue if the device is in contact with blood. The calvarium should be opened and
762 the brain sectioned if there is a risk of upstream emboli. If your risk analysis
763 identifies this potential risk for your device, we recommend that your pathologic
764 study include systematic descriptive evaluation of upstream/downstream and
765 surrounding tissue. If foreign bodies are observed, you should provide a
766 discussion of the amount of surface area affected as well as the methods utilized
767 to calculate this affected area.

768 IX. Records and Reports

769 A final report must be prepared, and any changes to the final study report must be documented as
770 report amendments in accordance with 21 CFR 58.185. All raw data, documentation, protocols,
771 final reports, and specimens (with certain exceptions) generated as a result of the animal study
772 must be retained (21 CFR 58.190). FDA recommends that you prepare the records and reports
773 for your animal studies such that we can most efficiently evaluate device safety and
774 performance. You should consider whether the data are best suited for statistical analysis or
775 better presented “raw.” When raw data are requested by the Agency, you should include
776 individual animal recordings and key study attributes as appendices to the final study report, and
777 organize their format and content with the goals of explaining all study outcomes to minimize
778 ambiguity. We recommend that the protocol also contain information about how the records will
779 be organized and stored; who will make entries for each attribute; and when interim inspection of
780 the records will be performed. We also recommend time and date stamping for study
781 observations, as this helps to capture events accurately, which aids in the assessment of the inter-
782 observational differences between study subjects. The final study report must include the
783 information specified in 21 CFR 58.185, including a description of all circumstances that may
784 have affected the quality or integrity of the data.
785

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786 Under 21 CFR 58.190, you are required to retain all raw data, documentation, protocols, final
787 reports, and specimens generated as a result of a non-clinical laboratory study for the durations
788 specified under 21 CFR 58.195.

789 X. Preparation of Regulatory Submissions

790 When preparing regulatory submissions, including IDE, 510(k), HDE, and PMA submissions
791 and de novo requests, we recommend that you include all relevant information collected as part
792 of your animal studies. The summary of nonclinical studies in your submission should discuss
793 the number of animal studies conducted, and include the following information for each of the
794 studies:
795
796 • the rationale for the model selected;
797
798 • the similarity of the selected model compared to humans;
799
800 • the general animal study methodology you used;
801
802 • whether there were standard operating procedures in place and followed during the study;
803 and
804
805 • how the quality assurance unit is independent and impartial with respect to the inspection
806 of the data and the reporting of the results.
807
808 In addition, you should include your rationale for your transition from pilot, validation, or proof
809 of concept animal studies to pivotal animal studies, or from one pivotal study to the next, as this
810 information assists us in understanding how you comprehensively assessed device safety, and
811 performance and handling across multiple studies. You should also describe any design changes
812 to the device that were implemented after completion of all animal studies.
813
814 We recommend that you also provide a tabular representation of key parameters for each study,
815 including the following information:
816
817 • the study groups;
818
819 • the number of animals in each group;
820
821 • identification of animals corresponding to study group allocation;
822
823 • study duration;
824
825 • the device design iteration used; and
826
827 • a summary of study outcomes.
828
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829 A signed and dated copy of the final study report should be included in your submission with
830 changes to the final study report documented as report amendments. You may also submit an
831 overall report of the study. In addition, you should provide an attachment to each final study
832 report for each animal study that includes study details, including signed and dated individual
833 scientific reports (e.g., the study director, the clinical veterinarian, the pathologist, and the
834 radiologist), accompanying test protocols, and raw data. These attachments should also identify
835 key study personnel and facilities, describe the overall results of the study, and discuss how the
836 results met the objectives of the study and demonstrated that the device is safe for human use.
837 To aid with the presentation of this information, FDA recommends that your overall animal
838 study summary identify and present the individual test reports in a tabular format, and provide
839 the locations of relevant appendices and attachments to the final study report within the
840 submission.
841
842 When compiling more than one study into a group of attachments to the final study report, FDA
843 recommends that you do so in the order in which the studies were performed so that we can
844 follow the device history and in vivo performance from the first to the last study, and evaluate the
845 means by which you assessed device safety and performance and arrived at your final
846 conclusions. A sample organizational template for relevant content of an animal study report for
847 regulatory submissions is provided in Appendix D.
848
849 In addition to these considerations, we recommend that you review any available FDA guidance
850 documents specific to your device type for more detailed animal study recommendations.
851

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852 Appendix A: List of Common Acronyms Related to Animal Studies

853 AAALACi: Association for Assessment and Accreditation of
854 Laboratory Animal Care, International
855
856 ACVIM: American College of Veterinary Internal Medicine
857
858 ACVECC: American College of Veterinary Emergency and Critical Care
859
860 ACLAM: American College of Laboratory Animal Medicine
861
862 APHIS: USDA Animal and Plant Health Inspection Service
863
864 CDRH: Center for Devices and Radiological Health
865
866 CFR: Code of Federal Regulations
867
868 FDA: United States Food and Drug Administration
869
870 GLP: Good Laboratory Practice (21 CFR Part 58)
871
872 IACUC: Institutional Animal Care and Use Committee
873
874 NHP: Nonhuman Primate
875
876 PHS: Public Health Service
877
878 QAS: Quality Assurance Statement
879
880 QAU: Quality Assurance Unit
881
882 SOAP: Subjective/Objective Assessment and Plan
883
884 USDA: United States Department of Agriculture
885
886 US: United States
887

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888 Appendix B: Sample Decision Tree for Medical Device Animal Studies
889 1. Have you completed a risk analysis that considered all sources of relevant information,
890 including your own knowledge of risks and failure modes that you believe exist with your
891 device, risks commonly attributed to this general device type, and post-market
892 information for similar marketed devices? Postmarket information can be obtained from
893 the published literature and the CDRH Manufacturer and User Facility Device
894 Experience (MAUDE) database
895 ([Link]
896
897 a. If yes, go to step 2.
898
899 b. If no, we recommend that you complete the risk analysis and go to step 2.
900
901 2. Have all of the evaluable risks been tested on the benchtop, to the extent feasible, using
902 the final design iteration (i.e., proposed market-ready device)?
903
904 a. If yes, go to Step 3.
905
906 b. If no and if feasible, we recommend completion of bench testing with the final
907 device design before proceeding to step 3.
908
909 3. Did the risk analysis suggest that an animal study is necessary to assess potential safety
910 problems?
911
912 a. If yes, go to Step 4
913
914 b. If no, consider submitting a Pre-Submission13 and request FDA feedback.
915
916 4. Is there an established animal model for the type of device you are testing (i.e., one that
917 has been described in the literature or used to support the clearance or approval of a
918 similar device for the same indications for use)?
919
920 a. If yes, go to Step 5.
921
922 b. If no, have you assessed the anatomy and physiology (e.g., angiographic,
923 radiographic, CT screening) of commonly utilized laboratory animal species (e.g.,
924 small hoofed stock, dogs, and nonhuman primates) for size and procedural
925 approach features?
926
927 i. If yes, and you can identify an animal model that would work, go to Step 5.
928
929 ii. If yes, and you identify significant challenges that prohibit the use of a
930 reasonable animal model for all or some of the animal studies recommended
931 by the risk analysis, FDA recommends that you contact the Agency for a
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932 discussion of these challenges and alternative approaches for collecting

933 evidence to demonstrate satisfactory device safety and performance prior to
934 clinical use via the presubmission process. Please note that FDA believes
935 such situations to be unusual. As part of this discussion, you should include
936 any available evidence that animal studies would not be feasible, propose
937 alternative solutions, including any available simulations, cadaveric studies,
938 and clinical information collected outside the United States. Please also note
939 that FDA generally does not consider high cost as sufficient justification for
940 not conducting animal studies.
941
942 iii. If no, FDA recommends that you consult an experienced laboratory animal
943 veterinarian to determine the availability and utility of common laboratory
944 species before proceeding to Step 5 or Step [Link].
945
946 5. Are there any particular features of the device that would result in study endpoints that
947 differ from those previously used in studies for other devices of the same type for the
948 same proposed indications, or are there new indications that suggest the use of different
949 or additional evaluation time points or methods?
950
951 a. If yes, you should identify the new endpoints, time points and methods, and
952 proceed to Step 6.
953
954 b. If no, FDA recommends that you use the endpoints, time points, and methods
955 reported for similar devices, and proceed to Step 6.
956
957 6. Is there anything known about the device that would indicate high variability
958 of animal responses, due to factors such as investigator training and familiarity with the
959 device or inherent challenges in the placement or tolerance of the device?
960
961 a. If you have investigated this issue and have determined that there is not a
962 significant learning curve or predicted animal response variability, proceed to
963 Step 7.
964
965 b. If evidence exists from either in vivo or in vitro studies that a significant learning
966 curve exists that would significantly increase animal response variability, FDA
967 recommends conducting pilot or proof of concept animal studies to evaluate this
968 issue prior to conducting pivotal animal studies and before proceeding to Step 7.
969
970 7. If, after consideration of all these issues, you would like FDA feedback on your proposed
971 animal study strategy, FDA recommends that you submit a Pre-Submission13 that
972 includes a proposal for your pivotal animal studies. This proposal should detail all
973 methods of assessment for identified risks that may be observed dynamically in life and
974 with gross pathology and histopathology, and include any specific questions for which
975 you would like FDA input.
976
977
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978 Appendix C: Recommended Animal Study

979 Research Controls to Consider
980 The requirements in 21 CFR Part 58 (e.g., adequate calibration and maintenance of experimental
981 equipment in accordance with standard operating procedures, 21 CFR 58.63 and 58.81(b)(11),
982 and proper identification of the test system, test article, control article, and all specimens
983 collected from the test system to preclude error in data recording and storage, 21 CFR 58.105,
984 58.107(c), 58.120(a)(5), and 58.130(c)) are intended to ensure the quality and integrity of the
985 data generated from the study. In addition to these requirements, we recommend that you
986 consider implementing the following controls to help keep the study focused, with clear goals,
987 and minimize problems that can interfere with a successful study.
988
989 • Whenever possible, use pilot studies to best aid in the selection of time points, animal
990 numbers, and interventions that minimize confounding and optimize animal use. The number
991 of animals to be used in the study should be stated with clear reasoning.
992
993 • In addition to defining the study objectives as required under 21 CFR 58.120(a), we
994 recommend that you include a priori acceptance criteria for success that are based on
995 clinically relevant risks (often identified in your Risk Assessment Plan). A plan for analysis
996 of these criteria should be defined and should include, where appropriate, the statistical
997 methods that are to be used with definitions of success and failure. If using a semi-
998 quantitative rating scale, define the score required that constitutes “success/pass” and provide
999 your scientific rationale.
1000
1001 • Ensure selection of normal healthy animals based on timely interpretation of laboratory work
1002 and veterinary medical examination prior to study enrollment.
1003
1004 • In addition to the requirement in 21 CFR 58.90(g) to analyze feed and water periodically for
1005 known contaminants, incorporate methods that permit nutritional adequacy for the species
1006 under study, such as:
1007
1008 o regularly scheduled interim weight measurements
1009
1010 o provision of adequate number of feeders in pen-housed animals
1011
1012 o consultation with attending veterinary staff regarding provision of special feeds or special
1013 nutritional supplements during periods when you may expect finicky eating behavior,
1014 such as the peri-procedural time frame.
1015
1016 • Consider use of an acclimation period after the source animals arrive at the test facility, such
1017 as 7 to 10 days, prior to study enrollment.
1018
1019 • Incorporate appropriate baseline assessments of animal health and behavior prior to study
1020 enrollment, including timely veterinary interpretation (e.g., fecal examination for parasites,

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1021 hemogram, and blood chemistry accompanied by the laboratory reference values). Under 21
1022 CFR 58.90(c), at the initiation of the study, animals must be free of any disease or condition
1023 that might interfere with the purpose or conduct of the study. Therefore, screen animals out
1024 or treat and verify medical readiness for study, thereby minimizing the inability to associate
1025 clinical pathology with the device vs. a pre-existing condition.
1026
1027 • Ensure proper aseptic surgical technique, and monitoring and intervention to control
1028 unintended infections.
1029
1030 • Incorporate practices and procedures, as appropriate, in addition to those required under 21
1031 CFR Part 58, that ensure the animal facility staff are providing adequate sanitation and
1032 environmental controls to prevent unintended injury and infection.
1033
1034 • Incorporate practices to ensure that training in the planned experimental methods have
1035 exceeded the device learning curve, such that there is low to non-existent inter-procedural
1036 variability.
1037
1038 • Under 21 CFR 58.29(c), there must be a sufficient number of personnel for the timely and
1039 proper conduct of the study according to the protocol. Therefore, you should incorporate
1040 practices to ensure that there is adequate personnel and staffing to make certain that animals
1041 are appropriately monitored throughout the duration of study and at the appropriate intensity
1042 and duration that would reasonably detect the predicted failure modes as well as any common
1043 experimental outcomes.
1044
1045 • Ensure that the protocol includes appropriate monitoring and timely postoperative monitoring
1046 and intervention to detect, control, and report common physical and physiological outcomes
1047 such as vascular spasms, arrhythmias, respiratory difficulty, seizures, gait disturbances,
1048 cognitive dysfunction, pain, and distress.
1049
1050 • Incorporate practices to ensure that transportation and shipping stress is minimized when
1051 moving peri-procedural animals to remote holding sites.
1052
1053 • Incorporate practices and procedures that enable animals in group settings to consume
1054 adequate amounts of water and food and to minimize inter-species injury.
1055
1056 • Incorporate practices that encourage adequate and timely intervention to obtain complete
1057 necropsies (gross and histopathology) when animals die unexpectedly in order to establish
1058 whether the cause of death is or is not device-related.
1059
1060 • Incorporate practices that encourage proper handling, storage, and preparation of tissue for
1061 chemical analysis and histological processing.
1062
1063 • Consider steps to minimize bias or the perception of bias including, but not limited to:
1064
1065 o Contributing Scientists with no financial conflicts,
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1066
1067 o Blinding, and
1068
1069 o The utilization of more than one observer.
1070
1071 • Incorporate programs that will provide physiologic homeostasis, such as adequate
1072 thermoregulation, and electrolyte, blood glucose, and caloric balance.
1073
1074 • Incorporate a program to maximize animal wellness through the provision of species-specific
1075 social adequacy and environmental enrichment.
1076
1077 • Incorporate procedures that standardize the timely methods for the collection, handling, and
1078 shipment of tissue specimens.
1079
1080

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1081 Appendix D: Sample Organization of Animal Study Test Report [Including

1082 Raw Data (as defined by 21 CFR 58.3(k))] Components to Facilitate Review
1083 The list below is intended as an example of the organization of a test report for recommended
1084 and required content. This sample does not include all of the requirements of 21 CFR 58.185.
1085 For more information on required content necessary to be in compliance with Part 58 reporting
1086 requirements, please see 21 CFR 58.120 and 58.185.
1087
1088 1. Report numbers (as applicable)
1089
1090 a. Institutional Animal Care and Use Committee/Ethics Committee protocol number
1091
1092 b. Study director protocol number(s)
1093
1094 c. Test Facility protocol number(s), if applicable
1095
1096 2. Title of the report
1097
1098 3. Description of compliance with GLP regulations. If not in compliance, your statement
1099 provided in your submission explaining the reasons why the study was not in
1100 compliance with GLP regulations should also describe in detail all deviations from the
1101 regulations. The statement should include information that will help FDA reconstruct
1102 the study, explain any confounding variables, and demonstrate that authentic and
1103 complete test data have been collected and reported.
1104
1105 4. Contact information (e.g., mailing address, street address, city, state, country and zip
1106 code for each contact)
1107
1108 a. Sponsor
1109
1110 b. Sponsor representative
1111
1112 c. Test facility name(s); provide additional information, if available:
1113
1114 i. USDA registration (yes/no)
1115
1116 ii. AALACi accredited (yes/no)
1117
1118 iii. PHS Assurance (yes/no)
1119
1120 d. Study director
1121
1122 e. Quality Assurance director
1123
1124 5. Final report signature

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1125
1126 a. Study director’s signature
1127
1128 b. Quality Assurance Statement and signature
1129
1130 6. Copy of the protocol reviewed by the Institutional Animal Care and Use Committee
1131 (IACUC), and signed by the IACUC chairperson and attending veterinarian
1132
1133 7. Executive summary
1134
1135 a. Overview of animal study
1136
1137 i. Study Schedule
1138
1139 ii. Objective of the study
1140
1141 iii. Acceptance criteria
1142
1143 iv. Rationale for selection or exclusion of animals, including supporting
1144 discussion and rationale if the proposed animal model could not be used
1145
1146 v. Characterization of test and control articles
1147
1148 a) Design iteration of device used
1149
1150 b) Referenced serial or model numbers
1151
1152 vi. Brief discussion of methods used, including insertion, approach, incision,
1153 monitoring, intervention, imaging, necropsy, and histology as appropriate
1154
1155 vii. Brief overview of results
1156
1157 a) Morbidity/mortality
1158
1159 (i) Gross necropsy information
1160
1161 (ii) In situ photography
1162
1163 (iii) Descriptive findings
1164
1165 b) Biologic response to the device to include such things as
1166
1167 (i) Inflammation
1168
1169 (ii) Resorption (if applicable)
1170
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1171 (iii) Injury

1172
1173 (iv) Healing
1174
1175 (v) Integration
1176
1177 c) Impact of animal on device
1178
1179 (i) Device structural integrity
1180
1181 (ii) Device functional integrity
1182
1183 d) Deployment/surgical success, positioning, and overall handling
1184
1185 e) System compatibility, if routinely used with other ancillary devices
1186
1187 f) Imaging characteristics
1188
1189 viii. Conclusions
1190
1191 a) Conformity with controls
1192
1193 b) Success in meeting acceptance criteria
1194
1195 c) Identification of related studies that were conducted or are
1196 scheduled to be completed that explain any outstanding issues
1197
1198 8. Indexed Secondary Attachments (raw data and individual test reports)
1199
1200 a. Vendor reports
1201
1202 b. Baseline and interim health examinations
1203
1204 c. Surgery and anesthesia reports
1205
1206 d. Imaging reports
1207
1208 e. Clinical pathology results
1209
1210 f. Electromechanical results
1211
1212 g. Copies of animal medical records
1213
1214 h. Signed and dated Contributing Scientist(s) reports (e.g., interventionalist, surgeon,
1215 radiologist, clinical veterinarian, clinical pathologist, pathologist etc.). These
1216 reports may need:
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1217
1218 i. Images (e.g., explant radiography images, in situ photography, gross and
1219 histopathology, angiography)
1220
1221 ii. Cinematography
1222
1223 iii. Electrophysiology strips
1224
1225 iv. If applicable and part of the raw data, consider providing case report
1226 forms.
1227
1228

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1229 Appendix E: Tabulated Summary of Relevant Federal Regulations and

1230 Guides (the list below is not intended to be exhaustive)

Topic Regulatory Citation

GLP Animal Care 21 CFR 58.90
Protocol 21 CFR 58.120 and 58.130
Quality Assurance Unit 21 CFR 58.35
Test and Control
21 CFR 58.105 and 58.107
Articles
Records and Reports 21 CFR 58.185, 58.190, and 58.195
Test System 21 CFR 58.3(i)
Federal Animal
Biomedical Research 9 CFR Chapter I, Part 3
Standards
The care, exercise, and housing of dogs are described in 9
CFR Chapter I, Part 3 Standards, Subpart A.
Housing, animal management, and species-specific space
Housing and Well-Being recommendations are provided in the National Research
of Dogs Council (NRC) publication, “Guide for the Care and Use
of Laboratory Animals,”4 which is the recommended
reference to which metrics are applied by AAALAC and
the PHS.
Sanitization and 9 CFR Chapter I, Part 3 Standards and in the “Guide for
Husbandry the Care and Use of Laboratory Animals.” 4
Environmental Control 9 CFR Chapter I, Part 3 Standards and in the “Guide for
of Transportation the Care and Use of Laboratory Animals” 4
Identification of warm-blooded animals (except suckling
Animal Identification rodents) is discussed in 21 CFR 58.90, and also, with
Systems respect to dogs and cats and all other animals used in
research, within 9 CFR Chapter 1, Part 2, Subpart E.
21 CFR 58.90 and in the NRC “Guide for the Care and Use
of Laboratory Animals,”4 Page 110. The European
Animal Quarantine and
Convention for the Protection of Vertebrate Animals Used
Conditioning
for Experimental and Other Scientific Purposes 39 provides
similar guidance to European member state facilities.
Social and 9 CFR 3.7 and 3.8, and in the NRC “Guide for the Care
Environmental Research and Use of Laboratory Animals,” 4 pages 52-56, 63-65, 82-
Standards 84.
1231
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1232 Appendix F: Additional Resources on Animal Care and Research

1233 1. FDA Guidance for Industry (2007). Good Laboratory Practices - Questions and
1234 Answers.
1235 ([Link]
1236 [Link])
1237 2. Hasenfuss G (1998). Animal models of human cardiovascular disease, heart failure and
1238 hypertrophy. Cardiovascular Research, 39(1) 60-76.
1239 3. National Research Council Board on Agriculture Subcommittee on Dog Nutrition.
1240 Nutrient Requirements of Dogs, Revised. (1985). Washington, D.C.: National Academy
1241 Press. ([Link]
1242 4. National Research Council Board on Agriculture and Renewable Resources
1243 Subcommittee on Goat Nutrition. Nutrient Requirements of Goats: Angora, Dairy, and
1244 Meat Goats in Temperate and Tropical Countries. (1981). Washington, D.C.: National
1245 Academy Press.
1246 5. National Research Council Board on Agriculture Subcommittee on Sheep Nutrition.
1247 Nutrient Requirements of Sheep. 6th rev. ed. (1985). Washington, D.C. National
1248 Academy Press. ([Link]
1249 6. National Research Council Board on Agriculture Subcommittee on Nutrient
1250 Requirements of Horses. 6th rev. ed. (2007). Washington, D.C. National Academy Press.
1251 ([Link]
1252 7. Flecknell P.A. (1996) Laboratory Animal Anesthesia, San Diego, CA: Academic Press
1253 Inc.
1254 8. Carr, John. 1998. Garth Pig Stockmanship Standards. Iowa, 5M Enterprises, LTD
1255 Sheffield, UK. Website with condition images.
1256 ([Link] Accession date
1257 11/14/08)

1
United States Department of Agriculture, 9 CFR Parts 1, 2, and 3 (Animal Welfare).
2
United States Public Health Service (2002). Policy on Humane Care and Use of Laboratory
Animals. Office of Laboratory Animal Welfare, National Institutes of Health. Bethesda, MD.
([Link]
3
United States Government Health Research Extension Act of 1985, Pub. L. 99-158; and US
Government Principles for the Utilization of and Care of Vertebrate Animals Used in Testing,
Research, and Training.
([Link]
4
National Research Council Guide for the Care and Use of Laboratory Animals, 8th ed. (2011).
Institute of Laboratory Animal Resources Commission on Life Sciences, Washington, D.C.
National Academies of Science Press. ([Link]
5
The FDA maintains an intergovernmental Memorandum of Understanding (MOU) between
NIH, FDA, USDA regarding common areas of regulatory interest in animal care and use.
([Link]

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6
Tsonis, P.A. (ed).(2008) Animal Models in Eye Research, 1st ed. Academic Press: Burlington.
7
Ma, C. and J-M Zhang (eds) (2011). Modeling Pain in Laboratory Animals: A Collection of
Protocols. 1st Ed. Humana Press: New York.
8
Howells DW, MJ Porritt, SSJ Rewell, V O’Collins, et. al. Different strokes for different folks:
the rich diversity of animal models of focal cerebral ischemia. J Cerebral Blood Flow Metab
2010; 30 (May 19): 1413-1431.
9
Rink C, G Christoforidis, A Abduljalil, M Kontzialis, et. al. Minimally invasive
neuroradiologic model of preclinical transient middle cerebral artery occlusion in canines.
PNAS 2008 (Sept 16); 105(37):14100-14105.
10
Potes JC, J ca Costa Reis, F Capela e Silva, C Relvas, et. al. The Sheep as an animal model in
orthopaedic research. Exper Pathol Health Sciences 2008; 2(1): 29-32.
11
Pearce AI, RG Richards, S Milz, E Schneider, and SG Pearce. Animal models for implant
biomaterial research in bone: A Review. Eur Cells Materials 2007; 13: 1-10.
12
An YH and RJ Friedman (eds.). (1999) Animal Models in Orthopaedic Research. CRC Press,
LLC., Boca Raton, Fl.
13
For more information on Pre-Submissions, see the FDA guidance, Requests for Feedback on
Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug
Administration Staff
([Link]
ments/[Link]).
14
The Interagency Coordinating committee on the Validation of Alternative Methods
(ICCVAM) provides many websites for decisions related to animal care and use, refinements,
reductions, and replacement of animal models and validated models
([Link]
15
The European Centre for the Validation of Alternative Methods (ECVAM) is a useful web link
to validated European alternative animal models.
([Link]
m_-[Link])
16
The Japanese Convention on the Validation of Alternative Methods is a resource for those
animal models and animal welfare items of interest from Japan. ([Link]
17
The Johns Hopkins Center for Alternatives to Animal Testing (CAAT) is a comprehensive
web resource for all subjects related to global animal care and use, animal welfare, and animal
alternatives. ([Link]
18
The National Center for 3Rs is a comprehensive web link for animal care and use and animal
refinement and replacement questions. ([Link]
19
AltTox Forum (sponsored by Proctor and Gamble and The Humane Society of the United
States) provides information about validated animal alternatives. (http:// [Link]/)
20
Tox Net is an NIH-sponsored website of available literature on alternatives.
([Link]
21
Bassert, Joanna M. Medical Records. Chapter 5. IN: McCurnin, Dennis M and Joanna M
Bassert (eds). 2010. Clinical Textbook for Veterinary Technicians, 7th edition. Saunders, St.
Louis, MO.
22
Reinhart, V. (2002). Comfortable quarters for laboratory animals ninth ed. Washington, D.C.
United States Department of Agriculture Animal Welfare Information Center

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23
Fisher, T. F. (1993). Miniature swine in biomedical research: Applications and husbandry
considerations. Lab Animal 22(5), 47-50
24
Guide for the Care and Use of Agricultural Animals in Research and Teaching, 3rd edition
2010, Federation of Animal Science Societies (FASS).
([Link]
25
Panepinto, L.M. (1986). Character and management of miniature swine. In H. C. Stanton and J.
H. Mersmann (Eds.) Swine in Cardiovascular Research, (1) (pp. 11-24). Ames, IA: Iowa State
University Press.
26
National Research Council Institute for Laboratory Animal Research Committee on
Guidelines for the Humane Transportation of Laboratory Animals (2006). Institute of Laboratory
Animal Resources Division on Earth and Life Studies, Washington, D.C. National Academies of
Science Press. ([Link]
27
National Research Council Institute for Laboratory Animal Research Committee on
Guidelines for the Humane Transportation of Laboratory Animals (2006). Nutrient Requirements
of Beef Cattle. 7th rev. ed. Washington, D.C.: National Academy Press.
([Link]
28
Hampshire, V.A., Davis, J.A. (2008). Postprocedural Care of Commonly Utilized Research
Animal Subjects. In R.E. Fish, M.B, Brown, P.J. Danneman & A.Z. Karas (Eds.) Anesthesia and
Analgesia in Laboratory Animals 2nd ed (pp. 219-237), London: Elsevier
29
Flecknell P.A, Waterman-Pearson A. (2000). Pain Management in Animals. London:
Harcourt Publishers Ltd.
30
Peterson N.C. (2004). Assessment of Pain Scoring. Contemp Top Lab Anim Sci,43(1):74-76
31
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.
32
Hellyer P.W. (2002). Pain Management. In Wingfield W.E and Raffe,MR (Eds). The
Veterinary ICU Book. Jackson Hole, WY: Teton NewMedia.
33
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
34
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.
35
Keown, J. F. (2005). How to Body Condition Score Dairy Animals. The University of
Nebraska Extension-Lincoln Institute of Agriculture and Natural Resources.
([Link]
36
State of Maine. Extension Programs and Resources. Bulletin #1010, Body Condition Scoring
for your Horse. Retrieved from: [Link]
37
Ohio State University College of Veterinary Medicine on-line learning system: How to Assess
Body Score in Dogs and Cats. ([Link]
38
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.
39
The European Convention for the Protection of Vertebrate Animals used for Experimental and
Other Scientific Purposes is a useful web resource for European principles relating to animal care
and use in certain member states.
([Link]

33