Guidance for Industry and FDA 
Staff 
 
Preparation and Review of 
Investigational Device Exemption 
Applications (IDEs) for Total 
Artificial Discs
 
 
 
Document issued on: April 11, 2008 
 
 
For questions regarding this document contact Barbara Buch, MD at 240-276-3737 or via email at 
barbara.buch@fda.hhs.gov or contact Sergio de del Castillo at 240-276-3751 or via email at 
sergio.dedelcastillo@fda.hhs.gov.   
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
 
Orthopedic Spinal Devices Branch 
Division of General, Restorative, and Neurological Devices 
Office of Device evaluation  Contains Nonbinding Recommendations 
Preface 
 
 
 
Public Comment 
Written comments and suggestions may be submitted 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.  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 at: 
http://www.fda.gov/cdrh/ode/guidance/1637.html.  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 
240-276-3151 to receive a hard copy.  Please use the document number (1637) to identify the 
guidance you are requesting. 
 
  Contains Nonbinding Recommendations 
Table of Contents 
 
A.  Introduction........................................................................................................................................1 
THE LEAST BURDENSOME APPROACH.......................................................................................2 
B.  Device Description..............................................................................................................................2 
C.  Report of Prior Investigations...........................................................................................................3 
1.  Clinical Data...................................................................................................................................3 
2.  Animal Data....................................................................................................................................3 
3.  Mechanical Data............................................................................................................................6 
4.  Biocompatibility Data..................................................................................................................10 
5.  Shelf  Life Data.............................................................................................................................11 
D.  Clinical Investigational Plan...........................................................................................................11 
1.  Choosing a Clinical Investigation Plan:  Feasibility or Pilot Study vs. Pivotal Study...........12 
2.  Purpose or Objective of the Protocol.........................................................................................12 
3.  Study Design.................................................................................................................................12 
4.  Choice of Control.........................................................................................................................13 
5.  Inclusion Criteria.........................................................................................................................13 
6.  Exclusion Criteria........................................................................................................................15 
7.  Number of Investigators, Investigational Sites, and Subjects..................................................17 
8.  Study Duration and Follow-up Schedule...................................................................................17 
9.  Post-operative Regimen...............................................................................................................17 
10.  Safety and Effectiveness Endpoints............................................................................................17 
11.  Subject Success.............................................................................................................................22 
12.  Study Success................................................................................................................................22 
13.  Statistical Analyses and Data Presentations..............................................................................23 
14.  Patient Data Report Forms (Case Report Forms (CRF))........................................................23 
15.  Risk Analysis................................................................................................................................24 
16.  Retrieval Study.............................................................................................................................26 
17.  Spinal Tumors..............................................................................................................................26 
E.  Monitoring........................................................................................................................................26 
F.  Labeling.............................................................................................................................................27 
G.  Informed Consent.............................................................................................................................27 
 
  Contains Nonbinding Recommendations 
Guidance for Industry and FDA Staff 
 
Preparation and Review of Investigational 
 
Device Exemption Applications (IDEs) for 
Total Artificial Discs 
 
 
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.  You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes 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 title page of this guidance.  
 
A.  Introduction 
 
This document was developed to describe our recommendations for IDE applications for 
total artificial disc devices.  It provides guidance for developers on the appropriate pre-
clinical tests and clinical trial designs to adequately evaluate the safety of these devices as 
well as their effectiveness to relieve symptoms of spinal etiology and improve quality of life.  
This document makes additional recommendations and supplements Guidance Document 
for the Preparation of IDEs for Spinal Systems (i.e., Spinal Systems Guidance).1
 
The purpose of this document is to provide guidance to industry sponsors and FDA staff 
about important preclinical and clinical information, which should be presented in an 
Investigational Device Exemption (IDE) application for total intervertebral disc replacement 
systems (i.e., total artificial discs).  FDA is issuing this document to help ensure consistency 
and understanding between FDA and sponsors when developing IDE submissions for total 
artificial discs. We hope this guidance will conserve FDA and industry resources and 
facilitate timely review. 
 
This IDE guidance document is applicable only to total artificial discs.  This guidance 
document is not applicable to other types of spinal systems that are designed to allow some 
degree of motion in the spine, such as spinal stabilization systems using pedicle screws or 
other flexible implants without fusion, disc nucleus replacements, partial intervertebral disc 
replacements, any spinal joint replacements (e.g., facet joint replacement), any other joint 
motion sparing or replacing implants, and combination products that may include biologic or 
                                                      
1 http://www.fda.gov/cdrh/ode/87.html
  1 Contains Nonbinding Recommendations 
pharmaceutical materials.  Because of the complexity of such devices and design-specific 
issues, sponsors are encouraged to submit pre-IDE submissions to the Orthopedic Spine 
Devices Branch (OSDB) to facilitate discussion regarding the important preclinical and 
clinical information required for an IDE application.  Please contact the OSDB Branch Chief for 
additional information regarding the pre-IDE submission process. 
 
This guidance does not pertain to spinal implant devices that are intended for intervertebral 
body fusion, which may include cages, vertebral body replacement devices, or spinal 
vertebral body augmentation devices for vertebroplasty.  For information about the 
preclinical testing FDA recommends for other spinal systems, please see the Spinal Systems 
Guidance,2 Clinical Trial Considerations: Vertebral Augmentation Devices to Treat Spinal 
Insufficiency Fractures,3 and Class II Special Controls Guidance Document:  Intervertebral 
Body Fusion Device.4
 
In this guidance, a spinal system is defined here as the complete implant configuration.  A 
component is a single element in a system. Construct references are typically made when 
discussing testing.  For the purposes of this guidance, system and device are used 
interchangeably.  
 
FDAs 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.  
 
THE LEAST BURDENSOME APPROACH 
The issues identified in this guidance document represent those that we believe need to 
be addressed. In developing the guidance, we carefully considered the relevant statutory 
criteria for Agency decision-making.  We also considered the burden that may be 
incurred in your attempt to comply with the guidance and address the issues we have 
identified.  We believe that we have considered the least burdensome approach to 
resolving the issues presented in the guidance document.  If, however, you believe that 
there is a less burdensome way to address the issues, you should follow the procedures 
outlined in the A Suggested Approach to Resolving Least Burdensome Issues 
document.  It is available on our Center web page at: 
www.fda.gov/cdrh/modact/leastburdensome.html.   
 
B.  Device Description 
In accordance with 21 CFR 812.25, your investigational plan must include a device 
description, which should include the following: 
                                                      
2 http://www.fda.gov/cdrh/ode/87.html
3 http://www.fda.gov/cdrh/ode/guidance/1543.html
4 http://www.fda.gov/cdrh/ode/guidance/1540.html
  2 Contains Nonbinding Recommendations 
  the devices intended use and indications for use; 
  supporting magnified sketches or photographs of the total artificial disc attached to a 
spinal model; 
  a table that includes each component name and corresponding part number; 
  a complete written description of the individual components, including how any 
components interconnect; 
  complete mechanical drawings with all dimensions and tolerances of each individual 
component and, if applicable, of the total system; 
  a list of all instruments unique to the implantation of the subject system and 
supporting magnified sketches or photographs of them; and  
  identification of the materials from which the device components are manufactured 
and any voluntary material standards to which these materials conform. 
 
C.  Report of Prior Investigations 
Please refer to the Report of Prior Investigations section of the spinal systems guidance on 
preparing reports of prior investigations.  In addition to the information in the spinal system 
guidance, you must indicate whether all non-clinical tests comply with Good Laboratory 
Practices (GLP) (21 CFR Part 58).  (21 CFR 812.27(b)(3))  Otherwise, we recommend you 
explain why you believe the GLP requirements do not apply. 
 
1.  Clinical Data 
Please refer to Item 1 of the Report of Prior Investigations section of the spinal systems 
guidance for information about this section. 
 
A description of how the prior investigations have influenced subsequent changes in 
device design, patient selection and/or surgical technique and instrumentation should be 
included within clinical data reports, where applicable. (21 CFR 812.27(a)) 
 
Refer to the Clinical Data Presentations for Orthopedic Device Applications (Clinical 
Data Presentations Guidance)5 for detailed descriptions of and sample tables for 
information concerning the items requested in this section. 
 
2.  Animal Data 
Animal data used to establish the relative safety of your total artificial disc prior to 
initiating human clinical studies must also be included. (21 CFR 812.27(a))  Reasons for 
conducting animal studies could include:   
  providing proof of concept;  
  evaluating different design concepts, surgical instrumentation, or technique;  
                                                      
5 http://www.fda.gov/cdrh/ode/guidance/1542.html
  3 Contains Nonbinding Recommendations 
  identifying failure mechanisms;  
  conducting functional studies (such as maintenance of motion and/or disc height 
without fusion or subsidence);  
  addressing biologic response to particle and substrate materials; and 
  assessing biocompatibility or toxicity. 
 
In accordance with 21 CFR 812.27(a), you must include complete reports of any animal 
testing conducted on the device or its components, whether adverse or supportive, that 
are relevant to the evaluation of the safety or effectiveness of your system.  The animal 
report must specify the purpose of the study and provide any supporting pathological, 
histological, and radiological evaluations.  The animal report should also include an 
executive summary of the evaluation by a pathologist.6  If testing was not done on the final, 
sterilized version of the system included in the IDE, describe the differences between that 
system and the version of the system used in your animal studies, and explain why you 
consider the testing and the results to be meaningful.    
 
Your report of any animal testing should include: 
  identification of the animal model and a rationale for the choice of animal model 
(e.g., relevance to human anatomy or disease); 
  identification of the device components or materials (e.g., particles) used in the 
study and a rationale for why these were selected; 
  the evaluation timepoints of the study and a rationale for choosing these 
timepoints; 
  the number of animals evaluated at each timepoint and rationale for the number of 
animals chosen; 
  identification of the test control; 
  the results; and 
  a discussion of the results in terms of the expected in vivo and clinical behavior of 
the device.    
We recognize that choosing and validating an animal model may be difficult because there 
is no perfect model.  Many animal studies have involved sheep, goats, primates, dogs, or 
kangaroos.  In choosing an animal model for evaluating your device or system, you should 
ensure the model you select addresses the anatomy, physiology, biomechanics, and in vivo 
loads expected in clinical use.  Each animal model should be appropriate to the purpose of 
the study.   
 
                                                      
6 Cunningham BW, Orbegoso CM, Dmitriev AE, Hallab NJ, Sefter JC, and PC McAfee. The 
effect of titanium particulate on development and maintenance of a posterolateral spinal 
arthrodesis: an in vivo rabbit model.  Spine 15: 1971-1981, 2002. 
 
  4 Contains Nonbinding Recommendations 
Functional Animal Study 
For functional animal testing, we recommend that you perform all testing on 
sterilized components of the final device design.  You should use a control for your 
functional animal testing to establish a frame of reference for the performance of your 
device and materials. 
 
The functional animal model should reflect the intended use of the device.  In 
particular, your test model and the levels of implantation in the animals should reflect 
the intended use of your device. 
 
Particulate Animal Study 
If the wear particles of any material in your device or system have not been 
comprehensively evaluated in the spine or at the indicated spinal level, FDA may 
recommend you conduct a study using a small animal model (e.g., rabbit).  The 
objective of this study is to evaluate the local and systemic responses (e.g., 
biocompatibility, neurologic response, tissue response, and toxicity) to the wear 
debris.   
 
The wear particles used in the study should represent the size, shape, amount, and 
chemical composition of those expected from in vivo use (i.e., representative of 
particles generated from durability and/or wear testing).  Regardless of the amount of 
wear debris generated from bench-top testing, one group of animals should receive a 
sufficient dose so that particles can be located during histologic analysis.  If wear 
particles cannot be identified and located, it may not be possible to draw conclusions 
about either particle transport or the local tissue reaction to particles from your 
device.  We recommend 10 million particles for the high-dose group, although a 
larger amount may be necessary depending on particle size and composition.  The 
histology results should account for the total amount of wear particles injected into 
the animal.  For instance, if the particulates are injected into the lumbar spine, these 
particles should be observed at the injection site and/or in other parts of the body. 
 
FDA recommends you document physical and neurological observations throughout 
the study.  Animals should be sacrificed at 3 and 6 month time points, though longer 
time points might be needed depending on the material or device.  You should harvest 
three (3) samples from three (3) different points of each organ/tissue evaluated in the 
following areas: spinal region, paraspinal region, dura, and local lymph nodes.  
Depending on the materials and the level the implant is indicated, FDA may 
recommend you evaluate additional tissues or organs such as spleen, kidneys, heart, 
liver, lung, and pancreas.  An independent toxicologist should harvest all samples and 
analyze the pathological slides generated from the samples.   
 
References to animal studies in the literature may be appropriate for evaluating the 
biological response to wear particles.  If you cite the literature to support the 
biological response of your device, explain how the particles in the literature studies 
are representative of the particles expected from in vivo use of your device (e.g., 
representative of wear particles generated from durability and/or wear testing).   
  5 Contains Nonbinding Recommendations 
 
Cytokine Analysis 
It may be appropriate to assess the potential for osteolysis by evaluating the cytokine 
response to wear debris.  This testing may be accomplished through evaluation of the 
cytokine response during either a small animal particle implantation study or a 
functional animal study using, for example, the methods described by Cunningham et 
al. 
 
3.  Mechanical Data 
FDA recommends you characterize your total artificial disc by preclinical mechanical 
testing.  Alternatively, you may submit a rationale explaining why you believe such 
testing is not necessary to establish the relative safety of your device.  Identification of 
appropriate mechanical testing influenced by the design, material, method of attachment 
to the spine, and target patient population must be included.  (21 CFR 812.27(a)).   
 
Your IDE must include complete reports for each test for all mechanical testing conducted 
on your system or its components, whether adverse or supportive, that is relevant to the 
evaluation of the safety or effectiveness of your total artificial disc.  (21 CFR.278(a))  
You must also include a comprehensive summary of all mechanical testing. (21 
CFR812.(b)(3))  Each test report should include:   
  an identification of the components that comprised the constructs or subconstructs 
tested; 
  an identification of any test standard(s) to which the testing conforms, including 
identification and justification of all deviations from the test standard; 
  the testing set-up; 
  the testing procedures; 
  a rationale supporting that the testing you conducted represents the worst case 
design; 
  a rationale for the loading modes chosen (axial, bending, torsional, shear, etc.); 
  the results, including the failure modes; and 
  a discussion of the results in terms of the clinical requirements of the system (with 
reference to expected physiological loads and any supporting literature). 
 
Unless you provide an adequate rationale, all mechanical testing should represent a worst 
case construct design of the total system and not mechanical testing of individual 
components.  The device components that comprise the chosen worst case construct 
should be final, sterilized components.  When there are differences between the system 
tested and your system, we recommend you explain how or why the results are relevant 
in establishing the relative safety of your system. 
 
The test environment is dependent on the type of mechanical test being conducted.  Some 
tests may be done under ambient conditions, while it may be necessary for other tests to 
  6 Contains Nonbinding Recommendations 
be conducted in a simulated physiologic solution (e.g., dynamic and wear debris testing).  
We recommend you include the rationale supporting the test environment you select for 
each type of mechanical testing. 
 
All testing should be well-described and summarized with a clear, detailed rationale 
supporting that the testing and results are appropriate and clinically relevant. 
 
Test standards are currently being developed by the American Society for Testing and 
Materials (ASTM) and the International Organization for Standardization (ISO) for static 
and dynamic characterization and wear assessment of total artificial discs.  Two of these 
standards are published (ASTM Standard F2345-05:  Standard Test Methods for Static 
and Dynamic Characterization of Spinal Artificial Discs; ASTM Standard F2423:  
Standard Guide for Functional, Kinematic, and Wear Assessment of Total Disc 
Prostheses) and we recommend that you refer to these standards when devising a test 
protocol.7   
 
Static and Dynamic Characterization 
We recommend static and dynamic mechanical testing to characterize the device 
fully.  For most artificial disc designs, we recommend you conduct axial compression 
and compression shear testing.  Depending on the design of your device, FDA may 
recommend additional testing. 
 
Static testing should involve six samples of a worst case construct.  Fatigue testing 
should also involve six samples of the worst case construct to generate an Applied 
Force vs. Number of Cycles (AF/N) curve.  Two or more samples should survive ten 
million cycles at a specific load.  If the frequency of the dynamic testing exceeds 1-2 
Hz, then you should explain the test frequency in terms of its effects on the device 
materials, test environment, test temperature, and machine accuracy.  For example, if 
your device contains viscoelastic materials, such as ultra high molecular weight 
polyethylene (UHMWPE), your explanation should address how the chosen test 
frequency will affect these materials. 
 
We recommend you conduct compression-shear testing using the devices maximum 
theoretical range of motion (ROM) in one or more of the directions of motion (e.g., 
full flexion/extension, full lateral bending).  For any direction you did not test, we 
recommend you include the rationale that supports omitting that testing. 
 
Many total artificial discs are unconstrained in rotation. Therefore, torsional testing 
may not be applicable.  Nonetheless, a rationale for not providing torsional testing 
should be included. 
 
Durability and Wear 
We recommend you describe the theoretical range of motion (ROM) for your device 
in the various directions of motion (i.e., flexion, extension, lateral bending, axial 
                                                      
7 http://www.fda.gov/cdr/ost/guidance/321.html  
  7 Contains Nonbinding Recommendations 
rotation) to adequately characterize the device.  You should also describe the method 
through which you determined the ROM of your device. 
 
The objective of the durability testing is to establish wear generation potential for the 
device as well as to possibly assess the stability.  The durability or wear testing 
should involve cyclic loading that incorporates all directions of motion.  This testing 
should be combined to incorporate all directions of motion into one test.  Because 
most devices will be subjected to coupled motions (simultaneous motion about 
multiple axes) in vivo, FDA recommends you couple two or more of the motions 
during durability testing.  We recommend subjecting each test specimen, regardless 
of test method used, to ten million cycles in all directions.  If one or more motions are 
tested separately, you should vary the order of the motions among different test 
specimens to determine if there is any effect by the order of testing. 
 
Because different areas of the spine have different ROMs, the parameters for the 
durability testing will depend on the intended locations (i.e., cervical or lumbar) for 
the device.  The table below outlines test parameters FDA recommends for cervical 
and lumbar disc replacements.  These parameters have been chosen based on testing 
that has been reported for various total artificial discs.  If you chose different 
parameters, we recommend you provide a rationale supporting your choice, which 
may include evaluation of the device in simulated motion studies in cadaver spines.  
Because the motion of the device can depend on the level of implantation and the test 
methods employed, if you provide cadaver testing results, we recommend you explain 
how the results from cadaver testing represent worst case ROMs for your device. 
 
Recommended Durability and Wear Test Parameters 
Spinal  Flexion/  Lateral  Axial  Frequency  Test Duration  Preload 
Region  Extension  Bending  Rotation  (Hz)  (N) 
(degrees)  (degrees)  (degrees) 
Cervical  7.5  6  6  2  10 million cycles  100 
Lumbar  7.5  6  3  2  1200 
 
You should perform all durability and wear testing in a physiological solution (e.g., 
bovine calf serum) and extract the wear debris from the test solution for 
characterization.  Wear debris should be extracted from the solution using a filter 
with a pore size that allows collection of sub-micron particles.  You should include a 
complete description of the debris extraction or filtering procedure.  In addition, you 
should characterize the wear debris in terms of size distribution, shape, and chemical 
composition and retain the wear debris for future analysis.  The methods described in 
ASTM F561 and ASTM F1877 or equivalent methods may be helpful in collecting 
and characterizing the wear debris. 
 
FDA recommends you collect and characterize wear debris at least once every 
million cycles to determine if wear is increasing, decreasing, or remaining the same.   
 
  8 Contains Nonbinding Recommendations 
Some artificial disc devices are constrained (i.e., have limited ROMs) and alternative 
testing may be needed to evaluate the device at the upper limits of the devices 
ROMs.  Testing at the upper limits of the ROMs should demonstrate that the device 
does not break down or generate excessive wear debris when the device reaches these 
limits.   
 
Depending on the amount of data that you submit in an IDE for your device (e.g., 
animal data and/or clinical data collected outside the U.S.), durability and wear 
testing may not be necessary when you submit your IDE.  In some cases, it may be 
possible to perform this testing concurrent with the clinical study and report the 
results in your IDEs annual reports and in your premarket approval (PMA) 
application.  We recommend you contact the OSDB to discuss your plans to address 
the biological response to wear debris.   
 
Subluxation and Expulsion 
We recommend you assess the risk of subluxation of the superior components, 
inferior components, and any disc spacer used in the system.  You should include a 
rationale to support that the testing conducted was adequate.  The device should be 
tested in shear (or compression-shear) to expected in vivo loads that include an 
appropriate factor of safety.  Depending on the design of the device, FDA may 
recommend you evaluate the risk of subluxation and expulsion in more than one 
loading direction. 
 
Creep and Stress Relaxation 
Because many disc replacement devices include viscoelastic materials that may be 
subject to creep and stress relaxation, we recommend you provide testing to assess 
this behavior and your rationale to support that the testing conducted was adequate.  
You should conduct creep testing under continuous compressive loading on the final, 
sterilized device to demonstrate that the disc height can be maintained over the life of 
the device.  You should also include an accompanying hysteresis analysis. 
 
Subsidence 
We recommend you address the risk of subsidence of device components into the 
vertebral bodies through appropriate testing.  You should include a rationale to 
support the test method used. 
 
Kinematic Testing 
We recommend you conduct a cadaver study evaluating the range of motion of the 
device in vivo compared to a normal spine.  Please explain how the chosen number of 
cadaver specimens supports statistically significant results. 
 
Device Migration 
Sometimes, total artificial discs rely on press-fitting, ligamentotaxis, and rapid bony 
ingrowth into the endplates of the device to achieve adequate fixation.  The rationales 
supporting your selection of tests and conclusions based on the test results should 
establish that the risk of device migration is minimal.  Generally, we recommend 
  9 Contains Nonbinding Recommendations 
testing in an in vivo animal model to demonstrate that the surfaces of the endplates 
allow for rapid bone ingrowth and adequate fixation.  We also recommend you 
provide complete test reports including a rationale for the test model selected, 
histology, characterization of ingrowth, and time to achieve ingrowth. 
 
Durability of Coatings 
We recommend you provide results from testing (e.g., shear, tension, abrasion) to 
characterize the stability and durability of any coatings on your device.  You should 
also include a rationale explaining how your testing supports your conclusions.  In 
addition, we recommend you describe the coatings in terms of materials, physical 
characteristics (e.g., thickness, morphology, pore size), and how the coating is 
applied to the device surface.  Testing should include an evaluation of the device 
coatings under expected in vivo conditions to demonstrate that the coatings do not 
shear off.  Methods described in ASTM F1044, F1147, F1160 and F1978 or 
equivalent methods may be appropriate for these tests.  If the coating is not 
permanent, we recommend you describe any potential in vivo by-products, including:   
  the degradation mechanism; 
  the type of chemical reaction, if any; and  
  whether the coating or any of its degradation products causes any damage to 
surrounding tissues. 
 
We believe testing in a functional animal model with appropriate histological analysis 
may provide the best characterization and evaluation of any coating. 
 
4.  Biocompatibility Data 
FDA may recommend biocompatibility testing depending on the materials used to 
comprise your system.  Please refer to the guidance entitled Use of International 
Standard ISO-10993, Biological Evaluation of Medical Devices Part 1: Evaluation and 
Testing8 for additional information.  We suggest you reference AAMI/ANSI/ISO 
10993-1 or an equivalent method for a description of the type of information you should 
provide to address biocompatibility.   
 
In addition, FDA may recommend animal data describing the response to the device 
material(s) in the spine (see Section C.2. - Animal Data). 
 
If any of the total artificial disc components is manufactured from a polymer, we 
recommend that you provide the following information to characterize the final, sterilized 
material: 
 
information describing leachables  
 
average molecular weight  
 
                                                      
8 http://www.fda.gov/cdrh/g951.html
 
  10 Contains Nonbinding Recommendations 
molecular weight distribution  
 
chemical and crystal structures  
 
percent of crystallinity  
 
degree of cross-linking of that polymer.  
 
 
For any materials manufactured from polymers or that have the potential for leachables, 
we recommend that you provide an exhaustive extraction analysis of the final, sterilized 
device.  Extractions should be done using both a polar (e.g., saline) and a non-polar 
solvent (e.g., hexane, acetonitrile).  We recommend that you provide your rationale for 
the solvents you select for the extraction tests.  The test report should include: 
 
the instrument sensitivities  
 
the type of solvent used  
 
the amount of leachables and impurities detected at part-per-billion (ppb) levels.  
 
 
We recommend that you identify each leachable and impurity, whether detected 
qualitatively or quantitatively, examples of which include: 
 
any low molecular weight materials  
 
residual monomers  
 
solvent  
 
sulfur contents  
 
catalysts  
 
initiators  
 
lubricants.  
 
 
 
5.  Shelf  Life Data 
We recommend you evaluate all devices that can be affected by shelf life, sterilization, or 
aging (e.g., those with polymers or resorbable compounds).  You should characterize the 
material of the final, sterilized device before and after aging to determine whether aging 
altered the material structure (e.g., molecular weight distribution, crystallinity, cross-
linking) or the mechanical properties of the device.  If shelf life or aging affects the 
components material, you should perform the same mechanical testing of that 
component or system before and after aging. 
 
D.  Clinical Investigational Plan 
The clinical studies submitted to support PMA applications should be designed and 
conducted in a manner that provides data that constitutes valid scientific evidence within the 
meaning of 21 CFR 860.7(c)(2).  For FDAs recommendations about data presentation, 
please refer to the clinical data presentations guidance.   
 
  11 Contains Nonbinding Recommendations 
Much of the information provided in the spinal systems guidance is directly applicable to 
IDEs for total artificial discs.  For the sake of brevity, only information specific to total 
artificial discs is presented in this guidance. 
 
1.  Choosing a Clinical Investigation Plan:  Feasibility or Pilot Study vs. 
Pivotal Study 
Unlike IDEs for many orthopedic implants, IDEs for total artificial discs often involve 
the introduction of new device designs or technologies or new clinical endpoints or 
assessments.  Therefore, protocols for total artificial discs may vary in scope from a 
feasibility or pilot study to a pivotal study used to support the safety and effectiveness of 
the device for a future PMA application.  These various types of studies are intended to 
address different questions and collect different types and amounts of safety and 
effectiveness information. 
 
Your investigational plan must contain the elements listed in 21 CFR 812.25.  In addition 
to the information in this section, please refer to Item 1 in the Investigational Plan section 
of the Spinal Systems Guidance for recommendations about information you should 
include in your investigational plan. 
 
2.  Purpose or Objective of the Protocol 
The clinical protocol should begin with one or more clearly defined objectives and one or 
more clearly defined hypotheses.  Please refer to Item 2 in the Investigational Plan 
section of the Spinal Systems Guidance for additional recommendations about 
information you should include in your protocol. 
 
3.  Study Design 
FDAs regulations implementing section 513(a)(3) of the Food Drug and Cosmetics Act 
allow for FDA to determine whether other evidence submitted or otherwise available 
constitutes valid scientific evidence for the purpose of determining the safety or 
effectiveness of a particular device.  The implementing regulations also allow for FDA to 
determine whether the available evidence, when taken as a whole, is adequate to support 
a determination that there is reasonable assurance that the device is safe and effective for 
its conditions of use for PMA submissions based on data provided from IDE studies.  21 
CFR 860.7(c)(2) identifies the following sources of valid scientific evidence:    
  well-controlled investigations 
  partially controlled studies 
  studies and objective trials without matched controls 
  well documented case histories conducted by qualified experts 
  reports of significant human experience with a marketed device from which it can 
be fairly and responsibly be determined by qualified experts that there is 
reasonable assurance of the safety and effectiveness of a device under its 
conditions of use.  
  12 Contains Nonbinding Recommendations 
 
While uncontrolled studies may be appropriate in some cases for feasibility studies, (e.g. 
to establish safety, to evaluate surgical technique, and/or endpoint, subject enrollment 
criteria and design appropriateness), when developing a future pivotal trial to 
demonstrate safety and effectiveness for artificial disc systems, FDA recommends that a 
multi-center, randomized, prospective, concurrently controlled clinical trial is 
appropriate.  Such a study design offers the benefits of prospectively acquired data.  It 
also provides advantages over other types of study designs by offering greater control of 
all parameters and by addressing some of the biases introduced by the other study 
designs. 
  
Depending upon the specific situation, randomized concurrently controlled studies, non-
randomized concurrently controlled studies, or historical-based studies may be 
appropriate so long as the chosen study design provides data that adequately supports the 
safety and effectiveness of the spinal system and minimizes inherent biases.  Because 
artificial disc devices are novel and not currently in wide usage, it may be difficult to 
establish validated objective performance criteria in place of clinical outcomes.  
Regardless of the type of control you incorporate into your protocol, you should provide 
a complete description of the investigational and control groups as described below.  You 
should also provide a rationale for your study design based on established scientifically 
sound clinical and statistical principles.  Your rationale should describe how your 
protocol addresses inherent biases and accurately reflects the intended use of your device.  
 
Please refer to Item 3 in the Investigational Plan section of the spinal systems guidance 
for additional recommendations about information you should include about your study 
design. 
 
4.  Choice of Control 
Regardless of the type of control you plan to incorporate into the protocol, you should 
provide a complete description of the investigational and control groups.  Please refer to 
Items 3.1 and 3.2 in the Investigational Plan section of the spinal systems guidance for 
additional recommendations about the choice of controls. 
 
If you plan to use a control based on a literature control, i.e., a meta-analysis, we 
recommend you provide a rationale that supports pooling of patients into a single control 
cohort from published studies.  You should demonstrate that any meta-analysis you 
provide is statistically valid.  We encourage you to consult with the review branch about 
literature controls. 
 
5.  Inclusion Criteria 
We recommend you provide a complete list of your inclusion criteria.  Your inclusion 
criteria should adequately define the patient group you plan to investigate.  The inclusion 
criteria appropriate for your study depend on your device, the target (disease) population, 
and the anatomic location of the disease process (i.e., cervical, lumbar).  Please refer to 
  13 Contains Nonbinding Recommendations 
Item 4 in the Investigational Plan section of the spinal systems guidance for additional 
recommendations about inclusion criteria. 
 
In addition to the inclusion criteria listed in the spinal systems guidance, we recommend 
the following additional criteria for total artificial disc studies: 
  description of any restrictions regarding prior fusion, non-fusion, or adjacent level 
surgeries; 
  description of the status of the adjacent spinal levels both radiographically and 
clinically (facet degeneration, disc height, osteophytes, etc.); 
  scoliosis of less than 5 degrees; 
  conditions of minimum bone density or quality for bony ingrowth or fixation;  
  condition of instability or presence of stability defined by accepted parameters; 
and 
  Minimum and maximum scores on baseline assessment scales.  
 
Because of the inherent instability of the spine that may occur from the resection of 
primary or metastatic tumors, the use of some non-fusion spinal systems may not be 
appropriate in patients with spinal tumors.  Information specific to tumors metastatic to 
the spine is described below in 17. Spinal Tumors. 
 
Studies involving patients with more than one level of fusion have typically demonstrated 
poorer outcomes than patients with single level of fusion.  Since little is known about the 
treatment of multiple levels with motion sparing devices if you plan to include an 
evaluation of the use of your device at two or more levels, you should include a 
statistically significant sample size and a clinical relevance explanation that supports 
actual clinical use or accurately reflects the intended use of your device or target 
population. We also recommend you stratify the results from multiple level fusion 
separately from subjects with single level fusion.  FDA also recommends that you limit 
any multiple fusion level study subjects to subjects with disease confined to one or two 
adjacent levels for study consistency. 
 
The next sections address specific disease processes and anatomic spinal regions 
individually. 
 
Degenerative Disc Disease (DDD) 
Please refer to Items 4.1 (lumbar DDD) 4.6 (cervical DDD) in the Investigational 
Plan section of the spinal systems guidance for recommendations about including 
subjects with these conditions. 
 
Scoliosis 
Currently, diagnosis of pediatric congenital and adolescent scoliosis may be 
considered contraindications for total artificial discs.  Axial, translational, and 
rotational forces of the spine in these patient populations may lead to early failure of 
  14 Contains Nonbinding Recommendations 
these types of devices.  Please refer to Item 4.2 in the Investigational Plan section of 
the spinal systems guidance for recommendations about including subjects with these 
conditions. 
 
Fractures Secondary to Trauma 
FDA believes the principles of acute fracture treatment contradict allowing 
immediate motion if fracture healing is desired. You should provide a rationale 
supporting that the safe use of total artificial discs for the treatment of fractures 
secondary to trauma.  Please refer to Item 4.3 in the spinal systems guidance for 
recommendations about including subjects with these conditions. 
 
Spondylolisthesis 
FDA believes that patients with moderate to severe (Myerding Grade II, III, IV and 
V) cases of spondylolisthesis, related instability or both are not appropriate 
candidates for total artificial discs.  If you plan to include subjects with mild 
spondylolisthesis (Grade I), however, you should provide a rationale supporting that 
your device is safe for the treatment of Grade I spondylolisthesis.  Please refer to Item 
4.4 in the Investigational Plan section the spinal systems guidance for 
recommendations about including subjects with these conditions. 
 
Revision Surgery for Pseudoarthrosis 
FDA believes that it is appropriate to contraindicate total artificial discs for patients 
undergoing revision surgery for failed fusions used to previously treat 
pseudoarthrosis. 
 
6.  Exclusion Criteria 
We recommend you provide a complete list of your exclusion criteria.  Your exclusion 
criteria should adequately define the patient group you plan to investigate.  Exclusion 
criteria may address a safety concern associated with a specific type of subject or exclude 
subjects who may negatively impact the study results or data analyses.  Please refer to 
Item 5 in the Investigational Plan section of the spinal systems guidance for additional 
recommendations about exclusion criteria. 
 
In addition to the exclusion criteria listed in the spinal systems guidance, we recommend 
the additional exclusion criteria discussed below. 
 
Exclusion Criteria That Address Safety Concerns 
Your exclusion criteria should address safety concerns by excluding subjects: 
 
  with less than 5 mm of disc space remaining (We recommend, however, you 
identify subjects with a remaining disc space of 5-7 mm because it may be 
appropriate to modify this criterion based on the particular intended use or 
mechanics of your device.); 
 
  15 Contains Nonbinding Recommendations 
  with an additional spinal condition, other than the condition you plan to study, 
that may increase symptoms with additional motion or preclude insertion of 
the device (You should clearly define and list the excluded conditions.); 
 
  on chronic medication affecting bone metabolism (steroids, osteoclast 
inhibitors, etc.); 
 
  who have congenital stenosis or acquired degenerative stenosis with central, 
lateral, or combined central/lateral stenosis of the spinal canal or cord in 
whom treatment that destabilizes the spine or in whom increased motion may 
increase symptoms; 
 
  with myelopathy (If you include subjects with myelopathy, you should 
provide a rationale supporting using your device design in these subjects and 
include a stratification of diagnostic groups); 
 
  with severe spondylolisthesis of greater than 3mm (> Myerding Grade I); 
 
  with severe degenerative disease, including facet degenerative arthrosis and 
adjacent level degeneration, which precludes safe implantation of the device 
without significant destabilization of any portion of the spinal column,  
 
  with an anatomic deformity that inherently renders instability of the spine or 
facet joints  
 
  who have undergone or will undergo any procedure that will leave the patient 
with deficient postoperative deficiency of the posterior elements or 
postoperative instability of the middle or anterior columns occurs, (e.g. with 
facet arthroplasty devices.); and 
 
  with any other spinal deformity, instability, scoliosis, or kyphosis that 
precludes safe use of your device or other surgical intervention.  (You should 
indicate and clearly define the range of radiographic measurements or clinical 
symptoms on which these diagnoses are made and which would exclude 
patients from your study; e.g., Cobb angle >10.) 
 
Exclusion Criteria That Simplify or Clarify the Study Design 
To help simplify the study design and to allow for interpretation of the study results, 
we recommend that you exclude subjects:  
 
  with multiple involved levels in the spine; and  
  with prior surgery at the surgical level you plan to study.  (If you include 
subjects with prior surgery, however, we recommend you provide a rationale 
supporting pooling these subjects with subjects who have had no prior 
surgeries.) 
  16 Contains Nonbinding Recommendations 
 
7.  Number of Investigators, Investigational Sites, and Subjects 
We recommend you specify the number of investigators, investigational sites, and 
subjects.  Please refer to Item 6 in the Investigational Plan section of the spinal systems 
guidance for additional recommendations about investigators, investigational sites, and 
subjects. 
 
8.  Study Duration and Follow-up Schedule 
In order to properly assess all safety and primary effectiveness outcomes, your study 
should be designed to include 2 or more years of follow-up data.  Please refer to Item 7 in 
the Investigational Plan section of the spinal systems guidance for additional 
recommendations. 
 
Because novel spinal devices are often developed to address spinal disorders in younger, 
more active populations, we recommend that you design your study to address the 
possibility of a post approval study that may continue 5-10 years after implantation (i.e., 
studies FDA may require as a condition of the approval of your PMA application9).  
Therefore, we recommend that your IDE protocol include consent by all subjects to long 
term follow-up.  In addition, you should enroll a sufficient initial number of subjects to 
submit long term data on a statistically significant number of subjects remaining after 
unexpected loss to follow-up. 
 
 
9.  Post-operative Regimen 
We recommend you describe in detail any additional patient care procedures you plan to 
employ during the treatment period, e.g., surgery, rehabilitation, immobilization, weight 
bearing ambulation. 
 
 
10. Safety and Effectiveness Endpoints 
For the primary and secondary evaluation parameters that are measured at each 
timepoint,  you should describe the specific parameter scales and methods of 
interpretation (i.e., success and failure criteria) along with your rationale and any 
validation of these measures.  Please refer to Item 8 in the Investigational Plan section of 
the spinal systems guidance for additional recommendations. 
 
Recommended endpoints for total artificial disc studies are summarized below, and are 
discussed in more detail in the sections that follow. 
 
For lumbar spinal studies, primary evaluation parameters should include  
  back and/or leg pain; and  
                                                      
9 See also the guidance entitled Procedures or Handling Post-Approval Studies Imposed by 
PMA Order: available at http://www.fda.gov/cdrh/osb/guidance/1561.html  
  17 Contains Nonbinding Recommendations 
  patient activities of daily living (ADL) function. 
 
For cervical spinal studies, primary evaluation parameters should include: 
  neck and arm pain; and 
  patient ADL function. 
 
FDA recommends you evaluate and document for each spinal level treated and the 
adjacent normal spinal levels, the clinical and radiographic:  
  absence of device migration; 
  absence of device failure;  
  absence of fusion; and  
  presence and amount of motion. 
 
Depending on the design of your device, FDA may also recommend you evaluate as 
study endpoints:   
  bone ingrowth;  
  adequacy or stability of fixation; or  
  other applicable parameters.  
 
The choice of the following parameters as primary or secondary depends on the intended 
use.  We recommend that you assess : 
  neurologic status, which should be evaluated at each time point; 
  disc height and vertebral height maintenance assessment; 
  range of motion at the treated level; 
  health-related quality of life; 
  patient satisfaction; and 
  return to work status. 
 
The success criteria for each of the individual primary evaluation parameters will differ 
depending upon the design of the system, the patient population, and the goals of the 
treatment.  (See Section D.10 Study Success) 
 
Radiographic Success 
For total artificial discs, the radiological assessments depend on the patient 
population and study goals.  These assessments may include integrity of implant, 
maintenance of correction, maintenance of spinal segment stability, lack of migration, 
and maintenance or improvement of range of motion.   
 
Radiographic evaluation should provide both safety information and effectiveness 
information about the investigational artificial disc device.  Measurement of the same 
radiographic parameter can often provide both safety and effectiveness information.  
  18 Contains Nonbinding Recommendations 
Please refer to Item 8.1 in the Investigational Plan section of the spinal systems 
guidance for additional recommendations about radiographic endpoints. 
 
Radiographic Safety Success 
We recommend you provide evidence that the operative level and adjacent levels are 
stable and do not allow slippage in any direction in situ.  We also recommend you 
document the degree of motion in each plane of potential motion for the operative 
and adjacent levels. 
 
There are two distinct purposes for radiographic evaluation of implant location, 
evaluation of the initial placement, and evaluation of any subsequent migration of the 
device.  You should determine and document whether the implant was successfully 
placed in the intended location at the time of surgery or immediately after the 
procedure.  At each follow-up interval visit you should clearly assess and document 
the position of the device in relation to the initial implantation location and in relation 
to the ideally desired location.  A radiographic report should include, but is not 
limited to, the position relative to the initial implantation, the position relative to the 
desired location, and the position during flexion and extension.   
 
In addition to the above measurements, you should report your radiographic 
evaluation of the adjacent segment degeneration and general status of those segments. 
 
FDA believes that for implant fixation to be considered stable, depending on the 
design of the device, the bone ingrowth area should exceed 75% of the bone to 
implant interface area intended for ingrowth. 
 
Radiographic Effectiveness Success 
For devices intended to maintain motion, we recommend you radiographically 
document maintained or improved motion.  Radiographic motion as determined from 
flexion/extension plain radiographs, MRIs, or other specialized radiographic methods 
may be appropriate to estimate both preservation of motion at both the operative and 
at the adjacent levels.  You should include an explanation of how motion is measured 
in your radiographic protocol. 
 
Radiographic effectiveness endpoints that we recommend you evaluate include: 
  successful preservation or improvement of motion (rotational, flexion, 
extension, lateral bending, translational, and angular motion or coupled 
motion of two or more of these) based on the physiology of the anatomic level 
being treated and levels adjacent to it; and the preoperative motion at the 
treated level as well as the design of your device; 
  absence of evidence of bridging trabecular bone between the involved motion 
segments; and  
 
For two-level treatment with the device, both levels should maintain motion to be 
considered a success.  
  19 Contains Nonbinding Recommendations 
 
Pain and Function 
In addition to the information below, please refer to Item 8.2 in the Investigational 
Plan section of the spinal systems guidance for general recommendations regarding 
pain and function assessments. 
 
We recommend you assess the subjects severity and frequency of pain pre-
operatively and post-operatively at specific follow-up times using a pain assessment 
score. You should attempt to distinguish pain due to problems with the spine, e.g., 
nerve root impingement, from the general pain that subjects might experience as the 
result of their overall medical condition, both at enrollment and post-operatively.  
You should also attempt to account for the type of analgesic medication the subject is 
using and how that may affect the pain assessment score.   
 
Evaluation of function should focus on the post-operative ability of subjects to 
function independently, e.g., how does their ability to move around the house or 
neighborhood, dress themselves, or accomplish other daily activities  compare to their 
pre-operative status.  Evaluation may also include, depending on the population 
studied, the subjects return to recreational activities.  Return to work is also a 
parameter of interest in the working population. 
 
When determining criteria for patient success for pain and function improvement, you 
should take into account the potential for a placebo effect10,11 and use a consistent 
numerical value [such as 15/50 on the Oswestry Disability Index (ODI)] for patient 
success determination on each subjective assessment scale.  You should clearly 
specify the clinically meaningful level of improvement, which may be different than 
the statistical level of improvement. 
 
Because one of the purported mechanisms of pain relief is preservation of motion at 
the spinal level treated with a total artificial disc, you should include an analysis to 
evaluate any correlation between range of motion and pain and function outcomes (in 
your final analysis only). 
 
Disc and Vertebral Height Assessment 
In addition to the information below, please refer to Item 8.3 in the Investigational 
Plan section of the spinal systems guidance for additional recommendations about 
disc and vertebral height assessment. 
                                                      
10 Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, 
Hollingsworth JC, Ashton CM, Wray NP.  A controlled trial of arthroscopic surgery for 
osteoarthritis of the knee.  N Engl J Med. 2002 Jul 11;347(2):81-8. Summary for patients in: 
J Fam Pract. 2002 Oct;51(10):813.   
11 Harris W.H: Traumatic arthritis of the hip after dislocation and acetabular fractures: 
Treatment by mould arthroplasty J Bone Joint Surg p.737, 51-A, No.4, June 1969. 
 
 
  20 Contains Nonbinding Recommendations 
 
We recommend you measure disc heights adjacent to the operative level and follow 
the stability of disc height measurements over time.  FDA does not necessarily 
recommend specific success criteria for this parameter, as these will depend on the 
intended use and expected performance of your device.   
 
Health-Related Quality of Life 
Please refer to Item 8.4 in the Investigational Plan section of the spinal systems 
guidance for FDAs recommendations about health related quality of life in these 
studies. 
 
Safety Endpoints 
Please refer to Item 9 in the Investigational Plan section of the spinal systems 
guidance for additional recommendations about safety evaluations. 
 
We recommend you report and categorize as a supplemental fixation, any subsequent 
procedures related to the index level.  This includes posterior fusion (whether 
removing the device or leaving it in place), decompression, facet rhizotomy, at the 
same, adjacent, or distant levels.  Other surgical interventions should be reported 
separately. 
 
We recommend you also include signs of myelopathy and gait disturbances as 
adverse events, particularly for cervical implant investigations.  Cervical tension 
signs (Spurlings sign) and gait analysis may be appropriate assessments to determine 
the presence of these signs for cervical implants that allow semi-constrained or 
unconstrained range of motion.  
 
Metal Ion Release 
Published information for use of hip implants using metal-metal articulating surfaces 
has raised safety concerns, e.g., the risk of tumor formation, chromosomal 
aberrations, carcinogenesis potential in human patients.12  Although retrieval 
analyses may be able to address some safety issues regarding metal-on-metal wear 
debris, FDA believes that metal ion release is an issue for devices implanted in the 
spine.  FDA believes that all investigational protocols for metal-on-metal articulating 
devices intended to maintain motion in the any part of the human spine should 
include serum metal ion level analyses.  You may wish to refer to the 
recommendations published in the literature to evaluate metal ion release levels in 
patients with metal-on-metal total artificial discs.  Your investigation should evaluate 
the potential for the risk of tumor formation and carcinogenesis.  Alternatively, you 
should provide a rationale with supporting references that either indicates that 
                                                      
12 Doherty AT, Howell RT, Ellis LA, Bisbinas I, Learmonth ID, Newson R, Case CP.  
Increased chromosome translocations and aneuploidy in peripheral blood lymphocytes of 
patients having revision arthroplasty of the hip. J Bone Joint Surg Br. 2001; 83(7):1075-
1081. 
  21 Contains Nonbinding Recommendations 
additional safety testing is not needed or that you have adequately addressed these 
with other testing.   
 
11. Subject Success 
Subject success may include a combination of objective and subjective criteria.  You 
should take into account the placebo effect (typically 20-30%13,14) when determining the 
amount of clinically significant improvement that constitutes subject success in 
subjective self-administered assessment scales. 
 
Subject success should be based on success in the:  
  primary evaluation parameter of pain;  
  primary evaluation parameter of function; 
  absence of permanent neurological deficit; 
  absence of secondary surgical intervention; and  
  absence of serious adverse events.   
 
Depending on the target population, study design, and study goals, it may be appropriate 
to include other assessments.  You should count subjects who undergo certain secondary 
surgical interventions or experience serious adverse events or neurological deficits as 
failures of treatment.  Improvement in pain and function should indicate clinically 
significant benefit, such as improvement of at least one subjective severity category to 
justify the risks of surgery (such as marked disability to moderate disability, or severe 
pain to moderate or mild pain).    
 
Please refer to Item 10 in the Investigational Plan section of the spinal systems guidance 
for additional recommendations about subject success. 
 
12. Study Success  
You should also define study success for your clinical trial which takes into consideration 
the purpose of the treatment and comparison to a control group as well as the study goals 
(e.g., superiority or equivalency).  All primary endpoint parameters, as well as safety 
information, should be accounted for in the definition of study success.  You should 
clearly identify and justify the pre-specified allowable difference (delta) used to define 
differences between study arms. 
 
                                                      
13 Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, 
Hollingsworth JC, Ashton CM, Wray NP. A controlled trial of arthroscopic surgery for 
osteoarthritis of the knee. N Engl J Med. 2002 Jul 11;347(2):81-8. Summary for patients in: J 
Fam Pract. 2002 Oct;51(10):813. 
14 Harris W.H: Traumatic arthritis of the hip after dislocation and acetabular fractures: 
Treatment by mould arthroplasty J Bone Joint Surg p.737 , 51-A,No.4,June 1969. 
 
  22 Contains Nonbinding Recommendations 
Study success rates should be provided at each postoperative time point, but there will be 
particular focus on the results at the study primary endpoint (e.g., 2 years). 
 
Please refer to Item 10 in the Investigational Plan section of the spinal systems guidance 
for additional recommendations about subject success. 
 
13. Statistical Analyses and Data Presentations 
We recommend you define the type of statistical analysis that you intend to perform 
before the study commences.  Either Bayesian or frequentist statistical methods of 
analysis may be appropriate.  Please see Statistical Guidance for Clinical Trials of Non 
Diagnostic Medical Devices15 and Guidance for the Use of Bayesian Statistics in 
Medical Device Clinical Trials.16
 
If you switch methods after the study begins, we recommend you explain and model the 
reasons for the switch in order to avoid possible biases.  We also recommend that you 
discuss with FDA any proposal to switch statistical methods before such a change is 
implemented. 
 
We believe statistical methods are not an adequate substitute for completing your study 
(i.e., following patients through the entire study or for ending the IDE prematurely).  You 
should provide statistical plans to account or adjust for missing data in your initial IDE. 
 
Subgroup analyses may help you and FDA better understand the behavior of the 
subpopulations for which the device is indicated.  Therefore, when you submit your PMA 
application, FDA may request further subgroup analyses to assess the safety and 
effectiveness of the investigational device in these subpopulations.  However, post-hoc 
subgroup analyses should not be used to demonstrate effectiveness in the absence of a 
statistically and clinically significant effect in the total population. 
 
In order to better assure that the study collects adequate data, your protocol should reflect 
the types of data presentations you plan to submit in your PMA application.   
 
Please refer to Item 11 in the Investigational Plan section of the spinal systems guidance 
for additional recommendations about statistical analyses. 
 
14. Patient Data Report Forms (Case Report Forms (CRF)) 
The CRFs that you develop should capture all relevant information from the protocol.  
Please refer to the spinal systems guidance for recommendations about CRFs.  Original 
source documents (such as doctors office notes, operative notes, radiographs or patient 
self-assessment questionnaires) must be consistent with the data recorded on these CRFs.  
(21 CFR 812.140(a))   
 
                                                      
15 http://www.fda.gov/cdrh/ode/odeot476.html  
16 http://www.fda.gov/cdrh/osb/guidance/1601.html  
  23 Contains Nonbinding Recommendations 
We also recommend your IDE include the forms and information described below.   
 
The operative data form should document implant type, size, number used, and any 
intraoperative observations or adverse events.  The adverse event form should identify all 
potential risks associated with implantation of your device.  The form should also provide 
space for reporting of other adverse events, device related or not, and include spaces for 
the date, action taken, and date of resolution of the event.  Where applicable, you should 
include the severity and association of the event to the device or procedure in the 
documentation. 
 
We recommend you submit copies of each of the clinical evaluation scales or assessment 
questionnaires, e.g., Visual Analog Scale (VAS), Oswestry Disability Index, Short Form-
36, patient satisfaction, work status. 
 
We recommend you include a separate CRF for the independent radiographic review. 
 
The study exit form should document the patients reason for exiting the study, e.g., 
study completion, withdrawal, or loss to follow-up. 
 
We recommend you include a special testing report form for reporting the results of any 
additional assessments specific to your investigational protocol (e.g., blood metal ion 
results). 
 
Please refer to Items 12 in the Investigational Plan section of the spinal systems guidance 
for full details. 
 
When using computerized or internet-based patient assessment forms, we recommend 
you follow the FDA guidance entitled Computerized Systems Used in Clinical Trials.17  
 
15. Risk Analysis  
In accordance with 21 CFR 812.25(c), your IDE must include a description and analysis 
of all increased risks to which subjects will be exposed by the investigation; the manner 
in which these risks will be minimized; a justification for the investigation; and a 
description of the patient population, including the number, age, sex, and condition.  
You should include information adequate to determine that the benefits and knowledge to 
be gained outweigh the risks and potential complications the subjects may experience.  In 
listing all of the potential risks, you should stratify the risks according to whether they 
are general to spinal surgery or specific to the device.  Please refer to Item 13 in the 
Investigational Plan section of the spinal systems guidance for additional 
recommendations. 
 
                                                      
17 http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm  
 
  24 Contains Nonbinding Recommendations 
Examples of potential risks related to device related complications include, but are not 
limited to: 
  loss of function; 
  fracture, subluxation, subsidence, or dislocation of the device; 
  fracture of the adjacent bony structures; 
  heterotopic ossification or segmental fusion (as relates to loss of motion); 
  excessive wear or migration of the device or any of its components, even if such 
failure does not lead immediately to revision surgery or symptoms; 
  facet degeneration at same level; 
  adjacent segment degeneration; 
  adjacent disc degeneration or intravertebral space height loss; 
  infection at the level of the device; 
  neurovascular compromise secondary to device impingement of these structures; 
and 
  toxicity, carcinogenic potential or other biologic local or distant tissue or systemic 
effects due to by-products, debris (metal ion release) or breakdown products 
related to the device functioning in situ under physiologic conditions. 
 
Examples of potential risks associated with the surgical approach include, but are not 
limited to:  
  neurological complications, temporary and permanent 
  vascular injury 
  sympathetic disturbance 
  painful or numb scar 
  hematoma 
  local drainage 
  new pain or pain progression 
  retrograde ejaculation 
  dysphagia 
  hoarseness/vocal cord dysfunction 
  abdominal adhesions. 
 
Examples of potential risks considered to be general complications of surgery include, 
but are not limited to:  
  visceral dysfunction 
  abdominal pain 
  disturbance of urinary function 
  25 Contains Nonbinding Recommendations 
  urinary tract infection 
  deep vein thrombosis 
  phlebitis 
  pulmonary embolism 
  myocardial infarction 
  cerebrovascular accident 
  death. 
 
16. Retrieval Study 
We recommend you incorporate a plan to conduct retrieval analyses of explanted devices 
into your protocol, because the long term performance of total artificial discs is not well 
characterized.  Please refer to Item 15 in the Investigational Plan section of the spinal 
systems guidance for additional recommendations about retrieval studies. 
 
In addition to the recommendations about retrieval studies presented in the spinal systems 
guidance, we recommend you analyze a biopsy (within the limits of safety) of 
surrounding bony and soft (neurovascular) tissue for any inflammatory or other reaction 
to the device, and, where appropriate, metal ion or material debris content in surrounding 
tissue.  Your protocol, labeling, and surgical technique manual should include specific 
instructions for the handling and returning explanted devices.  Investigator training 
should also address this aspect of the investigation. 
 
17. Spinal Tumors  
Devices that maintain motion may not be appropriate for use in subjects with primary or 
metastatic neoplastic disease, due to the disease processes and adjunctive treatments that 
affect bone quality, spinal stability, and subject longevity.  If you choose, however, to use 
a motion retaining device in patients with spinal neoplastic disease, you should provide a 
rationale explaining why such an investigation is scientifically sound and how the 
anticipated benefits to the subjects outweigh the risks to the subjects.  Please refer to Item 
16 in the Investigational Plan section of the spinal systems guidance for additional 
recommendations about devices intended to stabilize the spine when treating spinal 
tumors. 
 
E.  Monitoring 
Your investigational plan must include your written procedures18 for monitoring the 
investigation and the name and address of any monitor.  (21 CFR 812.25(c)).  Your monitor 
must be qualified by training and experience to monitor the investigational study in 
accordance with this part and other applicable FDA regulations.  (21 CFR 812.43(d)).  Please 
refer to the Monitoring section of the spinal systems guidance for additional 
                                                      
18 These procedures should address the response to noncompliance, as described in 21 CFR 
812.46. 
  26 Contains Nonbinding Recommendations 
recommendations about the monitoring procedures to be included in your IDE. 
 
Your comprehensive monitoring plan must include the following:  
 
  selecting qualified monitors (21 CFR 812.43(d)); 
  ensuring investigator adherence to the investigational plan and requirements (21 CFR 
812.43(c)(4)); and 
  ensuring investigator compliance in regard to record keeping and reporting (21 CFR 
812.25(j)). 
 
F.  Labeling 
In accordance with 21 CFR 812.20(b)(10), your IDE must include copies of all labeling19 for 
the system.  Please refer to the Labeling section of the spinal systems guidance for 
recommendations about labeling content. 
 
In addition to the information recommended in the spinal systems guidance, your surgical 
technique manual for an artificial disc system should include: 
  intended uses and indications; 
  device description;  
  contraindications;  
  precautions;  
  warnings; and 
  potential risks associated with the subject system or a reference to the product insert 
for this information.   
 
You should highlight or bold the text of instructions that affect the safety of use or are 
uncommon in current practice for emphasis.   
 
FDA also recommends you include information in the surgical technique manual for 
explanting the device and revising the original procedure.  In addition, your surgical 
technique manual should describe a salvage procedure alternative to revision or 
reimplantation. 
 
G. Informed Consent 
In accordance with 21 CFR 812.20(b)(11), your IDE must include copies of all forms and 
informational materials to be provided to the subjects to obtain informed consent.  In 
accordance with 21 CFR Part 50, you must obtain and document the informed consent of the 
subject before the subject may enter the study.  Your protocol should explain how you ensure 
that investigators properly obtain and document informed consent. 
 
                                                      
19 Labeling for an investigational device must meet the requirements of 21 CFR 812.5. 
  27 Contains Nonbinding Recommendations 
In addition, the informed consent document must contain the elements described in 21 CFR 
50.25.  Please refer to the Informed Consent section of the spinal systems guidance for 
additional recommendations about informed consent documents. 
 
 
 
  28