Guidance for Industry and/or
FDA Reviewers/Staff
Guidance Document for the
Preparation of IDEs for
Spinal Systems
Document issued on:  January 13, 2000
This document supersedes document the preliminary background document for the future development
of a spinal IDE guidance dated 8/26/98.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health
 Orthopedic Devices Branch
Division of General and Restorative Devices
Office of Device Evaluation Preface
Public Comment:
Comments and suggestions may be submitted at any time for Agency consideration to the
Orthopedic Devices Branch, HFZ-410, 9200 Corporate Blvd., Rockville, MD  20850. 
Comments may not be acted upon by the Agency until the document is next revised or updated.
 For questions regarding the use or interpretation of this guidance contact, contact Samie Allen
at 301-594-3090 or by electronic mail at SXN@cdrh.fda.gov.
Additional Copies:
World Wide Web/CDRH home page at http://www.fda.gov/cdrh/ode/87.pdf or CDRH Facts on
Demand at 1-800-899-0381 or 301-827-0111, specify number 2250 when prompted for the
document shelf number. 1
Guidance  Document for the Preparation of
IDEs for Spinal Systems
INTRODUCTION____________________________________________________________ 3
GENERAL IDE CONTENT INFORMATION ____________________________________ 4
REPORT OF PRIOR INVESTIGATIONS________________________________________ 5
1. Clinical Data_____________________________________________________________ 5
2.  Animal Data_____________________________________________________________ 5
3.  Mechanical Data _________________________________________________________ 6
4.  Biocompatibility__________________________________________________________ 7
5.  Bibliography_____________________________________________________________ 8
INVESTIGATIONAL PLAN ___________________________________________________ 8
1.  Feasibility/Pilot vs. Pivotal Study ____________________________________________ 8
2.  Purpose / Objective Statement ______________________________________________ 9
3.  Study Design ____________________________________________________________ 9
3.1  Concurrent Control________________________________________________________________ 10
3.2  Literature Control_________________________________________________________________ 10
4.  Inclusion Criteria________________________________________________________ 11
4.1  Lumbar Degenerative Disc Disease (DDD)_______________________________________________ 12
4.2  Scoliosis________________________________________________________________________ 12
4.3  Fractures________________________________________________________________________ 12
4.4  Spondylolisthesis _________________________________________________________________ 13
4.5  Revision________________________________________________________________________ 13
4.6  Cervical DDD ____________________________________________________________________ 13
5.  Exclusion Criteria _______________________________________________________ 13
6.  Number of Sites / Investigators / Patients ____________________________________ 14
7.  Duration / Follow-up Schedule______________________________________________ 14
8.  Effectiveness Evaluation__________________________________________________ 15
8.1  Radiographic Success______________________________________________________________ 15
8.1.1  Fusion Status_________________________________________________________________ 15
8.1.2  Radiographic Success for Nonfusion Systems ________________________________________ 16
8.2  Pain and Function_________________________________________________________________ 17
8.3  Height Assessment________________________________________________________________ 18
8.3.1  Disc Height Assessment ________________________________________________________ 18
8.3.2  Vertebral Height Assessment_____________________________________________________ 18
8.4  Health Related Quality of Life ________________________________________________________ 18
9.  Safety Evaluation________________________________________________________ 18
9.1  Subsequent Surgical Interventions ____________________________________________________ 19
9.2  Neurological Status________________________________________________________________ 19
10.  Patient / Study Success __________________________________________________ 20
1This document is intended to provide guidance.  It represents the Agencys current thinking on this topic.  It does
not create or confer any rights for or on any person and does not operate to bind FDA or the public.  An alternative
approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
page 1 10.1  Patient Success__________________________________________________________________ 20
10.2  Study Success___________________________________________________________________ 20
11.  Statistical Analyses / Data Presentations ____________________________________ 21
11.1  Statistical Analyses_______________________________________________________________ 21
11.2  Data Presentations _______________________________________________________________ 22
12.  Patient Report Forms ___________________________________________________ 23
13.  Risk Analysis__________________________________________________________ 23
14.  Post-Operative Regimen_________________________________________________ 23
15.  Retrieval Study ________________________________________________________ 24
16.  Spinal Tumors _________________________________________________________ 24
16.1  Inclusion Criteria_________________________________________________________________ 24
16.2  Duration / Follow-up Schedule_______________________________________________________ 24
16.3  Sample Size / Number of Sites & Investigators___________________________________________ 24
16.4  Controls _______________________________________________________________________ 24
16.5  Clinical Parameters________________________________________________________________ 25
16.6  Safety_________________________________________________________________________ 25
16.7  Patient / Study Success____________________________________________________________ 25
16.8  Data Presentations / Statistical Analyses_______________________________________________ 26
DEVICE DESCRIPTION_____________________________________________________ 26
MANUFACTURING_________________________________________________________ 27
MONITORING _____________________________________________________________ 27
IRB and INVESTIGATOR INFORMATION_____________________________________ 27
LABELING ________________________________________________________________ 27
1.  Package Labels _________________________________________________________ 28
2.  Package Insert__________________________________________________________ 28
3.  Surgical Technique Manual________________________________________________ 28
INFORMED CONSENT _____________________________________________________ 29
SALES ____________________________________________________________________ 29
ENVIRONMENTAL IMPACT ASSESSMENT ___________________________________ 29
1This document is intended to provide guidance.  It represents the Agencys current thinking on this topic.  It does
not create or confer any rights for or on any person and does not operate to bind FDA or the public.  An alternative
approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
page 2 INTRODUCTION
The purpose of this document is to provide guidance on important preclinical and clinical information,
which should be presented in an Investigational Device Exemption (IDE) application for spinal systems. 
This guidance document was prepared in response to discussions and correspondence between the
Orthopedic Devices Branch (ORDB) and sponsors of spinal systems. 
Additionally, on October 8, 1998, ORDB presented a preliminary background document that involved the
ideas pertaining to the development of IDEs for spinal systems to the Orthopedic and Rehabilitation
Devices Panel.  During the October 8, 1998 Panel meeting, ORDB received input from the Panel
members and from the public regarding that preliminary background document and revised it accordingly. 
Now, this guidance document replaces that preliminary background document.
The suggestions and recommendations written in this document reflect methodologies which have been
determined to be acceptable and which, if followed, should help to produce IDE applications with
scientifically valid data.  This guidance document suggests some important evaluation criteria, test
procedures, and endpoints.  If the same objectives can be achieved by other means, the sponsor should not
refrain from exploring alternative approaches.  This guidance document should be viewed as a living
document.  As science changes and scientific techniques are improved, CDRH will periodically revise the
document.
This IDE guidance document is applicable to most types of spinal systems including pedicle screw
systems, intervertebral body fusion devices (e.g., cages), vertebral body replacement devices, vertebral
disc replacements, etc.  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
interchangeable.
Most systems consist of multiple components (e.g., pedicle screw systems, cages with endcaps, cages
with biological components, etc.).  However, a system may also consist of a single component (e.g., 1-
piece vertebral body replacement device).  For systems intended for fusion, which the majority are, the
systems are typically used with a bone material (e.g., autograft, allograft, etc.). 
FDA regards all implanted spinal systems as significant risk devices.  Prior to marketing these systems, a
sponsor must obtain clearance of a premarket notification (510(k)) or approval of a premarket approval
(PMA) application.  In order to support the marketing application of specific types or designs of spinal
systems, clinical data may be necessary, and before initiating a clinical trial in the U.S., the sponsor must
have an IDE approved by the FDA.  Institutional review board (IRB) approval alone is not sufficient to
commence a clinical trial on human subjects involving an implanted spinal system.  Alternatively, in lieu of
an IDE and PMA, a sponsor may submit a product development protocol (PDP).  Any sponsor
considering this option should refer to the Guidance for Industry: Contents of a Product Development
Protocol for specific input regarding PDP applications.  The suggestions and guidance discussed below
are appropriate for evaluating the product in either case.
This guidance document provides a framework to assist in developing clinical studies and generating valid
scientific evidence which should provide reasonable assurance of the safety and effectiveness of a spinal
system for a stated intended use and indication.  This guidance document serves as a supplement to other
FDA publications on IDE applications and should not be construed as a replacement for these documents.
 ORDB would like to be consulted early in the development of preclinical tests and the investigational
protocol.  Although use of this document to prepare preclinical and clinical protocols will not ensure IDE,
PMA, or PDP approval or 510(k) clearance, following this guidance should reduce unnecessary work on
the part of sponsors and should allow for a more efficient review by FDA.
page 3 Section 205 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) requires FDA, in
consultation with the sponsor, to consider the "least burdensome" means that will allow appropriate
premarket development and review of a device without unnecessary delays and expense to the sponsor. 
This requirement to consider the least burdensome means applies to 510(k)s, PMAs, and PDPs.  FDA is
committed to working with the sponsor to meet this requirement and is open to alternative means of
developing an adequate protocol.  Please refer to the guidance Evidence Models for the Least
Burdensome Means to Market which is available at http://www.fda.gov/cdrh/ode/1154.pdf for details.
FDA regulations referred to in this guidance can be found in the Code of Federal Regulations, Title 21, as
follows:
 Protection of Human Subjects; Informed Consent (21 CFR 50)
 Standards for Institutional Review Boards for Clinical Investigations (21 CFR 56)
 Good Laboratory Practice (GLP) Regulations (21 CFR 58)
 Investigational Device Exemptions (21 CFR 812)
 Determination of Safety and Effectiveness (defines valid scientific evidence) (21 CFR 860.7)
 Environmental Impact Considerations (21 CFR 25)
All FDA publications referred to in this guidance document can be obtained by contacting the Division of
Small Manufacturers Assistance (DSMA) at 800-638-2041 (toll free) or 301-443-6597.  Some of the
publications can be obtained via DSMAs Internet site at www.fda.gov/cdrh/dsma/dsmamain.html. 
Specific questions and clarification regarding this guidance document should be directed to ORDB at 301-
594-2036.
GENERAL IDE CONTENT INFORMATION
Sponsors of clinical investigations should carefully consider how to adequately support the intended
uses/indications for safety and effectiveness of their specific system for a 510(k), PMA, or PDP.  Studies
should be designed to ensure that the data will provide valid scientific evidence (as defined in 21 CFR
860.7) which will satisfactorily answer all appropriate questions and support the intended uses/indications.
Any IDE should include the following major sections:
(1) Report of Prior Investigations;
(2) Investigational Plan;
(3) Device Description;
(4) Manufacturing;
(5) Monitoring;
(6) IRB and Investigator Information;
(7) Labeling;
(8) Informed Consent;
(9) Sales; and
(10) Environmental Impact Assessment.
What follows is a description of the specific type of information that should be submitted for each of the
10 major sections identified above for spinal systems.  However, some of the sections (e.g.,
Manufacturing, Sales, Environmental Impact Assessment) include generic information that applies to any
IDE.
page 4 REPORT OF PRIOR INVESTIGATIONS
The following information should be supplied to support the conclusion that patients in the trial will not be
placed at undue risk.  Complete reports of prior clinical, animal, and laboratory (e.g., mechanical) testing,
as well as a comprehensive summary of the testing, should be provided to justify the proposed study.
1. Clinical Data
A report of any available clinical data regarding the use of the subject system or its components,
whether adverse or supportive, that are relevant to the evaluation of the safety or effectiveness of the
subject system should be included.
A brief summary may be sufficient for spinal system types with which there is published experience
(e.g., pedicle screw systems, intervertebral body fusion devices with autogenous bone, etc.). 
However, for new designs of devices with little published experience (e.g., vertebral body
replacements, vertebral disc replacements, intervertebral body fusion devices with bone morphogenic
proteins, etc.), a more detailed report of any relevant clinical data should be provided.  Although it is
recognized that this level of detail may not be available for all studies, the type of information that
should be included in a more detailed report is as follows (items 3-7 are specific to spinal IDEs):
(1) a description of the study, including design and patient groups;
(2) patient selection criteria;
(3) time course distributions of patients:  theoretically due, expected (theoretically due minus deaths
and failures), actually evaluated, deaths, removals, revisions, reoperations, and supplemental
fixations;
(4) a description of the scales for the primary evaluation parameters and overall success;
(5) time course distributions of the primary evaluation parameters, overall success, and
complications;
(6) a description of any patient who underwent a subsequent surgical intervention (e.g., removal,
revision, reoperation, and/or supplemental fixation); and
(7) a description of how the clinical data are relevant and may be used to support the relative safety
of the proposed design and/or patient population.
2.  Animal Data
Animal data are sometimes needed to establish the relative safety of the subject system prior to
initiating a human clinical trial.  Reasons for animal studies include addressing biologic response to
particle and substrate materials, dosing studies, functional studies, etc. 
Complete reports of any animal studies conducted on the subject system or components of it, whether
adverse or supportive, that are relevant to the evaluation of the safety or effectiveness of the subject
system should be included.  The animal report should specify the purpose of the study and provide
supporting pathological, histological, and radiological evaluations.  In addition, the report should
describe any differences between the version of the system used in the animal studies and that
proposed in the IDE.
The following are some examples of questions that animal studies might be used to address:
 For an intervertebral body fusion device used in conjunction with a biological component (e.g.,
bone morphogenic protein), animal studies may provide information as to whether bony fusion
occurred or is progressing and the quantity and quality of bone formed inside the device (a stress
protected environment) as compared to an appropriate control group.  Animal studies are used to
evaluate dilution, dose, and concentration factors for certain systems.
page 5 For any system that includes a biological or drug component (e.g., bone morphogenic
protein, bovine protein, etc.), the sponsor should follow any applicable DGRD guidances
regarding the use of biological components with spinal systems.  Sponsors are also
encouraged to address any applicable guidances from the Center for Biological
Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER).
 Animal studies may be used to evaluate a novel system design in earlier development stages
(e.g., different design concepts of vertebral disc replacement devices).
 Animal studies may be used to support the biocompatibility of a totally new material, a new
material for use in orthopedics, or a new material for spinal exposure.  Additionally, these studies
may be used to address the probability of generating abrasion or wear particles of the new
materials.
Although animal studies may be necessary to address specific questions prior to human use, we
recognize that choosing and validating an animal model is difficult because there is no perfect animal
model.  Many animal studies for spinal systems have involved goats, monkeys, mini-pigs, or
kangaroos.  In choosing an animal model, the sponsor should consider the morphology, histology,
biomechanics, and kinetics as compared to the human situation.
3. Mechanical Data
All spinal systems require some mechanical testing or an acceptable rationale addressing why testing
is not necessary in order to establish the relative safety of the subject system.  The specific
requirements for mechanical testing are influenced by the design, material, method of attachment to
the spine, and patient indication. 
Complete reports of any mechanical testing conducted on the subject system or its components,
whether adverse or supportive, that are relevant to the evaluation of the safety or effectiveness of the
subject system should be included.  A comprehensive summary of all mechanical testing should be
included in addition to complete reports of each test.  The following elements, at minimum, should be
included as part of each test report:  identification of the components that comprised the constructs or
subconstructs tested; the set-up; the procedures; rationale that testing involved the worst case design,
material, and/or manufacturing-related processing; rationale for the loading modes chosen (axial,
bending, torsional, shear, etc.); the results; and a discussion of the results in terms of the expected in-
vivo and clinical performance of the system.  Unless adequate rationale is provided, all testing should
involve the worst case construct design of the total system and not testing of individual components. 
When there are differences between the proposed system and the system tested, an explanation of
how or why the results are relevant in establishing the relative safety of the proposed system should
be provided.
 Fatigue - The fatigue testing should involve a minimum of six samples of the worst case
construct to generate a stress (load) versus number of cycles (S/N) curve that characterizes the
asymptotic endurance limit (e.g., a minimum of two samples per load level with one load level
reaching a runout value of five million cycles) compared to a appropriate control device. 
Rationale for the components chosen as worst case should be provided.  The interconnection
mechanisms/systems may be tested in the same set of constructs or each in a separate set of
constructs.  Each interconnection mechanism should be tested or adequate rationale be provided.
For spinal systems that are intended to maintain disc mobility and not fuse, the fatigue testing
should be performed out to a minimum runout of 10 million cycles to support long term
implantation.  Additionally, testing should be performed out to a minimum runout of 10 million
cycles for intervertebral body replacement devices intended for tumor patients because these
page 6 patients may present a great difficulty in achieving fusion, and, therefore, the device is acting
more as a stabilizer.
 Static - The testing should involve a minimum of five samples of the worst case construct.  As
with the fatigue testing, the components tested and the loading mode should be justified.
Examples of the types of construct testing typically performed for a given type of spinal system in
order to establish relative safety are as follows:
 For lumbar and thoracic pedicle screw systems that are intended for fusion, static and
fatigue bending testing should be provided (e.g., ASTM F1717).
 For cervical, pedicle or lateral mass systems intended for fusion, static and fatigue testing
should be provided.  The loading mode (torsional or bending) is dependent on the design and
material.
 For intervertebral body fusion devices, static, fatigue, and expulsion (push-out testing)
testing should be provided.  The loading mode (axial, torsional, bending, and/or shear) is
dependent on the design, material, and levels of use.
 For vertebral body replacement devices, static and fatigue testing in bending and torsional
loading modes should be provided.
 For vertebral disc replacements, static and fatigue tests in multiple loading modes should be
provided.
Depending on the design of the system, the sponsor may need to perform different tests in lieu of
those identified above, perform additional tests in different testing modes, provide testing on individual
components of the subject system, etc.
While there is a voluntary testing standard available for pedicle screw systems (i.e., ASTM F1717),
many sponsors used modified versions to address different types of spinal systems.  Because there
may be testing standards in development, sponsors should contact appropriate standards bodies (e.g.,
ASTM, ISO) for information regarding test set-ups, parameters, etc. for their specific device type.
A statement as to whether all nonclinical tests comply with the GLP regulations (21 CFR 58) should
be provided.  Otherwise, a brief statement of the reason for the noncompliance should be provided.
4. Biocompatibility
Biocompatibility testing may be necessary based on the material(s) used to comprise the system. 
AAMI/ANSI 10993-1 is a recognized standard that a sponsor may refer to for a description of what
type of information should be provided to address this issue.  Additionally, for any biological or drug
component (e.g., bone morphogenic protein, bovine protein, etc.), the sponsor should follow any
applicable guidances from DGRD and CBER.
page 7 5. Bibliography
A bibliography of all published and unpublished information, whether adverse or supportive, that are
relevant to justifying the initiation of an IDE should be provided.  In addition, copies of this information
and a comprehensive summary of it should be provided.  This summary should clearly identify which
literature are used to provide supporting information for the proposed indications, study duration,
evaluation parameter scales, success definitions, system design, testing results, etc.
Examples of where the literature may be used to provide supporting information or address questions
are as follows:
 Can the proposed system dimensionally fit the spinal levels proposed?
 Was the rationale for the unique design features appropriate?
 Was the type of mechanical testing performed appropriate?
 Were the results of the mechanical testing adequate?
 What are appropriate study duration, parameter scales, success criteria, etc. for metastatic
tumor patients?  For other indications?  For specific spinal levels (i.e., cervical vs. lumbar, etc.)?
 Are the inclusion and exclusion criteria appropriate for the proposed indication?
 Are the proposed scales and success definitions validated or appropriate?
INVESTIGATONAL PLAN
The clinical study should be designed and conducted in a manner such that it provides data that will
constitute valid scientific evidence within the meaning of 21 CFR 860.7.
1. Feasibility/Pilot vs. Pivotal Study
Unlike IDEs for most orthopedic implants, IDEs for spinal systems often involve the introduction of
new device designs and investigational protocols.  Therefore, protocols for spinal systems may vary in
scope from a feasibility/pilot study to a study used to support the safety and effectiveness of a spinal
system (which will be referred to in this guidance as a pivotal study).  These various types of
studies are intended to address different questions and collect different types and amounts of safety
and effectiveness information.
The type of study (feasibility/pilot or pivotal) to be performed has an impact on many sections of the
IDE (e.g., Report of Prior Investigations, Investigational Plan, Informed Consent, Labeling, etc.).  All
subsections of the protocol should be discussed specific to the type of protocol being proposed.  The
sponsor should focus the IDE on one type of protocol at a time.  If a feasibility/pilot study is being
proposed, then the sponsor should include criteria that should be met prior to expansion to a critical
study.
 A feasibility/pilot study is used to collect preliminary safety and/or effectiveness information in a
very limited human clinical trial before conducting a study to support the safety and
effectiveness of a spinal system.  This type of study is typically recommended for spinal device
designs and investigational protocols where no data are available or no devices with similar
designs are available.  If data are already available or a number of similar devices already exist,
then no feasibility/pilot study may be necessary.  The scope and objective of this type of study
are limited. For example, this type of study may be performed to optimize the surgical technique,
evaluate a new system design, validate new patient assessment tools, identify clinically
meaningful endpoints, or to obtain information on which to base the design of a critical study. 
The purpose of a feasibility/pilot study may also involve the specialized training of investigators
for implantation of a novel device and/or implantation via a novel approach.  Depending on the
purpose of the feasibility/pilot study, a control may be necessary.  Even though it is not possible
page 8 to obtain statistical significance from such small studies, a limited evaluation of the safety and
effectiveness data should be made.  Sponsors should refer to the Guidance on the Review of
Investigational Device Exemptions (IDE) Applications for Feasibility Studies, IDE
Guidance Memorandum No. 89-1.
 A pivotal study for marketing purposes should be proposed when adequate preliminary safety
and/or effectiveness information has been provided to justify it.  Preliminary information may
come from feasibility/pilot studies, animal studies, or other preclinical studies.
2. Purpose / Objective Statement
The clinical protocol should begin with clearly defined objective(s) and hypothesis(es).  There should
be an overall statement of the purpose/objective of conducting the study (e.g., to evaluate the safety
and effectiveness of the system in the treatment of a specific condition as compared to the control
system).  In addition, the purpose should include a precise, medically accepted definition of the
condition to be treated and a scientifically sound rationale for the proposed clinical study.  The null
and alternative hypotheses for the proposed study should be stated in terms of the specific study
endpoints, outcomes, and parameters used to measure the success/failure of the system.  The study
should then be designed to test these hypotheses.
3. Study Design
A study design should be clearly described so as to collect data from relevant patient populations
effectively, to measure and compare appropriate clinical and radiographic assessments, and to reduce
the introduction of bias.  The choice of study design is guided by, among other things, the following:
 types of alternative treatments or devices for the proposed intended use;
 the adequacy of the information available regarding these alternative treatments or devices;
 the availability of patients for the proposed patient population; and
 the ease of statistical data comparisons.
A historical-based study is one approach.  This may involve the use of literature or retrospective data.
There are situations that FDA acknowledges that historical-based controls are appropriate, such as in
the case of a limited patient cohort based on indication.  However, the use of historical-based based
controls has many inherent problems and, therefore, many disadvantages.  For example, frequently,
the cohort of spinal literature does not present data completely in terms of desired study outcomes,
relevant time points, description of intended use, parameter scale definitions, success criteria
definitions, etc.  Additionally, statistically relevant comparisons, which are necessary to support the
marketing application, can be difficult to make.  Therefore, in some cases, prospectively acquired
data may best answer questions of safety and effectiveness.
An alternative study design is a nonrandomized, concurrently controlled study.  This study design
offers the benefits of prospectively acquired data, and, therefore, allows for tighter control of all
parameters.  However, the data that are acquired, by design, are inherently more biased than the
randomized study design.  For example, there may be differences in patient population, surgeon
experience, etc. between the investigational and control groups.  These biases should be addressed
when interpreting the data.
The use of randomized concurrently controlled studies provides many advantages over other types of
study designs by offering a tight control of all parameters and by addressing some of the biases
introduced by the other study designs.
page 9 Randomized concurrently controlled studies, nonrandomized concurrently controlled studies, or
historical-based studies may be proposed so long as the study design choice effectively addresses the
safety and effectiveness of the spinal system and the inherent biases.  Again, FDA is committed to
meeting the requirement of considering the least burdensome means of protocol development. 
Regardless of the type of control to be incorporated into the protocol, a complete description of the
investigational and control groups should be provided.  The sponsor should also provide a rationale for
the proposed study design, including how inherent biases are to be addressed. 
3.1 Concurrent Control
If selecting to use a concurrent control, the control group selected for study of an investigational
device should involve a PMA approved or 510(k) cleared system labeled for this indication or a
medically acceptable method of treatment for the indicated disease process.  The control group
and investigational group should, at a minimum, share the same clinical endpoints.  However, the
control and investigational groups do not necessarily need to be identical as far as method of
treatment.
Several approaches may be employed when selecting an appropriate control:
(1) The control treatment may resemble the investigational system in technique, patient
population, expected adverse events, and expected clinical and radiographic outcome.  For
example, if a sponsor were investigating an intervertebral body fusion device for lumbar
DDD, the control group, too, would be treated with interbody fusion.
(2) The control treatment may resemble the investigational system in patient population and
expected clinical and radiographic outcome.  For example, if lumbar DDD is to be treated
by spinal fusion, there may be comparisons of interbody fusion to posterolateral fusion or
comparisons of laparoscopic interbody fusion techniques to open interbody fusion surgical
techniques.  This study design allows for adequate comparisons to be made assuming that
anticipated differences in technique and outcome are appropriately accounted for.
(3) The control treatment may resemble the investigational device in patient population and
expected clinical outcome only.  For example, for the treatment of lumbar DDD, spinal
surgery may be randomized against a non-operative treatment of any sort.  It is important to
bear in mind that treatments that pose greater risk to patients should inherently provide
some greater benefit to the patient cohort.  The degree of invasiveness and profile of
adverse events associated with a treatment are important features to consider when
designing a study.  A study that finds that conservative, non-operative management of a
disease process is as successful as an invasive surgical treatment will probably not support
product approval for the surgical treatment but may support approval for the less invasive
option.  Again, all anticipated differences between treatment groups should be accounted
for when determining study success.
The method used to assign patients to the investigational or control group should be specified. 
Patients may be entered into the study consecutively within a pre-specified time period stated in
the protocol, as they present to the investigator, or selectively.  If patients are chosen selectively,
which, as a method inherently introduces bias, the study should involve a randomized, concurrent
control design.  If the groups are not to be randomized, selective registration is discouraged.
3.2 Literature Control
If selecting to use a literature control, the literature to support a study should, ideally, provide
comprehensive information on the standard of care used to treat a particular condition. 
page 10 However, references from the literature are frequently incomplete in their reporting of relevant
clinical parameters, such as indications for use, surgical techniques, and methods of evaluation.
Therefore, comparison to the literature may be problematic with regard to specific endpoints. 
True comparison to a standard of care is best accomplished prospectively due to the limitations
of the literature.  However, if the study involves literature controls, the sponsor should provide
adequate information describing the proposed literature controls that, at a minimum, should
include the following:
(1) The proposed literature controls and copies of the articles should be provided.  The methods
employed for identifying this body of literature should be clearly stated, e.g., MEDLINE
search under keyword X and/or Y.  Once the entire cohort of literature is identified, the
sponsor should present criteria by which literature was excluded from use as a control. 
Appropriate keywords for search include indications for use and the specific surgical
technique/outcome anticipated, e.g., intervertebral disc replacement for DDD.
(2) A table should be provided which includes the following information for each indication: 
identification of the reference; system(s)/treatment(s) used; diagnostic criteria; length of
follow-up; definitions of the fusion or other surgical outcome; results of appropriate primary
and secondary evaluation parameters with definitions of the scales used.  If converted
scales/scores were presented, a description for the basis for the conversion should be
provided.  Addition, the number of patients studied should be specified for each element at
each follow-up in the table.
An adequate number of appropriate control articles for a specific indication in order to
support the safety and effectiveness of the subject device should be provided.  FDA
recognizes that it may be difficult to extract the information from each reference if multiple
indications are involved.  If that is the case, then the sponsor should summarize the article,
identifying all indications involved and stratifying out any information possible by indication.
(3) A separate table should be provided which includes the complications from each of the
articles used to generate the table above.  A suggested format is to have columns entitled
as "complication, article #1, article #2, ..., literature range."  Please provide the number of
patients with a particular complication, total number of patients and the corresponding
patient rate (%) at each follow-up time.  These tables should also include subsequent
surgical interventions (i.e., removals, revisions, reoperations, and supplemental fixations) at
each follow-up time.  FDA recognizes that some of the individual complications may also be
reflected in the subsequent surgical interventions (e.g., a dural tear that led to a
reoperation); however, this information should still be summarized in one table.
4. Inclusion Criteria
Complete inclusion criteria are essential to adequately define the patient group to be investigated. 
The criteria for inclusion into any clinical study of a spinal system will differ depending on the disease
population targeted for the proposed treatment and the location of the disease process (i.e., cervical,
thoracic, lumbar).
Regardless of the indication being investigated for a particular spinal system, the following general
inclusion criteria should be considered:
 range of patient ages (skeletally mature, if applicable)
 spinal levels involved (e.g., C2-C7; L2-S1, etc.)
 limit on number of adjacent number of levels to be implanted (e.g., 1-level, 2-level, etc.)
 clinical and radiographic conditions for patient entry (e.g., preoperative pain score, location of
pain  back, leg, arm, neck, preoperative function score, preoperative neurological score,
page 11 radiographic evidence of ..., etc.)
 description with suggested time frame of any unsuccessful, non-operative or conservative
treatment (e.g., physical therapy, bracing, traction, medication trials)
 description of any restrictions regarding prior nonfusion surgeries
 patient must understand and sign the informed consent
 patient is able to meet the proposed follow-up schedule
 patient is able to follow the postoperative management program
If a sponsor is designing the inclusion criteria to reflect a minimum level of symptoms secondary to
disease, the sponsor should consider that systems that require the greatest degree of
intervention/convalescence and have the most morbidity should demonstrate an appropriate degree of
clinical and radiographic improvement.
For the purposes of this guidance, patients with spinal tumors who are participating in a clinical trial
are assumed to be treated with a vertebral body replacement.  The tumor type and life expectancy of
these patients are variable and unknown a priori.  As a result, special conditions apply to the design
of clinical trials for vertebral body replacements for the treatment of spinal tumors.  Information
specific to tumors metastatic to the spine is described in detail in Section 16 below.
4.1 Lumbar Degenerative Disc Disease (DDD)
Many protocols involve the investigation of systems for the treatment of lumbar DDD.  DDD
should be based on patient history and radiographic studies.  FDA suggests that the sponsor
consider the following:
DDD should be defined as back and/or radicular pain with degeneration of the disc as confirmed
by patient history, physical examination, and radiographic studies with 1 or more of the following
factors (as measured radiographically, either by CT, MRI, plain film, myelography, discography,
etc.):
 instability as defined by  3mm translation or  5(cid:176)  angulation;
 osteophyte formation of facet joints or vertebral endplates;
 decreased disc height, on average by >2mm, but dependent upon the spinal level;
 scarring/thickening of ligamentum flavum, annulus fibrosis, or facet joint capsule;
 herniated nucleus pulposus;
 facet joint degeneration/changes; and/or
 vacuum phenomenon.
4.2 Scoliosis
The sponsor is encouraged to provide a discussion of the scoliotic degrees and nature of
curvature at time of surgery for which the device is indicated.  Discussion should be provided
regarding the long-term goals of treatment and additional therapies envisioned. Special attention
should be given to age range of the patient cohort so as to appropriately study all populations that
would benefit.  For example, pediatric use should be considered for the treatment of scoliosis.
4.3 Fractures secondary to trauma
In designing a study for this indication, special attention should be given to the type of
fracture/degree of instability, level of fracture, percent retropulsion into the spinal cord, and the
number of levels involved.  The sponsor is encouraged to provide rationale for any data pooling
that is pertinent to the determination of sample sizes for study.
page 12 4.4 Spondylolisthesis
When studying spondylolisthesis, special attention should be given to the grade of disease, that is
to say, the amount of slippage.  The type of spondylolisthesis, degenerative or lytic, and the
location of any defect should be collected.  At the time of PMA submission, the sponsor may
need to demonstrate the poolability of patients across both types of spondylolisthesis.
4.5  Revision surgery for pseudoarthrosis
It is recognized that patients with failed prior fusion attempts are particularly difficult to treat. 
The sponsor is encouraged to collect information regarding type of prior surgeries and treatment
modalities (e.g., bone growth stimulators).  At the time of PMA submission, the sponsor may
need to demonstrate the poolability of patients across different numbers and types of prior fusion
surgeries.
4.6 Cervical DDD
The aforementioned criteria for lumbar DDD should be modified to reflect the anatomy and
symptomatology reflective of the cervical spine.  Additionally, the disease should be confined to
one or two adjacent levels for study consistency.  Rationale for the proposed anatomical sites
should be provided given the differences in spinal anatomy within the cervical spine.  DDD in
the cervical spine should be based on both radiographic and clinical assessments.  FDA suggests
that the sponsor consider the following:
Radiographically (at least one):
 degenerated disc on MRI;
 decreased disc height on plain film, CT or MRI; and/or
 disc herniation, as demonstrated by CT or MRI.
Clinically:  radicular symptoms (at least one):
 arm/shoulder pain;
 decreased reflexes;
 decreased strength; and/or
 decreased sensation.
5. Exclusion Criteria
Complete exclusion criteria are essential in adequately defining the patient group to be investigated. 
This is because exclusion criteria may address a safety concern associated with a specific type of
patient and/or allow for the exclusion of patients who may negatively impact the study results and
data analyses.  Below is a list of exclusion criteria that are common to many spinal studies.  If a
sponsor chooses to investigate patients with one or more of these conditions, then they should address
the impact on the patient safety, study design, and data analyses.
Exclusion criteria are used to help define the patient population in terms of the following categories:
safety concerns; follow-up concerns; those that simplify and clarify the study design, and a
combination of any or all of above.
Safety concerns:
 has either a systemic infection or infection at the site of surgery
 has osteopenia, osteoporosis, or osteomalacia to a degree that spinal instrumentation would be
contraindicated
page 13  has a disease of bone metabolism
 has an allergy to any component of the investigational device
 in the event that a biologic material is to be implanted, has a history of severe allergy or
anaphylaxis
 is pregnant or is interested in becoming pregnant during the duration of the study
Follow-up concerns:
 has a history of substance abuse (recreational drugs, alcohol).  The sponsor should supply
criteria that define abuse
 is a prisoner
Those that simplify/clarify study design:
 has had prior fusion attempts at the involved levels (except if studying pseudoarthrosis patients)
 has a condition or requires postoperative medications that may interfere with bony/soft tissue
healing (including tobacco use)
 has an additional spinal condition other than the condition to be studied
 is currently involved in a study of another investigational product for similar purpose
 demonstrates 3 or more Waddells Signs of Inorganic Behavior
 is a workers compensation case
Combination of any or all of above:
 has a known malignancy
 has a concurrent disease process that would place the patient in excessive risk to surgery. 
These disease processes should be outlined by the sponsor.
 has a disease process that would preclude accurate evaluation (e.g., neuromuscular disease,
psychiatric disease, etc.).  The sponsor should specify these based upon the endpoints of this
study.
 is involved in spinal litigation
 is obese, as defined by a standard measure (Metropolitan tables, body mass index)
6. Number of Sites / Investigators / Patients
The proposed number of investigators, investigational sites, and patients should be specified. The
number of patients per treatment group should be determined using sample size calculations based
upon the studys null and alternative hypotheses; see section 11 below.  Inadequate and/or unequal
patient numbers per investigator may decrease the probability that the patients for a given investigator
will be representative of the study population.  This may preclude the pooling of data between
investigators and/or sites.  Therefore, FDA recommends that the sponsor consider addressing
inadequate or unequal patient distribution in the study.  This may be accomplished by considering a
minimum number of patients per site to justify statistically pooling of a multicenter study (e.g.,  25
patients per indication and per treatment group enrolled at each site).
7. Duration / Follow-up Schedule
In order to properly assess all safety and primary effectiveness outcomes, not just fusion, a spinal
study should involve a minimum of 2 years of follow-up data.  However, a sponsor may propose a
shorter study with an adequate rationale.
The evaluation time points should be specified.  Evaluations are commonly performed at the following
time intervals:  preoperatively (within 2 months of surgery) to collect background and demographic
information and baseline clinical and radiographic data; operatively to collect surgical and safety data;
postoperatively at hospital discharge to collect safety data, and postoperatively at appropriate intervals
out to 2 years to collect clinical, radiographic, and safety data.  FDA also believes that each patient
page 14 should be followed annually until the last patient entered has had his/her 2-year follow-up evaluation. 
Additionally, for each evaluation time point, an appropriate window should be defined.  FDA suggests
the following evaluation schedule (e.g., baseline, 6 +/- 2 weeks, 3 months +/- 2 weeks, 6 +/- 1 months,
12 +/- 2 months, and 24 +/- 2 months and then annually).  Additional evaluation time points may be
necessary based on the design and purpose of the specific spinal system.
8. Effectiveness Evaluation
There are primary and secondary evaluation parameters for all spinal studies that should be measured
at each timepoint.  The specific parameter scales and methods of interpretation (success/failure
criteria) with rationale/validation should be included.  As a note, neurological assessments are
discussed in the section 9 below.
For lumbar spinal studies, primary evaluation parameters should include: radiographic success
(fusion or nonfusion, depending on spinal system type); back and leg pain; and function. 
Secondary evaluation parameters should include:  donor site pain; disc height assessment; and
health-related quality of life.  As a note, disc height assessment is not applicable for vertebral body
replacement devices.  Instead, the evaluation parameter is vertebral height assessment.
For cervical spinal studies, primary evaluation parameters should include:  radiographic success
(fusion or nonfusion, depending on spinal system type); neck and arm pain; and function. 
Secondary evaluation parameters should include:  donor site pain; disc height assessment; and
health-related quality of life.  As noted above, disc height assessment is not applicable for vertebral
body replacement devices.  Instead, the evaluation parameter is vertebral height assessment.
The success criteria for each of the individual primary evaluation parameters will differ based upon
the design of the system, the patient population, and the goals of the treatment.
8.1 Radiographic Success
8.1.1 Fusion Status
For systems intended for fusion (e.g., pedicle screw systems, intervertebral body
fusion devices, etc.), there are numerous radiographic methods that may be used to
evaluate fusion status (e.g., A/P, lateral, flexion and extension, etc.).
These radiographic evaluations should be performed at the baseline and at all the
postoperative evaluations starting at 3 months at each evaluation time point for the
duration of the study.  All radiographs used in the determination of fusion should be
read by at least two radiologists.  At least one of the two radiologists should be an
independent radiologist who is masked (when possible) to the treatment to address the
potential for observers bias.  For the radiographs for which the two radiologists are in
disagreement, a third independent, masked (when possible) radiologist should be
brought in to look at those radiographs.  The third radiological readings should be the
deciding evaluation (i.e., majority rules).  Keep in mind that there should be no
discussion of the radiograph until all readings are made.  In addition, the discrepancies
between the first two radiological readings should be quantified statistically, if possible.
For double level involvement, both levels should be fused to be considered a successful
fusion.  When two intervertebral body fusion devices are implanted per level, both
devices should be fused to be considered a successful fusion.  For a combination
system (e.g., system comprised of intervertebral body fusion device and pedicle screw
system), both sites should be fused for a patient to be considered a successful fusion.
page 15 For lumbar spinal systems, successful fusion should be based on all of the following
radiographic endpoints being demonstrated on roentgenographic examination (A/P,
lateral, flexion and extension):
 evidence of bridging trabecular bone between the involved motion segments (e.g.,
between the involved vertebral endplates for intervertebral body replacement
devices, between the facets, pedicle, and/or transverse processes for pedicle
screw systems);
 translational motion <3mm; and
 angular motion <5(cid:176) .
The tolerance for presence of radiolucent lines may be dependent on the type of spinal
system.  If the sponsor chooses to incorporate radiolucency data as a fusion criterion,
then specific information should be provided in order to better assure that adequate
radiological assessments are being made to measure the accurate presence or absence
of radiolucencies.  Even if the sponsor does not choose to incorporate the radiolucency
data as a fusion criterion, this data should be collected as confirmatory information.
FDA appreciates that the presence of rigid hardware, such as pedicle screw systems,
may confound the results of a flexion/extension series.  The definition of fusion,
therefore, should include the criteria listed above so as to capture movement
information as well as bony growth.
For cervical spinal systems, successful fusion should take into consideration the types
of radiographic techniques and criteria suggested for lumbar spinal systems above. 
The sponsor should provide the rationale for any proposed fusion criteria, particularly
for the quantitative translational and angular values considered appropriate for the
cervical spine.
FDA acknowledges that the radiographic assessment of many of the novel spinal
systems is confounded by the presence of opacifying hardware.  Therefore, it is
tempting to turn to other imaging modalities to assess the area in question.   Regarding
the use of other radiographic modalities to demonstrate fusion (CT scan, MRI, etc.),
the sponsor should demonstrate the validity and reliability of these modalities prior to
using these measures as primary study endpoints.  FDA generally expects sponsors to
use a more traditional method of assessing the fusion status in addition to any proposed
method that has not yet been validated.
8.1.2 Radiographic Success for Nonfusion Systems
For spinal systems intended maintain motion without fusion, the radiographic endpoints
should demonstrate maintenance of normal types and ranges of motion.  For
example, the following endpoints may be considered to define radiographic success for
the lumbar spine for nonfusion systems:
 no evidence of bridging trabecular bone; and
 evidence of range of motion appropriate for level involved.  The amount of motion
should be specified as part of the success criteria.
As described in Section 8.1.1 above for fusion systems, a sponsor should consider
incorporating radiolucency data as part of the fusion criteria or using it as confirmatory
information.
page 16 8.2 Pain and Function
Although pain and function are two separate endpoints, there is considerable overlap in their
assessments.  Pain may not be present at rest, but only with activity, causing enough discomfort
to limit a patients ability to function.  The patient may have severe enough discomfort with
activity as to avoid it altogether and, therefore, cause a limitation in function.  There are
assessment instruments that successfully capture the effect of pain on function.  There are also
assessments that successfully capture pain and function independently.  For any assessment
instrument used, the method of administration should be identified. 
For the independent pain assessment, measurements should address both pain severity and
frequency.  Pain should be measured by using a validated pain assessment instrument, such as a
visual analog scale (VAS), 5-point to 10-point scales, or another appropriate instrument.  Back
and leg (sciatica) pain should be considered for lumbar disease, and neck and arm (radicular)
pain should be elicited for cervical disease.  Patients who undergo autologous grafting
procedures should also be evaluated for postoperative donor site pain.  These areas of pain
should be assessed both pre- and postoperatively at specific follow-up times.
For the independent function assessment, the sponsor is advised that VAS, X-point scales, and
any such uni-dimensional assessment tools, do not fully capture functional status as a whole. 
Activity-specific function questions capture this endpoint more comprehensively, and, therefore,
the use of single question function assessment is discouraged.  FDA encourages the use of
pain/function specific evaluation instruments.
For assessments that capture both low back pain and function in lumbar spine studies, there are
various instruments such as the Oswestry Disability Questionnaire and the Roland-Morris
Disability Scale (see Fairbanks JC, et al., The Oswestry Low Back Pain Disability
Questionnaire Physiotherapy. 1980 Aug; 66(8): 271-271).  Other back-related function scales
include the Million Questionnaire, the Waddell Disability Questionnaire, and the Quebec
Disability Questionnaire.
For assessments that capture both neck pain and function in cervical spine studies, FDA
recommends that the sponsor consider the Neck Disability Index and Northwick Park Neck
Pain Questionnaire, which are both based upon the Oswestry Questionnaire format (see Vernon
H, et al., The Neck Disability Index: A Study of Reliability and Validity. J Manipulative
Physiol Ther. 1991; 14(7): 409-415, and see Leak A.M., et al., The Northwick Park Neck Pain
Questionnaire, Devised to Measure Neck Pain and Disability, British Journal of
Rheumatology 1994; 33:469-474).
Sponsors should keep in mind that if a combination pain/function assessment tool is used as part
of a study, then the protocol should also include independent assessments of leg and donor site
pain for lumbar studies or arm and donor site pain for cervical studies.
Success criteria for the primary pain parameters (back/leg for lumbar studies and neck/arm for
cervical studies) and for function should be clearly defined.  The success criteria for pain and
function is dependent on the scales used, the indication involved, and the goals of the treatment. 
With regards to the secondary pain assessment of donor site pain, the sponsor should present
the data; however, success criteria for this secondary pain parameter are not necessary.
FDA believes that whether combination pain/function scales or independent pain and function
scales are used, the success criteria for an individual patient should be based on a clinically
meaningful level of improvement.  The clinically meaningful level of improvement should be
page 17 clearly specified (i.e., X-pts or X% improvement from baseline).
8.3 Height Assessment
8.3.1 Disc Height Assessment
In disease processes where disc height diminishes, and perhaps is the cause of
pain/neurological symptoms, this endpoint is relevant in the determination of overall
success.  Many spinal implants, specifically intervertebral body fusion devices, attempt
to restore disc height.  Obtaining a measurement of disc height, however, may be
somewhat troublesome due to obscuration of the disc space by spinal implants. 
However, to the extent that this measurement can be made, postoperative disc height
should be maintained long term.  A baseline disc height measurement may be obtained
approximately 6 weeks postoperatively or may be extrapolated from the measurement
of adjacent, non-diseased disc spaces.  Both anterior and posterior disc heights should
be considered in evaluating this endpoint.
8.3.2 Vertebral Height Assessment
In disease processes where vertebral height diminishes, and perhaps is the cause of
pain/neurological symptoms, this endpoint is relevant in the determination of overall
success.  Many spinal implants, specifically vertebral body replacement devices,
attempt to restore vertebral height.  Obtaining a measurement of vertebral height,
however, may be somewhat troublesome due to obscuration by spinal implants. 
However, to the extent that this measurement can be made, postoperative vertebral
height should be maintained long term.  A baseline vertebral height measurement may
be obtained approximately 6 weeks postoperatively or may be extrapolated from the
measurement of adjacent, non-diseased vertebral bodies.
8.4 Health Related Quality of Life
Because the majority of spinal surgeries are performed on an elective basis determined by the
limitations on activities and the severity of symptoms as perceived by the patient, an important
aspect of ascertaining success is a measure of the patients overall well-being and satisfaction
and, therefore, should be considered in developing a study.
There are a number of assessment instruments geared to this purpose (e.g., SF-36 Short Form
Questionnaire).  An abbreviated, but still validated form of this survey, is the SF-12.  The lesser
used Nottingham Questionnaire and EuroQol are also acceptable surveys.  Therefore, although
the SF-36 is comprised of a physical section, as well as a mental section, the physical section
lacks the specificity to capture changes in back function.  The SF-36, as well as these other
instruments, provides insight into a patients overall status.  The SF-36 and SF-12 incorporate
several domains of health into a physical component summary (PCS) and mental component
summary (MCS).
9. Safety Evaluation
Safety assessment involves assessment of the complications, including subsequent surgical
interventions and neurological complication information.  A description of all subsequent surgical
interventions, deaths, and neurological complications, including details of their resolution, should be
provided.
All preoperative, operative, and postoperative complications, whether device-related or not, should be
page 18 recorded.  These include anticipated complications as well.  Pain, neurological, and function
symptoms should be considered complications when a patients complaint for any of these symptoms
results in an unscheduled visit or when a patient presents with new or worsening pain, neurological,
and/or function symptoms as compared to the previous visit.
9.1 Subsequent Surgical Interventions
Some complications lead to a subsequent surgical intervention.  FDA categorizes the subsequent
surgical interventions as follows:
 A revision is a procedure that adjusts or in any way modifies or removes part of the
original implant configuration, with or without replacement of a component.  A revision may
also include adjusting the position of the original configuration.
 A removal is a procedure where all of the original system configuration are removed with
or without replacement. 
 A reoperation is any surgical procedure at the involved level(s) that does not removal,
modification, or addition of any components to the system.
 A supplemental fixation is a procedure in which additional instrumentation not under study
in the protocol is implanted (e.g., supplemental placement of a rod/screw system or a
plate/screw system).
The sponsor should incorporate the four subsequent surgical interventions above into the protocol
as potential risks.  It is essential for the sponsor to capture the reason for each subsequent
surgical intervention and the action taken (e.g., replacement of a screw, placement of extra bone
grafting material, etc.).  Along with the presentation of the subsequent surgical interventions
pooled into the four categories above, each category should be further stratified.  For example,
the revision category data presentation may be stratified into revision for translated cage,
removal of screws, etc., depending on the reasons identified in a particular study.  As another
example, the removal category may be stratified into removal for pain at operative site but after
fusion, for pseudoarthrosis, etc.
FDA believes that some reasons for performing a removal may constitute a failure; however,
this is also very dependent on the device type.  The sponsor should clearly identify which
reasons for removal constitute a patient failure and provide a rationale.  For example, removal of
a cage at any time should constitute a failure; however, removal of a pedicle screw system after
fusion may not.  If removal surgery is recommended in the protocol for a given spinal system,
the sponsor should clearly indicate in their protocol how such removals will be interpreted in
terms of success and failure of the study.  Additionally, the sponsor should also identify any
other subsequent surgical intervention(s) that constitute a patient failure.
9.2 Neurological Status
Comprehensive neurological evaluation should be performed due to the potential risks of spinal
surgery, in particular, due to the proximity and vulnerability of the spinal cord.  While patients
may not present with neurological dysfunction preoperatively, spinal surgery introduces the risk
of spinal cord injury or other neurological damage.  Comprehensive evaluation is necessary. 
Therefore, assessments should include motor, sensory, and reflex evaluations, and, for studies
involving the lumbar spine, straight leg raising evaluations.
page 19 Many different assessments exist for evaluating neurological outcome.  It is important to select
an instrument that is sensitive enough to capture changes that might be anticipated in the
population under study.  Many of the patients receiving spinal implant surgery are not severely
neurologically compromised, and, therefore, not all spinal injury assessment tools can fully
capture these changes.  The Frankel scale, which discerns between severe degrees of spinal
cord injury, is not appropriate assessment tools for a relatively neurologically intact patient
cohort.  It is important to appreciate that a change that may be classified as minor by the spinal
cord injury assessment instruments may be devastating to the previously neurologically intact
patient.  Such instruments, therefore, should be carefully evaluated and used with caution.
A detailed neurological assessment should capture all degrees of change in the motor, sensory,
and reflex portions.  Sensory evaluation should be performed by dermatomal levels.  The motor
evaluation should measure strength in the major muscle groups distal to the level(s) of
involvement.  For surgeries involving the lumbar spine, a straight leg raising test should be
performed and the results recorded in terms of degrees of movement required to reproduce
symptoms.
10.  Patient / Study Success
Patient success will be used to assess the success rate of an individual patient within a study group. 
This information will be used as part of the labeling.  The study success will be used to determine the
safety and effectiveness between the investigational and control study groups.
There may not be sufficiently larger number of patients evaluated at the study endpoint (e.g., 2 years)
due to dropouts or censored (incomplete) data, accordingly, the sponsor should perform appropriate
statistical analyses, as described in Section 11.
10.1Patient Success
The success of a patient should be based, at minimum, on success in each of the primary
evaluation parameters of fusion (or radiographic success for nonfusion systems), pain, and
function as well as no permanent neurological deficit.  Depending on the proposed patient
population, study design, and study goals, other assessments may be included.
Individual patient success rates should be provided at each postoperative time point, but there
will be particular focus on the results at the study endpoint (e.g., 2 years).
10.2Study Success
Study success 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 evaluation
parameters, at minimum, as well as safety information, should be accounted for in the definition
of study success. 
One example of study success criteria of a lumbar equivalency study based on a comparison of
the individual patient success rates is as follows:
 patient success rate of investigational group is no worse than that of control; and
 complication rate (including subsequent surgical interventions and neurological
complications) of investigational group is no worse than that of control.
The sponsor should clearly identify and justify the pre-specified allowable difference (delta) used
to define no worse than.
Depending on the claims that a sponsor may be making (e.g., faster time to fusion, less pain at
page 20 earlier time points, etc.), it may be appropriate to incorporate the results of the longitudinal, trend,
and survival analyses (Section 11.2 below) as part of the study success criteria.
Study success rates should be provided at each postoperative time point, but there will be
particular focus on the results at the study endpoint (e.g., 2 years).
11.  Statistical Analyses / Data Presentations
11.1Statistical Analyses
A complete sample size justification should be provided in the IDE protocol. 
 sample size justification - A statistical rationale should be provided for the proposed
number of patients to be enrolled in the study, including control patients.  This number
should be based on the ability to detect minimal clinically and statistically significant
differences between the investigational and control groups with a given power, pre-
specified type I error, expected variability of the outcomes and expected success and
complication rates for both the investigational and control groups.  Additionally, the
expected withdrawal/lost to follow-up rate over time should be taken into account to adjust
for the sample size.  Consideration should also be given to the number of variables
incorporated into the study design (e.g., allograft versus autograft use, one versus two or
multi-level spinal fusions, etc.).  If pooling of the data cannot be justified at the PMA or
510(k) stage, a subgroup analysis using subgroups which are pre-defined in the IDE
protocol may be beneficial.
Additionally, the IDE protocol should include a description of the type of statistical analyses to be
performed for the PMA or 510(k) to assess the study results.  A rationale and description of
each of the statistical analyses to be employed in assessing the effectiveness of the treatment
should be provided.  This includes an appropriate statistical comparison of the treated patients to
the control patients for all evaluation parameters by considering comparable follow-up times. 
Statistical evidence of device effectiveness is essential.  However, this alone is not sufficient for
PDP or PMA approval or 510(k) clearance.  Sponsors should demonstrate both statistical and
clinical significance.  FDA believes that the following analyses should be performed for the
PMA or 510(k) and, therefore, be described in the IDE protocol: 
 poolability across investigators and sites  Appropriate statistical and clinical
justification, such as homogenity of treatment outcomes across investigators and sites, are
recommended.
 longitudinal data analyses with covariates  Longitudinal data analysis should be
performed for various data types such as continuous, binary, count, or ordinal (ranking)
data.  Appropriate statistical modeling approaches, including device code (e.g., 0 for control
and 1 for investigational device), important patient covariates and demographic
characteristics, should be considered in the statistical model in order to evaluate true device
effect and adjusting for possible differences in the distributions of important patient
covariates and demographic characteristics between control and investigational device
groups.  Computer software, such as SAS, S-Plus, or others is available to analyze such
repeated-measure data.
 trend analyses - Clinical outcomes may vary from time to time (time trend), device to
device (device effect), and crossover between device and time (device by time interaction).
 A simple comparison between two arbitrarily selected time points will not reveal true
device effect over time.  Therefore, FDA suggests that repeated measure analysis of
page 21 variance (RMANOVA) for continuous or quantitative data and longitudinal data analysis
should be performed.
 survival analyses  For success/failure (binary data), statistical survival analysis with a 
multivariate model (e.g., Cox proportional hazard regression) may be used to estimate the
time-specific cumulative fusion success probability and effect of important patient
covariates on fusion success/failure while accounting for patients who are dropouts or
censored (incomplete).
The sponsor should consider the following statistical issues:
 The number of study patients is likely to decrease over time due to dropouts or censored
(incomplete) data.  Statistical analysis based on partial data presents a challenge because one
cannot be sure that the dropout or censored patients will have the same clinical outcomes with
their partially observed clinical outcomes as they would have if they had completed the whole
follow-up schedule.  Therefore, the sponsor should make every attempt to obtain complete
follow-up on all patients entered into the study. 
 The reasons for any missing data, whether device, covariate, or clinical outcome related, should
be clearly explained.  The distribution of missing data between the control and active device
groups should be carefully evaluated.
 The sponsor should clearly state the definition of clinical outcomes to be compared between the
two treatment groups.  If change from baseline is used, then the comparability of clinical
outcomes and covariates at baseline should be demonstrated between the control and active
device groups in order to avoid the confounding effect between device effect and baseline
measurements.  Please note that, simple randomization does not guarantee comparability of
clinical measurements and covariates between investigational and control groups at baseline.  If
baseline values are quite different between two groups, then appropriate statistical analysis, such
as using the baseline as the covariate, should be employed.
11.2Data Presentations
The types of data presentations should be considered at the time of protocol development in
order to better assure that adequate data are collected.  Although it is not necessary to provide
this information as part of the IDE protocol, FDA believes that the following types of data
presentations, stratified by investigational and control groups, should be provided in an IDE
annual report, as well as in a PMA or 510(k):
 time course distribution of patient accounting (e.g., theoretically due, deaths, reoperations,
revisions, removals, supplemental fixations, expected, actual number followed, and follow-up
rate);
 written descriptions of the subsequent surgical interventions, deaths, and neurological
complications including any actions taken, resolutions, etc.;
 time course distributions of the following individual parameters  fusion, back or neck pain,
leg or arm pain, function (may be combined parameter with back or neck pain), vertebral
body height or disc height, health related quality of life, donor site pain, motor strength,
sensory, reflexes, and straight leg raisings (for lumbar studies).  These time course
distributions provide the number of patients at the different levels within a given each scale
(e.g., as for pain, function, etc.) or the number of patients that meet each criteria (as for
fusion).  For example, for fusion, the time course distribution for fusion would show the
page 22 number of patients who had translational motion, rotational motion, trabecular bone
formation, etc.  As another example, the time course distribution for leg pain would show
the number of patients with pain at level 1, level 2, etc.;
 time course distributions of all complications, including subsequent surgical interventions and
neurological complications for all patients; and
 time course distributions of the individual patient success rates for all patients.
In order to properly evaluate the data, it is imperative that the sponsor clearly identifies the
number of patients involved at a give time point in any data presentation.
12. Patient Report Forms
Copies of all patient report forms should be provided.  The forms should include all relevant
information from the protocol.  The following are the type of forms that should be part of a study.
 Enrollment form or Inclusion/Exclusion Criteria form - identifies all inclusion and exclusion
criteria in protocol
 Demographic and Preoperative Evaluation - includes demographic information and the clinical
and radiographic parameters to be measured
 Operative Data form
 Discharge form
 Postoperative Evaluation form - include the clinical and radiographic parameters to be measured
 Adverse Event form - identifies all potential risks from the protocol and provides for reporting of
other adverse events
The sponsor should also provide a table that specifies the time point(s) at which each patient report
form is to be completed.
13. Risk Analysis
This section should include adequate information to determine that the benefits and knowledge to be
gained outweigh the risks to the patients.  This information includes:
 a description and analysis of all increased potential risks to which patients will be exposed by
investigation;
 the manner in which the potential risks will be minimized; and
 rationale for the investigation.
When listing all of the potential risks, they should be stratified by those general to spinal surgery and
those specific to the system.  The sponsor should also provide a statement that all adverse
events/complications, device related or not, will be reported and recorded.
The list of potential risks should be the same in the Risk Analysis section, Adverse Event patient
report form, package insert, and informed consent document.
14. Post-Operative Regimen
Any additional patient care procedures to be employed during the treatment period (e.g., surgery,
rehabilitation, immobilization, weight bearing, etc.) should be detailed.
page 23 15. Retrieval Study
Because of the unknown long term device performance of some types of spinal systems, particularly
the resulting bony fusion characteristics, a sponsor should incorporate a plan that focuses on the
retrieval analyses of a spinal system that is implanted and subsequently removed.  Histological
information (e.g., bony ingrowth quality, bone quantity, response to potential wear debris, etc.) and
metallurgical information (e.g., metal wear, deformation, cracking, corrosion, etc.) should be collected
and reported in the annual reports.
16. Spinal Tumors
Studies to analyze the safety and effectiveness of vertebral body replacement devices for the
treatment of spinal tumors should take into account several factors which differentiate this population
from other vertebral body replacement patients in particular, and spinal disease patients in general. 
These factors include such things as the life expectancy of the patient, the total number of patients
eligible to participate, the specific purpose of the device, the duration of the clinical trial and the
appropriate clinical outcome parameters.
16.1Inclusion Criteria
For inclusion into a tumor study, the sponsor should consider the previous treatments (e.g.,
radiation, chemotherapy), type of tumor (primary benign, primary aggressive/malignant, or
metastatic), and the goals of the treatment.  FDA recognizes that a tumor study may involve a
broad range of disease entities and life expectancies.  Patients are expected to present with a
primary complaint of pain, neurological deficit, and/or functional deficit or with the intent to
prevent a pathological fracture.
16.2Duration / Follow-up Schedule
It is expected that long-term follow-up for many of the patients enrolled in a trial for this type of
device may not be possible and that there will be a large number of patients who would be
categorized as lost-to-follow-up.  As a result, from the standpoint of data collection, the goal of
the trial is to gather as much data as possible.  The sponsor should describe the follow-up
schedule and duration of the study based on the patient population at hand and the study goals. 
All patients should be followed until the last enrolled patient has reached the justified study
endpoint or has withdrawn from the trial due to death.
16.3Sample Size / Number of Sites & Investigators
The total number of patients that would meet the inclusion/exclusion criteria is relatively small
and the rate at which these patients would be available for enrollment is very low.  Therefore, no
limits will be placed on the number of sites/investigators that may be enrolled for a particular
clinical trial.  IRB approval will still be required for each enrolled site, however.  In addition,
monitoring in accordance with the IDE regulations will also be required.
16.4Controls
Controls should be incorporated.  A concurrent control population is preferred.  The concurrent
controls may be used at separate sites than the investigational patients and may involve use of
any currently acceptable standard of care for spinal tumors, e.g., anterior plates with bone graft,
PMMA, etc.
page 24 Other potential sources of control data are retrospective, consecutive data (case series) from the
participating investigators or literature.  Because of the large variability in treatments and
evaluated clinical outcome parameters, these possible sets of control data present potential
difficulties during data analysis.  In order to allow for proper comparison, the same clinical
outcome parameters from these populations should have been collected at similar time intervals.
 Consequently, these alternate sources of control data should be discussed in detail with FDA
prior to initiation of trial.
16.5Clinical Parameters
Patients should be evaluated for the following:
 pain (leg and/or back)
Attempts need to be made to distinguish pain due to problems with the spine, e.g.,
nerve root impingement, from the general pain that these patients might experience as
the result of their medical condition.
 neurological status
The same assessments used for evaluation of neurological status for patients with
other spinal devices are applicable to these patients.
 patient function (functional independence)
Evaluation of function should focus on the ability of patients to function independently,
e.g., how does their ability to better move around the house/neighborhood, dress
themselves, etc. compare to their pre-op status.
 radiological assessments
The radiological assessments depend on the patient population and study goals.  These
assessments may include integrity of implant, maintenance of correction, lack of
migration, and/or fusion.
 health-related quality of life
It is anticipated that an improvement in a patients quality of life will occur as a
result of receiving the implant.  Therefore, the sponsor should identify an instrument
that appropriately and adequately captures this aspect of outcome for the population
under study.
16.6Safety
Safety should be evaluated similar to that described in Section 9 above.
16.7Patient / Study Success
Individual patient success may be based on a clinically meaningful level of improvement for a
fixed number of clinical parameters.  The sponsor may also consider basing individual patient
success on a clinically meaningful level of improvement in the patients primary complaint or
reason for surgery (e.g., to relieve pain, prevent pathological fracture, etc.).  For example, a
patient who presents with a primary complaint of pain should improve in pain to be considered
successful for that parameter, but only maintenance or improvement in neurological status and
patient function are necessary to be considered successful for those parameters.  Patients
presenting with multiple primary complaints should improve in each one of them in order to be
considered successful.  A device that fails from the mechanical/positional standpoint (device
function) and requires that a patient undergo a second, corrective surgery will categorize that
subject as a failure.
page 25 Study success criteria based on a comparison of the individual patient success rates between the
investigational and control groups or a comparison of the individual parameters between the two
groups.
16.8Data Presentations / Statistical Analyses
Data presentations similar to those described in Section 11.2 apply, with all available data being
presented.  Because the life expectancy of the enrolled patients will be variable, there is the
potential to produce a dataset that is very uneven and predisposed to large losses of
information at later evaluation timepoints.  As a result, patient clinical behavior should be
assessed as a function of time using survivorship and longitudinal analyses.  These analyses will
show the effect of important patient covariates on success/failure while accounting for patients
who are dropouts or censored (incomplete).  Again, these analyses should involve all available
data.
DEVICE DESCRIPTION
In accordance with 812.25, adequate device description information should be submitted.  More
specifically, the following information, at minimum, should be provided for any spinal system:
(1) a table that includes each component name and corresponding part number;
(2) a complete written description of the individual components and how any components interconnect;
(3) complete mechanical drawings with all dimensions and tolerances of each individual component and,
if applicable, of the total system;
(4) supporting magnified sketches or photographs of the major interconnection mechanisms and of the
entire system attached to a spinal model;
(5) a description of the material(s) and any voluntary material standard(s) to which the material(s)
conform.  Depending on the material, biocompatibility issues may need to be addressed. 
Biocompatibility information should be included in the Report of Prior Investigations section of the
IDE;
(6) a description of anticipated changes to the system; and
(7) a list of all instruments unique to the implantation of the subject system, the material and voluntary
material standard to which they conform, and supporting magnified sketches or photographs of them.
For any concurrent control system, a written description, any available mechanical drawings and
photographs, and material information should be provided.
page 26 MANUFACTURING
As per 21 CFR 812.20(b)(3), a description of the methods, facilities and controls used for the manufacture,
processing, packaging, and storage of the device in sufficient detail so that a person generally familiar with
good manufacturing practices can make a knowledgeable judgment about the quality control used in the
manufacture of the device is to be provided.
As part of that information, the following should be provided for any spinal system:
(1) basic manufacturing information that deals with device design issues (e.g., application of coatings,
unique material processing, processing of the bone morphogenic protein, etc.); and
(2) sterilization information.  For systems provided sterile, the sterilization method(s) used, all parameters
of the sterilization cycle, the validation method, the resulting sterility assurance level (SAL), a
description of the packaging, and data supporting any pyrogenicity claims should be provided.  For
systems provided nonsterile which must be sterilized prior to use or for which is labeled as to be
resterilized, the recommended sterilization method(s), all parameters of the sterilization cycle, the
validation method, the resulting SAL, and a description of the packaging should be provided.
MONITORING
The following is not information specific to a spinal IDE but is necessary to complete the IDE submission:
(1) a copy of the written procedures for monitoring the investigation.  These procedures should meet the
minimum requirements described in 21 CFR 812.46; and
(2) the name and address of the monitor.
IRB and INVESTIGATOR INFORMATION
The following is not information specific to a spinal IDE but is necessary to complete the IDE submission:
(1) a sample of the investigator agreement.  At minimum, the agreement should include the information
described in 812.43(c);
(2) certification that all investigators participating in the investigation will sign the investigator agreement
prior to entrance into the study;
(3) the name and site address of each investigator who has signed the investigator agreement; and
(4) the name, address, and chairperson of each IRB.  In addition, any action taken by each IRB (e.g.,
approval) and how many IRBs are currently reviewing the investigation or will review it in the future.
LABELING
In accordance with 21 CFR 812.20(b)(10), copies of all labeling for the system should be provided.  The
Labeling section for the spinal system IDE should, at minimum, include sample package labels, a package
insert, and a surgical technique manual.  Although the information requested for each is generic to any
orthopedic device, the level of detail is typically greater for spinal systems (e.g., the listing of all inclusion
criteria, implantation procedures, system directions, etc.).
page 27 1. Package Labels
The draft package labels should include, at minimum, the following information:
 system and device names;
 quantity;
 material and voluntary material standard;
 sterile or nonsterile notation;
 name and address of business of manufacturer, packer, or distributor (in accordance with 21
CFR 801.1); and
 a statement that the use of the device is investigational for the proposed indication as follows:
CAUTION - Investigational Device.  Limited by Federal (or United States) law to
investigational use.
If the components of a system are packaged individually, then please provide draft package labels for
each type of component (e.g., screw, hook, rod, biologic material, etc.).
2. Package Insert
The draft package insert should include, at minimum, the following information:
 system name;
 brief device description with material information and any system directions;
 inclusion criteria;
 list of any pertinent contraindications, warnings, and precautions;
 list of potential adverse events/complications;
 sterile or nonsterile notation;
 recommended sterilization parameters if provided nonsterile or if resterilization is allowed; and
 a statement that the use of the device is investigational for the proposed indication as follows:
CAUTION - Investigational Device.  Limited by Federal (or United States) law to
investigational use.
The information provided in the package insert should be consistent with that provided in the rest of
the submission, including any inclusion criteria, potential risks, device description information, etc.
3. Surgical Technique Manual
The draft surgical technique should include, at minimum, the following information:
 system name;
 written procedures of how to implant the subject system along with supporting magnified
sketches or photographs of each major step; and
 a statement that the use of the device is investigational for the proposed indication as follows:
CAUTION - Investigational Device.  Limited by Federal (or United States) law to
investigational use.
If the protocol involves a concurrent control system, then the surgical technique manual should
include adequate instructions for implantation of the control system, or a separate surgical technique
manual for the control system should be supplied.
page 28 INFORMED CONSENT
In accordance with 21 CFR 812.20(b)(11), copies of all forms and informational materials to be provided
to the subjects in order to obtain informed consent are to be provided.  In addition, a statement that the
subject must sign the informed consent document prior to entrance into the study should be provided.
The informed consent document is to meet the general requirements as described in 21 CFR 50.20.  In
addition, according to 21 CFR 50.25(a), the informed consent should include the following items:
(1) a statement that the study involves research;
(2) an explanation of the purposes of the research;
(3) the expected duration of the subjects participation;
(4) a description of the procedures to be followed (e.g., evaluation time points, general types of
evaluations, any special postoperative regimen, etc.);
(5) identification of any procedures which are experimental (i.e., clearly identify the investigational
system of the study);
(6) a description of any reasonably foreseeable risks or discomforts to the subject;
(7) a description of any benefits to the subject or others;
(8) a disclosure of appropriate alternative procedures or courses of treatment that might be advantageous
to the subject;
(9) a statement describing the extent to which confidentiality of the subjects records will be maintained
and that notes that FDA may inspect the records;
(10) an explanation as to whether any compensation and/or medical treatments are available if injury
occurs and, if so, what they consist of or sources of further information;
(11) an explanation  of whom to contact for answers to questions about the study and the subjects rights
and whom to contact in the event of a research-related injury; and
(12) a statement that participation is voluntary and that subjects may refuse to participate or discontinue
participation at any time without penalty or loss of benefits.
If necessary, additional elements to the informed consent document as per 21 CFR 50.25(b) may need to
be addressed.
While the information requested above is not specific to a spinal IDE, it is important that the informed
consent document be consistent with the information provided in the Device Description section and the
Investigational Plan section, including the proposed patient population, purpose, duration, follow-up time
points, evaluation parameters, potential risks, etc.  This is because there are some variations between
spinal IDEs in terms of the designs, surgical approaches, patient groups, and parameters.
SALES
The following is not information specific to a spinal IDE but is necessary to complete the IDE submission.
 In accordance with 812.20(b)(8), if the system is to be sold, the amount to be charged and an explanation
of why the sale does not constitute commercialization of the system are to be provided.
ENVIRONMENTAL IMPACT ASSESSMENT
The following is not information specific to a spinal IDE but is necessary to complete the IDE submission.
 An environmental assessment as described in 21 CFR 25.31(a) or a statement of categorical exclusion
from this requirement under 21 CFR 25.24(e)(7) is to be provided.
page 29 Note:  FDA acknowledges that the spine area may be considered complicated to sponsors.  ORDB
is eager to provide input prior or during the development of an IDE for spinal systems, especially
in the areas of:
 appropriate mechanical testing for a specific system design;
 appropriate animal study design;
 presentation of existing clinical data; and
 specific and general protocol questions (appropriateness of inclusion criteria, evaluation
parameters, success criteria, control group, etc.).
page 30