Guidance for Industry and FDA Staff 
 
Pre-Clinical and Clinical Studies 
for Neurothrombectomy Devices 
 
  
 
Document issued on: June 18, 2007 
 
 
For questions regarding this document contact Carlos Pena, Ph.D., M.S., at (301) 827-3340 or 
carlos.pena@cdrh.fda.gov or Neil Ogden at (240) 276-3600 or neil.ogden@cdrh.fda.gov.  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health 
 
General Surgery Devices Branch 
Division of General, Restorative, and Neurological Devices 
Office of Device Evaluation  Contains Nonbinding Recommendations 
 
 
Preface 
 
Public Comments  
 
Written comments and suggestions may be submitted at any time for Agency consideration 
to the Division of Management, Food and Drug Administration, 5630 Fishers Lane, Room 
1061, (HFA-305), Rockville, MD, 20852.  Alternatively, electronic comments may be 
submitted to http://www.fda.gov/dockets/ecomments.  When submitting comments, please 
refer to the exact title of this guidance document.  Comments may not be acted upon by the 
Agency until the document is next revised or updated.  
 
 
Additional Copies 
 
Additional copies are available from the Internet at: 
http://www.fda.gov/cdrh/ode/guidance/1586.html.  You may also send an e-mail request to 
dsmica@fda.hhs.gov to receive an electronic copy of the guidance or send a fax request to 
240-276-3151 to receive a hard copy.  Please use the document number (1586) to identify the 
guidance you are requesting. 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
Table of Contents 
 
1.  INTRODUCTION............................................................................................................1 
The Least Burdensome Approach..........................................................................................2 
2.  REGULATORY PATHWAY.........................................................................................2 
3.  BIOCOMPATIBILITY...................................................................................................3 
4.  PRE-CLINICAL EVALUATION..................................................................................3 
A.  Test Protocols.................................................................................................................3 
B.  Test Methods and Conditions........................................................................................3 
C.  Actual Device Evaluated................................................................................................3 
D.  Statistical Analysis.........................................................................................................3 
5.  BENCH TESTING ..........................................................................................................4 
6.  ANIMAL TESTING........................................................................................................4 
A.  Usability.........................................................................................................................4 
B.  Safety.............................................................................................................................4 
C.  Effectiveness..................................................................................................................5 
7.  CLINICAL STUDIES.....................................................................................................5 
A.  Subject Selection............................................................................................................5 
Inclusion Criteria...............................................................................................................5 
Exclusion Criteria..............................................................................................................6 
Onset to Treatment with Neurothrombectomy Devices....................................................6 
Magnitude of the Clot Load:  Location, Size, and Etiology..............................................7 
Control Groups...................................................................................................................7 
 
B.  Initial Assessments.........................................................................................................7 
Angiography......................................................................................................................7 
Imaging Assessments.........................................................................................................8 
Neurologic Evaluation.......................................................................................................8 
 
C.  Follow-Up Assessments.................................................................................................9 
Angiography......................................................................................................................9 
Imaging Assessments.........................................................................................................9 
Neurologic Evaluation.......................................................................................................9 
 
D.  Outcome Measures.........................................................................................................9 
Safety Endpoints................................................................................................................9 
Effectiveness Endpoints...................................................................................................10 
 
8.  MEASURES OF SUCCESS..........................................................................................11 
9.  ALTERNATIVE SOURCES OF CLINICAL INFORMATION..............................11 
  Contains Nonbinding Recommendations 
 
 
Guidance for Industry and FDA Staff  
 
Pre-Clinical and Clinical Studies for 
Neurothrombectomy Devices 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on 
this topic.  It does not create or confer any rights for or on any person and does not operate to 
bind FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the FDA staff responsible for implementing this guidance.  If you cannot 
identify the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance.  
 
1. Introduction  
This guidance document describes FDAs recommendations for pre-clinical and clinical studies 
that involve neurothrombectomy devices conducted to support premarket submissions for 
neurothrombectomy devices indicated for ischemic stroke.  A neurothrombectomy device is 
intended to retrieve or destroy blood clots in the cerebral neurovasculature by mechanical (i.e., 
snare or suction), laser, ultrasound technologies, or combination of technologies.   
This guidance document does not describe all elements required for premarket notification 
(510(k)) submissions, investigational device exemption (IDE), or premarket approval (PMA) 
applications.  This guidance document supplements other FDA publications on 510(k) 
submissions, IDE, and PMA applications and is not a replacement for these documents.  
 
Premarket Notification -510(k) Information  
For general information on 510(k), refer to 21 CFR 807.87, the guidance entitled Format for 
Traditional and Abbreviated 510(k)s1 and Premarket Notification 510(k) in the (Center 
for Devices and Radiological Health) CDRH Device Advice at 
http://www.fda.gov/cdrh/devadvice/314.html.   
 
Investigational Device Exemption Information  
For general IDE information, refer to 21 CFR Part 812 or to the Introduction IDE 
Overview, at http://www.fda.gov/cdrh/devadvice/ide/index.shtml.  
 
Premarket Approval Application (PMA) Information  
For general information about PMA applications, refer to 21 CFR 814 or Application 
Methods, at http://www.fda.gov/cdrh/devadvice/pma/app_methods.html.  
 
                                                 
1 http://www.fda.gov/cdrh/ode/guidance/1567.html  
page 1  Contains Nonbinding Recommendations 
 
FDAs guidance documents, including this guidance document, do not establish legally 
enforceable responsibilities.  Instead, guidance documents describe the Agencys current 
thinking on a topic and should be viewed only as recommendations, unless specific regulatory or 
statutory requirements are cited.  The use of the word should in Agency guidance documents 
means that something is suggested or recommended, but not required.  
The Least Burdensome Approach 
The issues identified in this guidance document represent those that we believe need to be 
addressed before your device can be marketed.  In developing the guidance, we carefully 
considered the relevant statutory criteria for Agency decision-making.  We also considered 
the burden that may be incurred in your attempt to follow the guidance and address the issues 
we have identified.  We believe that we have considered the least burdensome approach to 
resolving the issues presented in the guidance document.  If, however, you believe that there 
is a less burdensome way to address the issues, you should follow the procedures outlined in 
the A Suggested Approach to Resolving Least Burdensome Issues document.  It is 
available on our Center web page at: http://www.fda.gov/cdrh/modact/leastburdensome.html.   
 
2.  Regulatory Pathway 
The regulatory pathway, i.e., premarket notification submission (510(k)), de novo classification, 
or premarket approval application (PMA), for a neurothrombectomy device depends on the 
identification of an appropriate predicate device, the technology of the device, and its indications 
for use.  Mechanical neurothrombectomy devices indicated for retrieval of clots in patients with 
ischemic stroke are regulated as class II devices, product code NRY, requiring 510(k), 21 CFR 
870.1250.   
 
In general, FDA will attempt to review neurothrombectomy devices that are based on methods or 
technologies, other than mechanical, as class II devices.  If we are unable to make a substantial 
equivalence determination from the descriptive characteristics and performance data you submit, 
we will first consider whether de novo classification can provide the proper degree of regulatory 
control.  If so, we will communicate this to you in a not substantially equivalent letter, which 
begins the de novo process.2 
 
Whether de novo classification is appropriate depends, in part, on the risk profile of your device.  
If we are unable to find a device substantially equivalent to a legally marketed predicate device, 
and de novo classification is not appropriate, a premarket approval application may be required.3   
Regardless of the regulatory pathway, you should conduct a thorough evaluation of device safety 
and effectiveness.  The remainder of this document describes the preclinical and clinical studies 
                                                 
2 For information about the de novo classification process, please see New Section 513(f)(2) - 
Evaluation of Automatic Class III Designation, Guidance for Industry and CDRH Staff at 
http://www.fda.gov/cdrh/modact/classiii.html. 
3 See section 513(a) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360c(a)).  See also 
the discussion of PMA applications at http://www.fda.gov/cdrh/devadvice/pma/ and Quality 
System Information for Certain Premarket Application Reviews, Guidance for Industry 
and FDA Staff at http://www.fda.gov/cdrh/comp/guidance/1140.pdf. 
page 2  Contains Nonbinding Recommendations 
 
we generally recommend to ensure a thorough evaluation for all neurothrombectomy devices 
indicated for ischemic stroke.   
 
3.  Biocompatibility  
We recommend you provide biocompatibility testing of the device materials, as described in the 
guidance entitled Use of International Standard Organization (ISO) standard ISO-10993, 
Biological Evaluation of Medical Devices Part 1: Evaluation and Testing.4  We 
recommend you select tests appropriate for the duration and level of contact with your device.  
For a 510(k) submission, if identical materials, with identical material processing, are used in a 
predicate device with the same type and duration of subject contact, you may identify the 
predicate device in lieu of providing biocompatibility testing. 
 
4. Pre-clinical Evaluation 
Pre-clinical evaluation through bench and animal testing helps assess the usability, safety, and 
effectiveness of neurothrombectomy devices indicated for ischemic stroke.  Our 
recommendations for bench and animal testing are described below.  However, depending on the 
design, technology, and performance of your device, we may recommend additional pre-clinical 
evaluation.  
 
A.  Test Protocols 
We recommend the test protocol describe clearly defined test objectives and a rationale in 
support of your belief that the endpoints and pass/fail criteria are meaningful and clinically 
relevant. 
 
B.  Test Methods and Conditions 
We recommend you provide a clear description of the test methodology and actual test 
conditions.  We recommend you conduct pre-clinical testing, where appropriate and feasible, 
in an environment that simulates actual clinical conditions. 
 
C.  Actual Device Evaluated 
We recommend you indicate whether you used a neurothrombectomy device fabricated by 
representative manufacturing process.  Otherwise, we recommend you submit a rationale 
explaining your belief that the device you used in testing will provide a sufficient assessment 
of the final finished device.   
 
D.  Statistical Analysis 
We recommend you provide your sample size justification.  We recommend the results you 
report include, where appropriate:   
  number of samples 
  range of values 
  mean 
                                                 
4 http://www.fda.gov/cdrh/g951.html 
page 3  Contains Nonbinding Recommendations 
 
  standard deviation 
  95% confidence interval.   
 
We also recommend you provide a probability measure that is indicative of the statistical 
significance of any comparisons you make to other devices or control groups. 
 
5. Bench Testing 
We recommend you conduct bench testing to evaluate your devices:  
  maneuverability 
  flexibility 
  durability 
  torque strength.   
We recommend you establish device failure endpoints for each of these characteristics so that 
appropriate information can be conveyed in the instructions for use.   
 
6. Animal Testing 
If you conduct any animal testing, we recommend the testing address usability, (i.e., 
maneuverability and flexibility), safety, and effectiveness, as described below.  The General 
Surgery Devices Branch is available to answer your questions about animal testing.   
 
A. Usability 
We recommend you evaluate the maneuverability and flexibility of the neurothrombectomy 
device in an animal model.  We recommend you evaluate the users ability to reliably deploy 
and use the neurothrombectomy device under clinical conditions in a location in the animal 
(i.e., cerebral neurovasculature) that reflects the indications for use of the device.  We also 
recommend that you use animal testing to evaluate the maximum number of attempts that the 
user can safely retrieve or destroy blood clots. 
 
B. Safety 
Cerebrovascular vessels lack support from adjacent tissues and may pose additional, 
increased safety concerns compared to the peripheral vasculature.  If the device will contact 
or interact with the vessel wall (e.g., laser or suction devices), we recommend you evaluate 
the extent of potential tissue damage the device may cause, preferably in a vessel of 
comparable size in an animal model.   
 
We also recommend you evaluate the vessel wall integrity and monitor blood vessels 
proximal, adjacent, and distal to the clot site during device deployment, clot retrieval or clot 
destruction.  For devices that emit energy, we recommend you monitor any temperature 
changes in the vessel wall and adjacent tissue during use of your device.  
 
We recommend you evaluate the hemorrhagic and thrombogenic potential of the 
neurothrombectomy device.   
 
page 4  Contains Nonbinding Recommendations 
 
To evaluate the hemorrhagic potential of the device, we recommend you perform  
histological evaluation of the vessels and tissues at the site of the clot following use of the 
device.   
 
To evaluate the thrombogenic potential of the device, we recommend you quantify thrombus, 
including number, size, and location proximal, adjacent, or distal to the clot site in a vessel of 
comparable size in an animal model. 
 
C. Effectiveness 
We recommend you demonstrate that the device captures or destroys thrombi of variable 
size, coagulation, and composition (e.g., fibrin, plasminogen, platelet composition).  We also 
recommend you characterize whether your device causes the formation of smaller blood 
clots, either during or after its use. 
We recommend you characterize revascularization success by using injected clots in an 
animal model with a comparison control group.   
 
7. Clinical Studies  
FDA believes that neurothrombectomy devices addressed by this guidance document are 
significant risk devices as defined in 21 CFR 812.3(m)(4).5  Therefore, clinical studies of 
neurothrombectomy devices must be conducted under the Investigational Device Exemptions 
(IDE) regulation, 21 CFR Part 812.  In addition to the requirement for having an FDA-approved 
IDE, sponsors of such trials must comply with the regulations governing institutional review 
boards (21 CFR Part 56) and informed consent (21 CFR Part 50).  The General Surgery Devices 
Branch is available to discuss any questions you have about the development of an IDE protocol 
or to discuss clinical data collected outside the United States.   
 
 Your clinical study should address the recommendations below: 
 
A. Subject Selection 
 
Inclusion Criteria 
We recommend your clinical study enroll patients with evidence of a treatable occlusion, 
such as angiographic evidence of occlusion (Thrombolysis in Myocardial Infarction 
[TIMI] grade 0 flow) or contrast penetration with minimal perfusion (TIMI grade I flow) 
in a vascular distribution consistent with the subjects neurologic findings.  We 
recommend you assess the degree of occlusion with cerebral angiography.  If you plan to 
use a different method, you should contact the General Surgery Devices Branch.   
 
Your inclusion criteria should also specify subjects who present with a National Institutes 
of Health Stroke Scale (NIHSS) 4.  We recommend you employ a randomization 
scheme that will stratify sufficient numbers of subjects by NIHSS score to ensure a 
similar distribution of scores between treatment and control arms.  We believe this 
randomization scheme improves outcome comparisons. 
                                                 
5 See http://www.fda.gov/oc/ohrt/irbs/devices.html#risk. 
page 5  Contains Nonbinding Recommendations 
 
 
Your protocol should specify whether you intend to enroll patients who will be receiving 
approved drug therapy for ischemic stroke, who have failed approved drug therapy for 
ischemic stroke or who are not eligible for approved drug therapy for ischemic stroke.  If 
you intend to study your device in combination with drug therapy that has not been 
approved for this indication for use or route of administration, we recommend that you 
contact the FDA Office of Combination Products to determine jurisdiction.  Further 
information is available at the Office of Combination Products website, available at 
http://www.fda.gov/oc/combination. 
 
Exclusion Criteria 
We recommend you exclude subjects with: 
  neurologic signs that are rapidly improving at the time of randomization or 
treatment 
  NIHSS >30 or coma because subjects in poor neurologic condition have a very 
high mortality and are unlikely to benefit from revascularization and the risk of 
hemorrhage in this population is exceedingly high 
  pregnancy 
  known serious sensitivity to radiographic contrast agents 
  current participation in another investigational drug or device study 
  CT or Magnetic Resonance Imaging (MRI) evidence of hemorrhage on 
presentation 
  CT scan showing hypodensity involving greater than 1/3 of the middle cerebral 
artery (MCA) territory (or suspected stroke region) on presentation 
  CT or MRI evidence of mass effect or intracranial tumor (except small 
meningioma) 
  angiographic evidence of carotid dissection, high grade stenosis that will prevent 
access to the clot, or vasculitis 
  uncontrolled hypertension defined as systolic blood pressure >185 or diastolic 
blood pressure >110 that cannot be controlled except with continuous parenteral 
antihypertensive administration. 
  use of IV heparin in the past 48 hours with PTT > 2.0 
  use of warfarin anticoagulation with INR > 3.0  
  platelet count < 30,000. 
 
Onset to Treatment with Neurothrombectomy Devices 
We recommend initiating treatment using the neurothrombectomy device within 8 hours 
of symptom onset.  If you plan to initiate treatment in subjects more than 8 hours after 
symptom onset, we recommend you explain the delay.  We recommend you record the 
time of symptom onset.   
page 6  Contains Nonbinding Recommendations 
 
The initiation and completion of treatment with the neurothrombectomy device relative to 
the onset of symptoms should fall within the time window defined by the study protocol.  
(Therefore, we recommend you exclude subjects who awaken from sleep with 
symptoms.)  We recommend you record the time from symptom onset to initiation and to 
completion of treatment with the neurothrombectomy device and that you exclude 
subjects treated outside the time window designated by your protocol.  If your trial is 
designed to initiate treatment in subjects more than 8 hours after symptom onset, we 
recommend you discuss your trial design with the General Surgery Devices Branch 
before you submit your IDE.6 
 
Magnitude of the Clot Load:  Location, Size, and Etiology 
To obtain meaningful comparisons of the treated and control population, we recommend 
that you include only subjects with stroke in either the anterior or posterior circulation.  
We are aware of the difficulty in enrolling subjects for either the anterior or posterior 
circulation and will, therefore, consider studies including both types.  If you include both 
types, we recommend that you provide a subset analysis of each type.   
We recommend you assess the source, size, and density of the subjects clot.  These 
assessments can include CT-Angiograms or other techniques to assess clot properties.    
Subject variables that impact the likelihood of an embolic source versus an atheromatous 
or stenotic occlusion are important to document to identify subjects for future study.  
Therefore, we recommend you document the following subject variables: 
  presence of atrial fibrillation or other arrhythmias that predispose to embolic 
strokes 
  results of cardiac echocardiograms 
  the presence and degree of carotid stenosis  
  history of other atheromatous (cardiac) disease.   
 
Control Groups 
We are aware of the difficulty in recruiting subjects for stroke treatment studies, and the 
need to provide control subjects with the current standard of care for ischemic stroke.  
Due to these challenges, we will consider various study designs if they are scientifically 
sound and addresses the relevant safety and effectiveness questions including randomized 
comparison to other legally marketed devices or therapies, or concurrent controls 
comparing treatment arm to standard of care.  We recommend you discuss your study 
design and any statistical issues with the General Surgery Devices Branch before you 
submit your IDE.   
 
B. Initial Assessments 
Initial assessments should include the following measurements. 
Angiography 
                                                 
6 Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI 
trial.  Stroke 2005;36(7):1432-8.  
page 7  Contains Nonbinding Recommendations 
 
We recommend you use an angiographic grading scheme.  Stroke studies published to 
date have used the TIMI grading scale of flow.7,8,9  The TIMI scale has grades 0-3, with 0 
being complete occlusion, and 3 normal flow.  We recommend you include a grading of 
the collateral flow.10  For further discussion on revascularization, refer to Section 12. 
Endpoints.   
Imaging Assessments 
We recommend the initial evaluation include CT scans to rule out intracranial 
hemorrhage or other excluded pathology.  The CT scans should also be used to assess the 
volume of hypodensity.  In centers where MRI scans of subjects with acute stroke are 
used instead of CT scans, MRI scans may be used to demonstrate lack of hemorrhage.   
 
We also recommend you assess subjects with 3 or 4-vessel cerebral angiography.  We 
recommend you document the location of clot and flow (TIMI scale).  We also 
recommend you document the presence or lack of collaterals because this can be an 
important predictor of clinical outcome.11 
 
We recognize that the use of diffusion and perfusion mismatch on MRI imaging, or 
evidence of ischemic penumbra on CT perfusion scans may be useful for selecting 
subjects who are more likely to benefit from revascularization.  If your study is designed 
to evaluate effusion and diffusion mismatch, we recommend that you discuss this with 
the General Surgery Devices Branch before you submit your IDE.  
 
Neurologic Evaluation 
We recommend you evaluate subjects using the NIHSS score before enrollment and 
before treatment begins.  We also recommend you obtain the subjects historical Barthel 
Index and modified Rankin scale (mRS) scores from the subject or caregiver to determine 
pre-event status.  
                                                 
7 G J del Zoppo, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M; the PROACT 
Investigators. PROACT: A Phase II Randomized Trial of Recombinant Pro-Urokinase by Direct 
Arterial Delivery in Acute Middle Cerebral Artery Stroke.  Stroke 1998; 29:4-11. 
8 Intra-arterial Prourokinase for Ischemic stroke.  The PROACT II Study: A Randomized 
Controlled Study.  JAMA 1999;282(21):2003-2011. 
9 Gobin YP, Starkman S, Duckwiler GR, Grobelny T, Kidwell CS, Jahan R, Pile-Spellman J, 
Segal A, Vinuela F, Saver JL.  MERCI 1: a phase 1 study of Mechanical Embolus Removal in 
Cerebral Ischemia.  Stroke 2004;35(12):2848-54. 
10 Higashida RT, Furlan AJ, Roberts H, Tomsick T, Connors B, Barr J, Dillon W, Warach S, 
Broderick J, Tilley B, Sacks D; Technology Assessment Committee of the American Society of 
Interventional and Therapeutic Neuroradiology; Technology Assessment Committee of the 
Society of Interventional Radiology. Trial design and reporting standards for intra-arterial 
cerebral thrombolysis for ischemic stroke. Stroke. 2003 Aug;34(8):e109-37. 
11 Higashida RT, Furlan AJ, Roberts H, Tomsick T, Connors B, Barr J, Dillon W, Warach S, 
Broderick J, Tilley B, Sacks D; Technology Assessment Committee of the American Society of 
Interventional and Therapeutic Neuroradiology; Technology Assessment Committee of the 
Society of Interventional Radiology. Trial design and reporting standards for intra-arterial 
cerebral thrombolysis for ischemic stroke. Stroke. 2003 Aug;34(8):e109-37. 
 
page 8  Contains Nonbinding Recommendations 
 
 
C. Follow-Up Assessments 
Follow-up assessments should include the following measurements. 
 
Angiography 
We recommend all subjects have angiography to assess the extent of restoration of flow 
immediately following the procedure.  We recommend an independent radiologist review 
all angiograms and any other imaging used to evaluate restoration of flow.  Independent 
scoring of the TIMI grade is important when follow-up angiography is used in efficacy 
analyses.  
 
Imaging Assessments 
We recommend you obtain CT scans within 24 hours after neuro-thrombectomy, and at 
discharge to assess for hemorrhage or other events.  We also recommend you obtain 
follow up MRI scans, CT scans, or other imaging assessments at 30 and 90-day follow-up 
time points.  We recommend you document the occurrence and rate of all asymptomatic 
and symptomatic hemorrhages.  We also recommend you obtain CT scans immediately 
after any neurologic decline that occurs within the 90-day follow period.   
 
Neurologic Evaluation 
We recommend you obtain the NIHSS and mRS immediately following the procedure, as 
well as at 24 hours, 7-10 days (or at discharge from hospital), 30 days, and 90 days 
following the procedure.  We recommend a certified examiner or neurologist who is 
masked to the treatment group perform assessments.  We also recommend you obtain the 
NIHSS score, mRS, Barthel Index and Glasgow Outcome Scale scores, or any other 
scores used in the primary outcome measure at 30 and 90-days following the procedure.  
During the study, we recommend you document the severity of any subject experiencing 
a neurologic deterioration with the NIHSS. 
 
D. Outcome Measures 
Outcome measures should include the following measurements. 
 
Safety Endpoints 
We recommend you record and report all adverse events, regardless of whether you 
believe they are device-related, for all subjects, including those excluded based on 
angiographic findings for adverse events for 24 hours, or until alternative stroke 
treatment is initiated, whichever comes first. 
 
The adverse events recorded should include:   
  failure to deploy the device or remove the clot  
  perforation, dissection or other damage to the vessel wall 
  vessel rupture 
  hemorrhage, including subarachnoid hemorrhage from vessel injury  
page 9  Contains Nonbinding Recommendations 
 
  hemorrhagic transformation of the treated stroke 
  thrombus formation proximal, adjacent, or distal to the clot site 
  death from any cause 
  re-occlusion or stroke in other territories previously not involved  
  partial restoration12 
  distal thrombus formation 
  neurologic deterioration. 
 
We also recommend that you categorize the severity of adverse events.  Serious adverse 
events (which preclude treatment success in a subject) should include symptomatic 
intracerebral hemorrhage, arterial dissection, myocardial infarction, and death.  We 
recommend you report asymptomatic hemorrhage rates and new strokes in a previously 
uninvolved anterior or posterior circulation. 
 
We recommend you document separately adverse events related to neurological 
worsening, and we believe that a change in the NIHSS of 4 points should be recorded as 
neurologic deterioration and an adverse event. 
 
We also recommend you document adverse events that occurred during deployment of 
the device and include that information when you identify these events.   
 
Effectiveness Endpoints 
Determination of the primary efficacy endpoint for your device will depend upon its 
design, technology, and indications for use.  Endpoints should address the following 
measurements. 
 
Clinical Endpoints  
Your clinical effectiveness endpoint should be outcome assessments at 30 days and 
90 days by any appropriate, validated neurologic impairment scale, disability 
measure, or handicap scale.  Examples of appropriate measures include the mRS, 
NIHSS score, Barthel Index, and Glasgow Outcome Scale.  The selection of 
appropriate clinical endpoints and statistical approaches depends on the device and 
study design. 
 
Imaging Endpoints 
We recommend you record revascularization success using TIMI grading of flow 
before and after treatment with your device.  Revascularization success should be 
defined as establishment of TIMI grade II or III flow in all vessels on angiography 
following the procedure.  We also recommend you assess the reproducibility of any 
technique in your study to assess infarct volume and include an appropriate control 
group to validate this surrogate endpoint.  We believe size of infarct on CT as a 
                                                 
12 Treatment of Basilar Artery Embolism with a Mechanical Extraction Device. Stroke 
2002;33:2232-2235. 
page 10  Contains Nonbinding Recommendations 
 
surrogate endpoint has not been validated, however, it may be appropriate as a 
secondary surrogate endpoint. 
 
8. Measures of Success 
Definition of study success depends on the primary efficacy measures you select.  For studies 
using clinical outcomes using mRS, we recommend you define success as a significantly 
increased number of subjects having a good (score of 0-2) outcome compared to untreated 
controls, or equivalent outcome compared to treatment with other efficacious devices or 
therapies.  We recommend you measure safety success in comparison to the control (equivalence 
or superiority).  The primary safety and efficacy endpoints should include an analysis of intent-
to-treat subjects, treated subjects, and observed subjects.   
 
9. Alternative Sources of Clinical Information  
If you believe published reports may be adequate to support safety and effectiveness of your 
device, you may submit them for our review.13 
 
                                                 
13 See the guidance, The Least Burdensome Provisions of the FDA Modernization Act of 
1997: Concept and Principles; Final Guidance for FDA and Industry at 
http://www.fda.gov/cdrh/ode/guidance/1332.html. 
page 11