Contains Nonbinding Recommendations  
Clinical Considerations for  
Investigational Device  Exemptions  
(IDEs) for Neurological Devices  
Targeting Disease  Progression and 
Clinical Outcomes  
Guidance  for Industry and Food and 

Drug Administration Staff 
 
  
Document  issued on November 7, 2016.  
 
The draft  of this document was issued  on  March  7, 2016.  
 
For questions about this document, contact the  Neurostimulation Devices Branch at 301-796
6610. 
 
 
 
 
 
 
 
  U.S. Department of  Health and Human Services  
Food  and Drug Administration  
Center for Devices and Radiological Health  
Office of Science and Engineering Laboratories  
Office of Device Evaluation  
Division of Neurological and Physical  Medicine Devices  
Neurostimulation Devices Branch   Preface 
 
 
 
Public Comment  
You may submit electronic comments and suggestions  at any time for Agency  consideration to  
http://www.regulations.gov . Submit written comments to the Division of Dockets Management, 
Food and Drug Administration, 5630 Fishers  Lane, Room 1061, (HFA-305), Rockville, MD 
20852. Identify all comments with the docket number [FDA-2016-D-0539].  Comments may not be  
acted upon by the Agency  until the document is next revised or updated.  
 
 
Additional Copies  
Additional copies are  available from the  Internet. You may  also send an e-mail request to  
CDRH-Guidance@fda.hhs.gov  to receive a copy  of the guidance. Please use the document  
number 1500021 to identify  the guidance you are requesting.  
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   Table of Contents 
 
 
I. Introduction  ................................................................................................................................. 4 
 
II. Scope  .......................................................................................................................................... 5 
 
III. Clinical Study Considerations................................................................................................... 5 
 
A. Biological Markers and Clinical Endpoints  .................................................................... 6 
 
1. Biomarker Tests  .................................................................................................... 6 
 
2. Clinical Outcome Assessments  ............................................................................. 7 
 
  B. Trial Designs: Study  Approaches and  Limitations  ......................................................... 7 
 
C. Investigational Plans  ....................................................................................................... 8 
 
  D. Safety  .............................................................................................................................. 9 
 
  E. Benefit-Risk Considerations ............................................................................................ 9 
 
IV. Informed Consent Documents  ................................................................................................ 10 
 
V.  Labeling  ................................................................................................................................... 11 
 
A. Indications for Use  ........................................................................................................ 11 
 
B. Warnings and Precautions  ............................................................................................. 11 
 
 
3 
  Clinical Considerations for Investigational 

Device Exemption (IDEs) for Neurological
  
Devices Targeting Disease Progression and
  
Clinical Outcomes 
 
Guidance for Industry and Food and Drug  

Administration Staff 
 
This guidance represents the current thinking of the Food and Drug Administration  (FDA or  
Agency) on this topic.  It does  not establish any rights for any person and is not binding on  
FDA or the public.  You  can use an alternative approach if  it  satisfies the requirements of the  
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff  
or Office responsible  for  this guidance as listed on the title page.  
 
I. Introduction  
The U.S. Food and Drug  Administration (FDA)  recognizes the value of medical device 
innovation to address unmet clinical needs and improve patient care, particularly, when novel  
treatments may revolutionize how neurological diseases or  conditions  are treated. FDA 
developed this guidance to assist sponsors  that intend to submit an investigational device  
exemption (IDE) to the  FDA to conduct clinical trials  on medical devices targeting  neurological  
disease progression and clinically  meaningful patient centered outcomes.  
Medical devices intended to slow, stop, or reverse  the effects of neurological  disease 
(neurological devices)  face challenges with regard to collecting safety and  efficacy data in a 
clinical study, when less  invasive pharmacotherapy  approaches may be better understood or  
more-well accepted in the clinical community.  The Center for Devices and  Radiological Health  
(CDRH) is issuing this guidance for  Industry and FDA staff to assist  in considering the benefits  
and risks  of medical devices that  target either  the cause  or progression of the neurological 
disorder or condition such as Alzheimers disease, Parkinsons Disease,  or  Primary Dystonia, 
rather than their symptoms,  and  importantly, address  an unmet medical need of the patient.     
FDA believes that  neurological devices intended to slow disease progression and improve  
clinical outcomes that are meaningful to patients  may represent  a revolutionary option for  
patients. This guidance provides considerations for  the research and development  of such 
devices, as well as  FDA review considerations to aid in the promotion of  this innovative sector  
of technology.  
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  We recommend that  you use this document to help determine  the types of data that may be 
needed to support an IDE application and to help in the design of clinical trials.  The clinical  
considerations mentioned in the guidance represent FDAs current thinking based on the  
information available at this time.   For this reason, we strongly suggest that sponsors who wish 
to conduct such studies  submit a Pre-Submission to facilitate discussion of  pre-clinical test 
protocols, clinical trial designs, and proposed indications for use.  For additional information, 
please see the guidance document, Request for Feedback on Medical Device Submissions: The  
Pre-Submission Program and Meetings with Food and Drug Administration Staff  
(http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocumen 
ts/ucm311176.pdf). 
 
FDA's  guidance documents, including this guidance, do not establish legally  enforceable  
responsibilities. Instead, guidance documents describe the Agency's current thinking on a topic  
and should be viewed only  as  recommendations, unless specific regulatory  or statutory  
requirements are  cited. The use of the word should in Agency  guidance means that something is  
suggested or recommended, but not required.  
 
II. Scope  
This guidance is intended to apply to neurological medical devices that  are  designed to slow, 
stop, or reverse the progression of disease  and result in clinically meaningful patient outcomes. 
This guidance provides  general study design considerations for  clinical trials that investigate  
neurological devices using  biological markers and  clinical outcome assessments.  
 
III. Clinical Study  Considerations  
The use of intermediate clinical endpoints, surrogate endpoints, and/or  biomarker tests can  
contribute to device development, regulatory evaluation, and ultimately, an assessment of the  
benefits and risks associated with a device on  a shorter time scale.   For purposes of this  
guidance,  CDRH defines intermediate clinical endpoints, surrogate endpoints and biomarkers as  
follows:  
An intermediate endpoint is itself a clinical endpoint concerning a symptom or measure  
of function that is not the ultimate outcome of the  disease. Improvement according to an 
intermediate endpoint is of value to patients even if this does not lead to reduced 
morbidity or mortality.  An intermediate endpoint may  also be a clinical endpoint 
measured  at an earlier time point than has historically been  accepted. A treatment effect  
shown by  an intermediate endpoint may also be taken as reason to expect a  favorable 
ultimate outcome; in this  sense, the intermediate endpoint plays the role of  a surrogate.  
A surrogate  endpoint is a measurement used in trials as a substitute for a  clinical 
endpoint, and is expected to reflect  clinical outcomes based on epidemiologic, 
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  therapeutic, pathophysiologic, or other scientific evidence. For example, blood pressure  
measurements are sometimes used as endpoints in trials of antihypertensive therapeutics,  
and as a surrogate  for clinical endpoints of stroke, myocardial infarction, or mortality.   
A biomarker is a characteristic that is objectively  measured  and evaluated  as an indicator  
of normal biologic processes, pathogenic processes, or responses to a therapeutic  
intervention. A biomarker can be  a physiologic, pathologic, or anatomic characteristic or  
measurement that relates  to an aspect of normal or  abnormal biologic  function or process.  
However, challenges remain  with use of these metrics.  Identifying meaningful endpoints that  
measure the  rate of progression of a neurological disease  such as  Alzheimers disease,  
Parkinsons Disease, or  Primary Dystonia, especially  over short periods of time (e.g., on the  
order of  weeks or months)  such as during a clinical  trial  can be subtle and difficult to assess.  
Similarly, biological markers may not be accompanied by  clinically meaningful observable  
changes. These considerations become especially important when patients forgo currently  
approved treatments in earlier stages of disease, and in some cases undergo a more invasive  
treatment, when less invasive pharmacotherapy treatments exist and may be better understood.  
This guidance is intended to leverage advances in the state of science and  facilitate more 
efficient device development  and  regulatory evaluation to promote innovative devices to market  
that are reasonably safe and effective.    
A.  Biological  Markers  and Clinical Endpoints  
Biomarker tests  that rely  on biological  imaging  assessments (e.g., MRI) have  been  
proposed as candidates  for measuring disease progression.  However, changes  in any 
specific imaging modality  alone may not  represent a fundamental change in the 
underlying  cause or  progression of a  given disease  because anatomical  changes do not  
always correlate with  neurological  disease progression  or more importantly,  clinically 
meaningful benefits to the patient. Nevertheless, clinically meaningful outcomes  may 
require longer periods of  time to evaluate (e.g., years). Therefore, both could provide  
important evidence  for medical devices that target  neurological disease cause or 
progression and address an unmet clinical need.  
1.  Biomarker Tests  
Biomarker tests can objectively measure and evaluate normal biologic processes,  
pathogenic processes, or  responses to a therapeutic intervention. Neurological  
biomarkers may include biological proteins, neurotransmitters, amino acids and 
metabolites in the blood, cerebrospinal fluid, or brain parenchyma. In the  context of  
neurological disease, a biomarker  test would measure the physiologic response (i.e., 
neurological biomarkers)  to a therapeutic intervention. When biomarkers are chosen 
as a metric, there should be well established evidence and agreement in the clinical  
community that the chosen biomarker  test  reflects a characteristic that is important to  
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  the underlying disease process and that it is associated with a clinically meaningful 
outcome  measure.  It is therefore important that supporting studies for the validation  
of biomarker  tests used in previous clinical trials  be included in the proposals  
submitted.  The FDAs  Medical Device Development Tools (MDDT) program  is one  
way to qualify tools (e.g., biomarker  test) that medical device sponsors  can use in the  
development and evaluation of medical devices  
(http://www.fda.gov/medicaldevices/scienceandresearch/medicaldevicedevelopmentt 
oolsmddt/default.htm). The context of use depends on the product area, the stage of  
medical device development, and the role of the tool in device  evaluation.  
 
2.  Clinical Outcome Assessments  
Clinical outcome assessments should consist of  direct  quantitative  measurement of  
the effect of a treatment  upon disease progression and its impact upon the patient.  
Clinical outcome assessments include patient-reported, clinician-reported, and 
observer-reported outcomes such as  symptom reduction, decreased need for  
medication, or improvement in functional and quality of life measures. However,  
changes in the clinical features of a neurological disease may only  represent the 
symptomatic effect of an  intervention and this should be considered when designing a  
study (e.g., concurrent  use of biomarker  tests  to objectively measure and evaluate a 
treatment may also be  appropriate). The patient population, the nature of  the 
underlying  condition, and how they  will be studied over time should be considered 
when developing  clinical effectiveness endpoints. Any rationale for use of  a specific  
clinical outcome assessment should address the above points. Additionally, 
investigational treatment approaches should incorporate standard care regimens  or 
evaluate the  investigational device  compared to standard care regimens, including  
trials designs that involve symptomatic treatment  so patients may  continue  to treat 
their underlying conditions. The labeling of the device should be consistent with the  
manner in which it was studied. 
 
B. Trial Designs: Study Approaches and Limitations  
Distinguishing between symptomatic and  disease-altering  treatments  may be  challenging, 
since a positive  outcome  in one (symptomatic benefit) may or may not be  related to the  
other (treatment of the underlying disease or  condition). Study designs should aim to  
distinguish between symptomatic  benefit(s)  and  disease-altering benefit(s)  that slow 
disease progression and quantify the magnitude of such benefits in terms of  biomarkers  
and clinical outcome assessments. In some cases,  studies may be prolonged due  to  the 
desire to understand disease progression in the target patient populations where other  
therapies  exist and have proven effectiveness.  
 
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  Depending on the study  objectives, trial designs  may be considered  for determining  
whether or not  a device can slow the progression of a neurological  disease  by using  
biomarker tests  and providing clinical outcome assessments  for patients. FDA advises  
early engagement with CDRH through the Pre-Submission process to obtain more  
detailed feedback  for a particular device and related trial designs intended to target  
disease progression and clinical outcomes.  
 
C. Investigational Plans  
An  IDE application must include the complete investigational plan or, where appropriate, 
a summary of the investigational plan (21 CFR 812.20(b)(2)). Investigational plans  must 
also include a description of the device  and its important components (21 CFR  
812.25(d)).  
 
A written overview describing  all anticipated phases of the clinical investigation (e.g., 
feasibility and pivotal study stages) should be included, outlining the studies planned at  
each phase and describing any plans to pool data from more than one phase. Specifically, 
a detailed description of the initial feasibility study (i.e., study to define clinical metrics  
or device design)  should be provided, including an overview of later phase  studies, if  
these studies are already  in the planning stages.  
 
For each planned clinical  study, the following should be provided:  
 	  the proposed indications  for use, which should include the target population;  
 	  the study type (e.g., pivotal, expansion [i.e., continuation of  a feasibility or  pivotal 
study], or  feasibility trial);  
 	  the design of the study, including objectives, any  masking, randomization, and 
controls  (e.g., best medical management, delayed  time-to-treatment in the control  
arm in comparison to active treatment);  
 	  the total time planned for subject follow-up;  
 	  the number of subjects  you plan to enroll (sample size);  
 	  the number of investigational sites, both inside and outside the U.S.;  
 	  the subject inclusion and exclusion criteria;  
 	  primary safety  and effectiveness endpoints described as specific objective clinical 
targets;  
 	  a study plan detailing tests and testing methodologies  you plan to test in the  
subjects;  
 	  a schedule/time table of  all clinical tests to be performed for pre- and post
operative evaluation of the subjects. We recommend you evaluate subjects at  
intervals that are  appropriate for distinguishing between symptomatic and disease 
progression effects; and  
 	  the participating investigators, if known.  
 
 
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D. Safety 
Due to the potential risk  of participating in a  medical device study evaluating disease 
progression and related  clinical outcome assessments, examining patient safety  is 
particularly  important. Surgical complications  (if any) and perioperative  as well as  
longer-term adverse events should be  captured. The choice of a primary  safety endpoint  
and tracking potential adverse events will depend on the device design and the patient  
population for which the  device  is indicated. Furthermore, there  should be a clearly  
delineated protocol of reporting  and adjudicating  adverse  events, including mortalities  
related or not related to the  studys treatment and/or procedure, to the Data and Safety  
Monitoring Board (DSMB), Institutional  Review Board (IRB)  and/or FDA.  In cases  
where a medical device may  already be currently  marketed, when possible, safety 
information should be leveraged when studying the device  for a new  indication.  
 
A risk analysis should also be part of  any study, including steps to mitigate  risks as well 
as  identify the most likely  types of  adverse events and acceptable levels for the most  
probable and the most serious adverse  events.   
E. Benefit-Risk Considerations  
FDA recommends using  a benefit-risk framework to facilitate the incorporation of  
evidence  and knowledge  from different domainsclinical, nonclinical, and patient  
perspective  to support  a comprehensive, balanced decision-making approach. The  
framework should focus  on device technology, relevant facts, uncertainties, and key areas  
of judgment to add clarity  and predictability to the regulatory process.  
 
FDA  may approve an  IDE application where only a subset of the eligible study subject  
population would accept  the risks as weighed against the benefits, provided there is  
enough information and an adequate informed consent process in place for study patients  
to make informed decisions.  
 
It is important to acknowledge that individual patient preferences vary, and that a patient  
may not assign the same  values to various risks and anticipated benefits as their  
physician, family member, or other individual. Furthermore, patient  preferences vary,  
both in preferred modality  of treatment/diagnostic procedure (often devices are one  
option to be considered in a treatment care path which may include surgery or  
medication), as well as in risk tolerance. Some patients are willing to take on higher  risks  
to potentially achieve a small benefit, whereas others are more risk  averse.  In  certain  
circumstances, some patients may be willing to participate in clinical studies that offer no  
or limited direct benefit to subjects, but have anticipated societal benefits in  advancing  
medical science.   
 
9 
  FDA may disapprove an IDE application if there is reason to believe that the risks to the  
subjects outweigh the anticipated benefits to the subjects and the importance of the  
knowledge to be  gained.1  Assessment of benefits and risks should not necessarily be  
made in comparison to the most technologically  advanced alternative but rather to 
commonly used therapies and treatments.  
 
The factors considered when making benefit-risk determinations of medical device 
submissions seeking premarket approval or  de novo  classification are detailed in  
Guidance for Industry and Food and Drug Administration Staff - Factors to Consider  
When Making Benefit-Risk Determinations in Medical Device Premarket  Approval and 
De Novo Classifications  
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc 
eDocuments/UCM517504.pdf?source=govdelivery&utm_medium=email&utm_source=g 
ovdelivery).  FDA reviews these submissions to  determine whether the device will have  
the effect it purports or is represented to have under the conditions of use prescribed,  
recommended, or suggested in the labeling of the  device. 2   FDA staff review  this  
information and determine whether the probable benefits of the device outweigh its  
probable risks. In the  context of medical devices targeting neurological disease 
progression, the potential long term benefit of using a neurological device to slow the  
progression of disease is a  significant factor to consider. At the same time,  patients who  
forgo currently approved treatments in earlier stages of disease, and in some cases  
undergo a more invasive  treatment, when less invasive pharmacotherapy  treatments exist 
and may be better understood, potentially take on greater risk(s) in managing their  
disorder or condition. FDA recognizes that patient  tolerance for risk  for potential benefit 
will vary depending on a  number of factors, including the nature of their  disease or  
condition and the availability of  existing treatments, as  well as the risks and benefits of  
the proposed intervention. FDA encourages any sponsor that  is  considering developing  
such devices to have early  interaction with the appropriate  FDA review division. 
Assessing  probable benefits and probable risks is an essential part of  FDAs evaluation of  
devices  targeting neurological disease progression and clinical  meaningful patient 
centered outcomes.  
 
IV. Informed Consent Documents  
Clinical investigations are required to comply  with 21 CFR parts 50 and 56 regarding informed 
consent and IRB review  when the data support applications or submissions to FDA. Informed 
consent documents provide potential participants  adequate information to consider when 
deciding  whether or not  to participate. FDA believes that, in most cases, neurological devices  
targeting the progression of disease  are significant risk devices as defined in 21 CFR 812.3(m).  
 
                                                           
1  21 CFR 812.30(b)(4). 
   
2  Section 513(a)(3)(A) of the Federal Food,  Drug, and  Cosmetic  Act  (FD&C Act).
  
10 
  Sponsors intending  to  study the safety and  effectiveness of  these devices in  a clinical  
investigation in the United States must therefore submit an  IDE  application to FDA and obtain  
IRB approval for their studies (21 CFR 812.2). Your  IDE application must include a copy  all  
information to be provided to subjects to obtain informed consent (21 CFR 812.20(b)(11)). In 
your application, we  recommend that  you explain your method of administering the informed 
consent documents.  
 
Your  informed consent documents must contain the elements specified in 21 CFR 50.25.  We 
recommend that an  informed consent document  for a neurological device targeting the  
progression of a disease  describe:  
 	  the possibility that the proposed treatment may have little or no effect upon halting or  
delaying the progression of the disease, or could increase rate of progression;  
 	  options for discontinuing participation in the study should the subject be dissatisfied with 
the study; and  
 	  the potential need for long-term follow up to evaluate the effect of the treatment. 
 
V. Labeling  
Investigational plans are  required to include  copies of all labeling, including patient information,  
for the device (21 CFR 812.25(f)). Labeling of investigational medical devices must comply  with  
21 CFR 812.5.  
 
A.  Indications  for Use  
 
The labeling should be consistent with the indications for use statement that identifies the  
intended patient population. For  neurological devices targeting the progression of a 
disease and clinical outcomes, the target population should be a disease population that  
may substantially  benefit from using the device  and early onset disease populations may  
present  one population of candidates to study disease progression and its impact on  
patients. 
 
B.  Warnings and Precautions  
 
The labeling must describe all relevant hazards, adverse effects, interfering substances or  
devices, warnings, and precautions (21 CFR 812.5(a)). For  example, your labeling should 
alert users to potentially injurious outcomes associated with use or misuse of the device, 
including a lack of clinical benefit, and should describe actions users should take to avoid 
potentially injurious events. 
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