Contains Nonbinding Recommendations
Feasibility and Early Feasibility 
Clinical Studies for Certain Medical 
Devices Intended to Therapeutically 
Improve Glycemic Control in Patients 
with Type 2 Diabetes Mellitus
Guidance for Industry and Food and 
Drug Administration Staff
Document issued on May 6, 2022.
The draft of this document was issued on May 20, 2021.
For questions about this document, contact OHT3: Office of Gastro-Renal, ObGyn, General 
Hospital, and Urology Devices/DHT3A: Division of Renal, Gastrointestinal, Obesity, and 
Transplant Devices at (301) 796-7030.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health Contains Nonbinding Recommendations
Preface
Public Comment
You may submit electronic comments and suggestions at any time for Agency consideration to 
https://www.regulations.gov. Submit written comments to the Dockets Management Staff, Food 
and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. 
Identify all comments with the docket number FDA-2021-D-0131. 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 email request to CDRH-
Guidance@fda.hhs.gov to receive a copy of the guidance. Please include the document number 
19045 and complete title of the guidance in the request. Contains Nonbinding Recommendations
Table of Contents
I.  Introduction ............................................................................................................................. 1 
II.  Background ............................................................................................................................. 1
III.  Scope ....................................................................................................................................... 2
IV.  Clinical Study Recommendations ........................................................................................... 3
A.  Purpose/Objective ............................................................................................................... 4
B.  Study Design and Sample Size ........................................................................................... 4
C.  Study Duration and Follow-up Schedule ............................................................................ 5
D.  Inclusion/Exclusion Criteria ............................................................................................... 6
E.  Patient Demographics ......................................................................................................... 8
F.  Treatment Parameters/Protocol (including post-operative regimen) .................................. 9
G.  Safety Endpoints and Data ................................................................................................ 10
H.  Effectiveness Analysis and Data ....................................................................................... 11
I.  Statistical Analysis Considerations ................................................................................... 12 Contains Nonbinding Recommendations
Feasibility and Early Feasibility 
Clinical Studies for Certain Medical 
Devices Intended to Therapeutically 
Improve Glycemic Control in Patients 
with Type 2 Diabetes Mellitus
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
This guidance document provides recommendations for feasibility and early feasibility clinical 
studies for certain medical devices intended to therapeutically improve glycemic control in 
patients with Type 2 Diabetes Mellitus (T2DM). These medical devices are intended to 
therapeutically reduce glycated hemoglobin (HbA1c) in T2DM patients independent of 
medication (e.g., insulin) delivery.
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, 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.  Background
Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder that is characterized by high blood 
sugar levels, insulin resistance, and relative lack of insulin. In 2020, it was estimated that 10.5% 
1 Contains Nonbinding Recommendations
of the United States (U.S.) population, or roughly 34.2 million Americans, have diabetes and that 
T2DM accounts for 90% to 95% of all diabetes cases.1
Due to the prevalence of T2DM in the U.S., many medical device manufacturers and researchers 
seek to develop therapeutic medical devices that are intended to improve glycemic control in 
patients with T2DM. Historically, there have been several legally marketed medical devices that 
help patients manage T2DM, including medical devices intended to measure or monitor glucose 
(e.g., blood glucose monitors, continuous glucose monitors) or dose and deliver insulin (e.g., 
insulin pens, pumps, syringes). Medical devices that are therapeutically intended to improve 
glycemic control in patients with T2DM are an increasing area of interest. Manufacturers 
frequently request the Agencys feedback regarding feasibility and early feasibility clinical 
studies2 for these medical devices. This guidance represents the Agencys initial thinking on 
feasibility and early feasibility clinical studies for these medical devices. FDAs 
recommendations may change as more information becomes available.
Prior to initiating a pivotal clinical study, or to receive additional feedback on feasibility study 
design, the Agency encourages manufacturers to submit a Pre-Submission to obtain detailed 
feedback on the clinical investigation of medical devices within the scope of this guidance that 
are intended to therapeutically improve glycemic control in patients with T2DM. For more 
information on Pre-Submissions, refer to the guidance Requests for Feedback and Meetings for 
Medical Device Submissions: The Q-Submission Program.3
III.  Scope
The scope of this guidance document is limited to the design of feasibility and early feasibility 
clinical studies of medical devices that are intended to therapeutically improve glycemic control 
in patients with T2DM. Such medical devices include, but are not limited to, neurostimulators, 
and those that mimic or result in anatomical changes similar to those made by bariatric surgical 
procedures, alter the anatomy and/or physiology of the small intestines, or manipulate the 
sympathetic nervous system. 
Clinical investigations of medical devices that measure or monitor blood sugar, calculate or 
deliver insulin and/or glucagon doses (either automatically or manually), assist in islet cell 
therapeutics (e.g., delivery devices), or Software as a Medical Device (SaMD) to improve 
glycemic control in patients with T2DM are all outside the scope of this guidance document. 
1 Center for Disease Control, National Diabetes Statistics Report 2020: Estimates of Diabetes and its Burden in the 
United States, available at www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf.
2 For information on the distinction between feasibility and early feasibility studies, see FDAs guidance 
Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain 
First in Human (FIH) Studies, available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/investigational-device-exemptions-ides-early-feasibility-medical-device-clinical-studies-including.
3 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program.
2 Contains Nonbinding Recommendations
IV.  Clinical Study Recommendations
We recommend you conduct a clinical study to determine the feasibility and safety of any new 
medical device that is therapeutically intended to improve glycemic control in patients with 
T2DM to support initiation of further clinical investigation (e.g., additional feasibility or pivotal). 
The study should generally be conducted under the Investigational Device Exemptions (IDE) 
regulation, 21 CFR part 812, for studies conducted in the U.S. Generally, we believe medical 
devices addressed by this guidance document are significant risk medical devices subject to all 
requirements of 21 CFR part 812. See the FDA guidance titled Significant Risk and 
Nonsignificant Risk Medical Device Studies.4 In addition to the requirements of 21 CFR part 
812, sponsors of such trials of a medical device conducted in the U.S. must comply with 
applicable regulations governing institutional review boards (21 CFR part 56) and informed 
consent (21 CFR part 50). 
When data from clinical investigations conducted outside the U.S. are submitted to FDA for 
these medical devices, the requirements of 21 CFR 812.28 may apply.5 21 CFR 812.28 outlines 
the conditions for FDA acceptance of clinical data from investigations conducted outside the 
U.S. when submitted to support premarket submissions. For more information, see the FDA 
guidance Acceptance of Clinical Data to Support Medical Device Applications and 
Submissions: Frequently Asked Questions.6
Specific recommendations for feasibility and early feasibility clinical studies for medical devices 
intended to improve glycemic control in patients with T2DM are summarized below. These 
study recommendations reflect FDAs current thinking regarding study design for medical 
devices intended to therapeutically improve glycemic control in patients with T2DM.
In providing these recommendations, we often refer to clinical practice guidelines for the 
management of T2DM. For the purposes of this guidance, use of the term clinical practice 
guidelines collectively refers to clinical practice guidelines from the American Diabetes 
Association (ADA),7 American Association of Clinical Endocrinologists (AACE),8 and the 
American College of Endocrinology (ACE).9 FDA believes that the recommendations provided 
in this guidance are consistent with the recommendations made in these clinical practice 
guidelines.
4 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/significant-risk-and-nonsignificant-
risk-medical-device-studies.
5 This applies to data from clinical investigations that began on or after February 21, 2019 and are submitted to 
support a premarket submission, including IDEs, premarket approval applications (PMAs), and 510(k)s.
6 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-clinical-data-support-
medical-device-applications-and-submissions-frequently-asked.
7 American Diabetes Association. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in 
Diabetes - 2020. Diabetes Care 2020;43(Suppl. 1): S98S110.
8 A. J. Garber et al. (2019). Consensus Statement by the American Association of Clinical Endocrinologists and 
American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2019 
Executive Summary. Endocr Pract. 25(1): 69-100.
9 Y. Handelsman et al. (2015). American Association of Clinical Endocrinologists and American College of 
Endocrinology - Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan - 2015. 
Endocr Pract. 21 Suppl 1: 1-87.
3 Contains Nonbinding Recommendations
A.  Purpose/Objective
The objective of an early feasibility study is to evaluate the device design concept with respect to 
initial clinical safety and device functionality in a small number of subjects (generally fewer than 
ten (10) initial subjects) when this information cannot practically be provided through additional 
nonclinical assessments or appropriate nonclinical tests are unavailable. For novel medical 
device technologies with little to no human-based data or an unfinalized device design, we 
recommend that you consider if an early feasibility clinical study is appropriate. For more 
information on early feasibility studies, see FDAs guidance Investigational Device Exemptions 
(IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human 
(FIH) Studies.10 When consistent with the goal(s) of the study, the recommendations made in 
this document should be considered when designing an early feasibility clinical study.
The objective of a feasibility clinical study is to gather initial safety and effectiveness data to 
support initiation of further clinical investigation. FDA recommends that the primary endpoints 
should address safety by collection of all adverse events and effectiveness. For effectiveness, we 
recommend assessing glycated hemoglobin (HbA1c), as this is a widely recognized objective 
measure of glycemic control recommended by ADAs clinical practice guideline and as a 
surrogate for risk of developing complications.11 Other measures of effectiveness can also be 
collected by the study sponsor to help focus further device study.
B.  Study Design and Sample Size
The sample size for your study should consider the phase of medical device development, risk 
profile of the medical device based on similar medical devices and associated procedures, animal 
or bench performance data, and/or information to support any anticipated benefits. As noted 
above, early feasibility studies generally enroll less than ten (10) initial subjects. 
Feasibility and early feasibility clinical studies for therapeutic medical devices that are intended 
to improve glycemic control in patients with T2DM should primarily be designed to collect 
safety data on a medical device. Although these studies are typically not large enough to 
statistically assess device effectiveness, an effectiveness endpoint should be included in the study 
to capture preliminary clinical evidence with respect to glycemic control. Continued inadequate 
glycemic control (i.e., insufficient progress toward glycemic targets in response to the study 
device) in patients with T2DM not only signifies a concern with lack of effectiveness, it also 
presents a significant safety concern, putting the patient at risk for complications associated with 
poor glycemic control (e.g., cardiovascular complications, neuropathy, nephropathy, 
retinopathy).
10 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-
ides-early-feasibility-medical-device-clinical-studies-including.
11 Agiostratidou, Gina, et al. Standardizing clinically meaningful outcome measures beyond HbA1c for Type 1 
diabetes: A consensus report of the American Association of Clinical Endocrinologists, the American Association of 
Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. 
and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care 
40.12 (2017): 1622-1630.
4 Contains Nonbinding Recommendations
FDA recommends that feasibility and early feasibility clinical studies be controlled whenever 
possible. The Agency acknowledges that early feasibility and some feasibility clinical studies are 
not designed for formal hypothesis testing of success criteria; however, descriptive statistics of 
outcomes in treatment and control subjects can help support that the medical device risk is 
appropriate for an anticipated benefit and provide justification for a subsequent and larger 
clinical study. Further, the use of a control group and/or run-in period can clarify if any 
improvements in glycemic control are due to the medical device or due to effects from 
participation in a clinical study in which the subjects may receive increased clinical attention, 
promoting better adherence to medications, and other lifestyle changes. Glycemic control is 
greatly affected by patient behaviors such as diet, exercise, and adherence to medication use, 
which can confound the results of the clinical study, especially in the short-term.
C.  Study Duration and Follow-up Schedule
Both feasibility and early feasibility studies should be designed to include a follow-up period that 
is appropriate for the risk posed and anticipated benefit from medical device use. If the medical 
device requires a surgical, endoscopic, or radiological procedure during use, and/or alters 
anatomy, or otherwise presents high risk to study subjects, FDA recommends for a feasibility 
study to include at least a 12-month follow-up period to evaluate medical device safety and 
effectiveness, including an assessment of the durability of effects on glycemic control.
For both feasibility and early feasibility studies, FDA recommends the following:
 If the medical device may interact with concurrent treatments for T2DM or other medical 
conditions (e.g., alter absorption of medications), assessment and follow-up should 
monitor for such interactions.
 The clinical study protocol should prospectively specify collection of all adverse event 
information at regular intervals, with additional specific assessments of known probable 
medical device- and procedure-related adverse events.
 Baseline and follow-up assessments should include evaluation by a diabetologist or 
endocrinologist.
 The clinical study protocol should state that subjects will be followed until resolution or 
stabilization of any adverse event related to the medical device and/or procedure.
 The clinical study protocol should include any instructions and arrangements for 
unscheduled appointments for management of adverse events.
5 Contains Nonbinding Recommendations
D.  Inclusion/Exclusion Criteria
In general, premarket study populations in regard to disease state, health status, and potential 
comorbidities should be representative of the patient population for which the product is 
intended. However, for feasibility and early feasibility studies where medical device safety and 
treatment effect are not yet known, a narrow patient population as described below may be more 
appropriate depending on the anticipated risk that the medical device and/or medical device-
related procedure(s) pose.
A common consideration for feasibility and early feasibility clinical studies examining the 
potential for improving glycemic control in patients with T2DM is that patient treatment targets 
should be met. The clinical practice guidelines referenced in this guidance recommend the target 
HbA1c of < 7% or 8%, depending upon the patients needs. Some patients may have higher 
HbA1c targets based upon a complex medical history, additional risks from hypoglycemia, 
and/or shortened life expectancy, but depending on the device and study design, patients who are 
at their HbA1c target may not be appropriate for inclusion in a feasibility study. Sponsors should 
justify the inclusion and exclusion criteria they propose for their feasibility or early feasibility 
clinical study.
We recommend that you consider the following for the inclusion/exclusion criteria of your 
feasibility and/or early feasibility clinical study protocol:
  We recommend that the study enroll subjects who can anticipate benefit from escalation 
of care. Thresholds for escalation of treatment should be consistent with clinical practice 
guidelines, as well as clinically appropriate. We recommend the inclusion of patients with 
minimum HbA1c > 7% to 8%, depending on the goals of the study and if it is clinically 
appropriate, considering potential medical device- and/or procedure-related risk.  
 
Similarly, the maximum HbA1c for enrollment should be such that further delay in non-
experimental care, results in risks to the study subject that outweigh the anticipated 
benefit. We recommend that the upper limit for feasibility clinical studies be risk-based 
and not more than an HbA1c of 10%, as patients with an HbA1c greater than 10% are 
generally clinically considered to have uncontrolled glycemia and non-experimental 
treatment escalation is likely in the best interest of the patient.12
  In assessing the patient population for the clinical study, the balance of anticipated 
benefits and risks of the medical device and/or medical device-related procedure to the 
patient should be carefully considered. For example, for patients with good glycemic 
control, especially those on minimal medications, there may be no anticipated benefit 
from participating in the study; however, the patient would be exposed to all the 
increased risks of the study. Furthermore, patients with good glycemic control may not be 
representative of patients who may ultimately benefit from the medical device. This 
could limit the utility of the data from these patients to support future clinical studies. 
12 A. J. Garber et al. (2019). Consensus Statement by the American Association of Clinical Endocrinologists and 
American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2019 
Executive Summary. Endocr Pract. 25(1): 69-100.
6 Contains Nonbinding Recommendations
Therefore, we recommend that you consider the following when developing clinical 
study inclusion/exclusion criteria regarding baseline diabetes therapy:
o  If the medical device and/or medical device-related procedure(s) result in the 
modification of anatomy (e.g., tissue ablation) and/or involve an implant, or 
otherwise presents high risk to study subjects, we recommend that you limit 
enrollment to patients who have failed to reach treatment targets when taking at 
least two non-insulin diabetes medications, one at maximum tolerated dose and 
another at half-maximum dose. You should provide the rationale in your IDE 
application for the acceptable baseline medication management considering the 
study-related risks and previously collected effectiveness data.
o  If the medical device and/or medical device-related procedure(s) do not result in 
modification of anatomy or involve an implant, it may not be as important that 
subjects have failed to reach treatment targets using other diabetes therapies prior 
to study enrollment. Your IDE application should clearly articulate the rationale 
for the acceptable baseline medication management relative to the potential study 
risks.
o  Clinical practice guidelines referenced in this guidance document recommend 
medical nutrition therapy for all people with T2DM. Study subjects should have 
attempted to reach glycemic targets with therapeutic lifestyle changes (e.g., as 
documented in patient medical records) before being subjected to investigational 
medical device-related risk in a clinical study.
 Subjects should have T2DM but be otherwise healthy under optimal medical 
management. We recommend the following inclusion/exclusion criteria considerations 
for T2DM-related comorbidities:
o  If complications from the medical device and/or medical device-related 
procedure(s) may require surgery, subjects with medical conditions that could 
make them unsuitable for surgery or general anesthesia should be excluded.
o  T2DM associated comorbidities should generally be controlled and stable (e.g., 
cardiovascular disease, hypertension, dyslipidemia, nephropathy, retinopathy, 
neuropathy), and inclusion/exclusion criteria should reflect this. For example, we 
recommend that subjects do not have impaired renal function; thus, an estimated 
glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 is recommended. An eGFR 
below this number is associated with subsequent risk of all-cause and cardiovascular 
mortality, kidney failure, acute kidney injury, and chronic kidney disease 
progression.13
13 Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Clinical Practice 
Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Inter., Suppl.2013; 3: 1150.
7 Contains Nonbinding Recommendations
o  Thyroid disorders and other endocrinopathies can affect both the ability to lose 
weight and potentially impact glycemic control. We recommend inclusion of only 
those patients whose endocrinopathy is controlled and stable. For patients with 
primary hypothyroidism, we recommend that thyroid function tests be performed 
to demonstrate adequate control and that you provide the range of acceptable 
thyroid stimulating hormone (TSH) values as a study inclusion criterion. 
 Factors that affect red blood cell turnover may result in a falsely low or high HbA1c and 
adversely affect the interpretation of the clinical study effectiveness measure. This should 
be considered in the protocol. We recommend that you exclude subjects with factors that 
affect red blood cell turnover (e.g., anemia, recent blood transfusion, expect to receive a 
blood transfusion over the duration of the study).
 The inclusion/exclusion criteria should address any considerations that are appropriate for 
risks associated with pre-determined rescue medications that may be offered during the 
study.
 Dietary supplements or herbal preparations may have unknown effects on glycemic 
control, risk of bleeding, cause adverse events, and/or interfere with laboratory testing 
(such as biotin). Therefore, dietary supplement use could affect the interpretation of the 
study results and should be considered in the clinical study protocol. Ideally, these 
substances should not be used during the study.
 Female subjects of childbearing age should have a negative urine or serum pregnancy test 
(at Screening Visit and at the time of the index procedure) and agree to use a reliable 
mechanical or hormonal form of contraception during the study.
 Subjects who are enrolled in the study may be expected to perform blood glucose 
monitoring, record all medications, and provide details of any symptoms or adverse 
events that occur during the study at follow-up visits. Further, medical device-related 
procedures may involve preparation, pain, and/or identification of possible adverse events 
that should be communicated to the study investigator. As such, study subjects, either 
independently or with the assistance of a parent/guardian/care-partner, should be able to 
perform the requirements of the study.
 The inclusion/exclusion criteria should address any considerations for concomitant 
medication use that is appropriate for the risk(s) associated with such medication use.
E.  Patient Demographics
You should describe characteristics of your patient populations that could affect the results of the 
study, including:
 Age, race, and ethnicity;
8 Contains Nonbinding Recommendations
 Sex and gender;14
 Body mass index (BMI); and
 State of T2DM disease (e.g., HbA1c levels).
For more information regarding the evaluation and reporting of age, race, ethnicity, and sex-
specific data in medical device clinical studies, see FDAs guidances Evaluation of Sex-
Specific Data in Medical Device Clinical Studies15 and Evaluation and Reporting of Age-, 
Race-, and Ethnicity-Specific Data in Medical Device Clinical Studies.16
F.  Treatment Parameters/Protocol (including post-operative 
regimen)
A safety monitoring plan should be included in the clinical study protocol to detect and manage 
hypoglycemia or continued uncontrolled hyperglycemia and serious adverse events. This 
management should be integral to the study protocol. The following list should be considered in 
development of your safety monitoring plan. Depending on specific aspects of your medical 
device study, this list may not be exhaustive.
 For a medical device with novel technology and/or with an undefined risk profile, it may 
be appropriate to define stopping rules in the clinical study protocol and/or limit the rate 
at which patients are enrolled to allow for sufficient time for serious adverse events to 
become evident and be reported. Stopping rules should consider outcomes from pre-
clinical studies and adverse events associated with similar medical devices and/or 
medical device-related procedures. For a medical device with initial clinical safety 
information, stopping rules for further studies should be based on the current data.
o  Study stopping rules should be based on the type and number of adverse events 
that would discontinue further enrollment of patients for safety until additional 
mitigation measures can be implemented.
o  The clinical study protocol should include individual patient stopping rules based 
on the safety of the individual. A plan should be in place for pausing or stopping 
treatment and removing all or part of implanted medical devices as would be 
appropriate for the patients short-term and long-term safety. Patients who 
experience study-related adverse events should be followed until the end of the 
study, resolution, or stabilization of the adverse event, whichever is longer.
14 As gender-conforming therapies may have an impact on insulin or other hormones, instances should be noted 
where a persons gender-identity may be different than their sex.
15 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-sex-specific-data-
medical-device-clinical-studies-guidance-industry-and-food-and-drug.
16 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-and-reporting-age-race-
and-ethnicity-specific-data-medical-device-clinical-studies.
9 Contains Nonbinding Recommendations
 The primary goal of the treatment/intervention is to improve glycemic control and 
subjects should be protected from prolonged hyperglycemia. Therefore, for patient safety, 
a medication management plan for those not achieving glycemic control (i.e., adequate 
HbA1c level) should be built into the clinical study protocol. We recommend that 
patients be assessed at least every three months to consider dose escalation and or 
addition of another diabetes medication. If at the three-month period glycemic indices 
have not improved, rescue therapy should be considered. For example, sponsors could 
consider rescue therapy if HbA1c is not < 8%, or the interval improvement has not been 
> 0.5%. At minimum, if at the six-month period the subject has not met treatment targets 
or an HbA1c < 8%, rescue therapy should again be considered. Though HbA1c of 8% is 
above most patients desired target HbA1c, we recommend the 8% limit to initiate rescue 
medication to allow the medical device/procedure to demonstrate its potential therapeutic 
effect, while protecting the subject from prolonged hyperglycemia over the short term. 
How medication will be titrated and used for rescue should be addressed in the protocol 
as this could also confound study results if not controlled as a study variable. Treatment 
algorithms for maintenance of adequate glycemic control may also help prevent losing 
subjects from the study.
 The clinical study protocol should include a pre-determined list of preferred rescue 
medications for study subjects to minimize study variables.
We recommend that you explain in your IDE application which evaluations will be performed to 
address risk associated with any endocrinopathies.
Clinical practice guidelines recommend that medical nutrition therapy be maintained for all 
people with T2DM.17,18 Study subjects should follow a standard lifestyle modification program 
under control of the study.
G.   Safety Endpoints and Data
FDA recommends collection of all adverse events as the safety endpoint. FDA intends to 
consider the number of adverse events, severity of events, medical device design, and patient 
population in assessing the success of a feasibility study.
To ensure robust collection of safety information, adverse events should be:
 Prospectively collected without regard to medical device- or procedure-relatedness;
 Defined using pre-specified, standardized criteria;
17 A. J. Garber et al. (2019). Consensus Statement by the American Association of Clinical Endocrinologists and 
American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2019 
Executive Summary. Endocr Pract. 25(1): 69-100.
18 Y. Handelsman et al. (2015). American Association of Clinical Endocrinologists and American College of 
Endocrinology - Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan - 2015. 
Endocr Pract. 21 Suppl 1: 1-87.
10 Contains Nonbinding Recommendations
 Graded for severity according to a standard adverse event grading system (e.g., Common 
Terminology Criteria for Adverse Events19 or the Clavien-Dindo Classification of 
Surgical Complications20);
 Categorized according to whether they meet the established serious adverse event 
definitions;21
 Assessed for resolution status; and
 Adjudicated by an independent clinical events committee.22
If study subjects used dietary supplements or herbal preparations while under study, we 
recommend that you capture such use, and use of these substances should be discussed in the 
study results.
H.   Effectiveness Analysis and Data
FDA recommends that you collect medical device effectiveness23 data in both early feasibility 
and feasibility clinical studies. We recommend that you assess change in HbA1c as this is a 
widely recognized objective measure of glycemic control. Reduction in HbA1c indicates 
improved glycemic control with T2DM therapy.
We recommend that the HbA1c assay used be specified in the clinical study protocol. HbA1c 
assays do not all have the same performance characteristics, with some being more accurate than 
others. If possible, we recommend use of a National Glycohemoglobin Standardization Program 
(NGSP)-certified assay and/or a laboratory-based HbA1c measurement method that has been 
well-validated for accuracy and precision.
Because rescue medications may be used for subject safety during the study, a comparison of the 
treatment arm to a parallel control arm for the number of subjects on rescue medications to 
achieve glycemic targets can also be considered to support effectiveness. FDA considers the 
ability to achieve glycemic targets with reduction in baseline diabetes medications as a benefit.
19 For more information, see https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
20 Dindo, D., Demartines N., Clavien P.A. (2004). Classification of surgical complications: a new proposal with 
evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 240:205213.
21 For the purposes of this guidance, the term serious adverse event is used consistent with the FDA guidance 
Factors to Consider When Making Benefit-Risk Determinations for Medical Device Investigational Device 
Exemptions, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/factors-
consider-when-making-benefit-risk-determinations-medical-device-investigational-device.
22 For more information, see Establishment and Operation of Clinical Trial Data Monitoring Committees,
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishment-and-
operation-clinical-trial-data-monitoring-committees.
23 For these medical devices, FDA considers the devices ability to therapeutically improve glycemic control to be 
the primary effectiveness measure and is an important indicator of its anticipated benefit to subjects. As such, FDA 
recommends that both feasibility and early feasibility studies include collection of effectiveness data.
11 Contains Nonbinding Recommendations
FDA does not believe that continuous glucose monitoring (CGM) data are presently sufficiently 
accurate to measure the primary effectiveness endpoint for glycemic control. However, as 
secondary effectiveness endpoint data, CGM may provide useful information about the 
effectiveness of the medical device. You should consider the accuracy and reliability of the 
CGM system when considering its role in your clinical study design.
I.  Statistical Analysis Considerations
For both feasibility and early feasibility clinical studies, the safety and effectiveness endpoints 
should be analyzed using an intent-to-treat (ITT) approach. The extent of missing data should be 
reported and justified.
If your study includes a control arm, the safety and effectiveness endpoints should be 
descriptively compared between treatment and control subjects.
12