Contains Nonbinding Recommendations
Draft Not for Implementation
Medical Devices with Indications 
1 
Associated with Weight Loss - Clinical 
2 
Study and Benefit-Risk Considerations 
3 
4   
Draft Guidance for Industry and  
5 
Food and Drug Administration Staff 
6 
7   
DRAFT GUIDANCE 
8 
9   
10  This draft guidance document is being distributed for comment purposes 
11  only. 
12   
13  Document issued on September 15, 2023. 
14   
15  You should submit comments and suggestions regarding this draft document within 60 days of 
16  publication in the Federal Register of the notice announcing the availability of the draft 
17  guidance. Submit electronic comments to https://www.regulations.gov. Submit written 
18  comments to the Dockets Management Staff, Food and Drug Administration, 5630 Fishers Lane, 
19  Room 1061, (HFA-305), Rockville, MD 20852. Identify all comments with the docket number 
20  listed in the notice of availability that publishes in the Federal Register. 
21   
22  For questions about this document, contact OHT3: Office of Gastro-Renal, ObGyn, General 
23 Hospital, and Urology Devices/DHT3A: Division of Renal, Gastrointestinal, Obesity, and 
24 Transplant Devices at (301) 796-7030.
25
26 U.S. Department of Health and Human Services
27 Food and Drug Administration
28 Center for Devices and Radiological Health
29 Contains Nonbinding Recommendations
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Preface
30 
31   
Additional Copies 
32 
33   
34  Additional copies are available from the Internet. You may also send an email request to CDRH-
35 Guidance@fda.hhs.gov to receive a copy of the guidance. Please include the document number 
36 GUI00021016 and complete title of the guidance in the request.
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Table of Contents
38 
39   
40 I.  Introduction ............................................................................................................................. 1 
41  II.  Background ............................................................................................................................. 2 
42  III.  Scope ....................................................................................................................................... 3 
43 IV.  Clinical Performance Testing Considerations ........................................................................ 4 
44  Study Design ....................................................................................................................... 5 
45    Study Duration and Follow-up Schedule ............................................................................ 6 
46   Inclusion/Exclusion Criteria...............................................................................................6
47 Patient Demographics.........................................................................................................7
48 Treatment Parameters/Protocol...........................................................................................8
49 Safety Endpoints and Data..................................................................................................8
50 Effectiveness Endpoints and Data......................................................................................9
51 Adverse Events.................................................................................................................10
52 Statistical Analysis Considerations...................................................................................12
53 (1) Sample Size...............................................................................................................12
54 (2) Analysis Methods......................................................................................................12
55 (3) Missing Data.............................................................................................................13
56 (4) Subgroup Analyses...................................................................................................14
57 Pediatric Studies................................................................................................................14
58 V. Benefit-Risk Considerations.................................................................................................19
59 Benefit-Risk......................................................................................................................19
60 Use of Modified Clavien-Dindo to Assess Risk...............................................................21
61 Balancing Weight Loss and Adverse Events for an Indication of Weight Loss...............22
62
63 Contains Nonbinding Recommendations
Draft Not for Implementation
Medical Devices with Indications 
64 
Associated with Weight Loss - Clinical 
65 
Study and Benefit-Risk Considerations 
66 
67   
Draft Guidance for Industry and  
68 
Food and Drug Administration Staff 
69 
70   
71  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
72  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person 
73  and is not binding on FDA or the public.  You can use an alternative approach if it satisfies 
74  the requirements of the applicable statutes and regulations.  To discuss an alternative 
75  approach, contact the FDA staff or Office responsible for this guidance as listed on the title 
76  page.  
77   
I.  Introduction 
78 
79  This draft guidance document provides recommendations regarding clinical study design for 
80  devices with indications for use associated with weight loss, and also includes discussion on how 
81  FDA considers the benefit-risk analysis to support such indications.1 Examples of indications 
82  associated with weight loss include indications for weight loss, weight reduction, weight 
83  management, or obesity treatment in patients who are overweight or have obesity.2 Due to the 
84  wide variety of device designs, among other things, there can be variability in the demonstrated 
85  weight loss and risk associated with these devices. The recommendations reflect current review 
86  practices of premarket submissions (e.g., Premarket Approval (PMA) Applications, 
87  Investigational Device Exemption (IDE) Applications, Premarket Notifications (510(k)s), and 
88  De Novo classification requests) for these devices and are intended to promote consistency and 
89  facilitate efficient review of these submissions. 
90   
91 In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
92 Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
93 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
1For further information on how FDA considers benefit-risk factors when evaluating substantial equivalence in  
510(k)s generally, see https://www.fda.gov/regulatory-information/search-fda-guidance-documents/benefit-risk-
factors-consider-when-determining-substantial-equivalence-premarket-notifications-510k.
2For further information on weight-loss and weight-management devices, see also https://www.fda.gov/medical-
devices/products-and-medical-procedures/weight-loss-and-weight-management-devices. 
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94  the word should in Agency guidances means that something is suggested or recommended, but 
95 not required.  
96 
II.  Background 
97 
98  Prior to issuing this draft guidance, FDA requested public comment on a concept for balancing 
99  the benefit of weight loss with the risks of adverse events in a discussion paper (September 
100  2019).3 FDA considered public comments and incorporated the feedback as appropriate in 
101  developing this draft guidance. The discussion paper continued FDAs efforts to be transparent 
102  and informative about how we regulate devices with indications associated with weight loss. 
103  
104  Additionally, FDA has previously engaged stakeholders regarding how we can help to ensure 
105  patients have access to appropriately safe and effective devices indicated for weight loss:4 
106    On November 16-17, 2005, FDAs Pediatric Advisory Committee held a public 
107  meeting on Clinical Trial Design Issues for Pediatric Obesity Devices.5 
108    On October 16-18, 2011, FDA, Dartmouth Device Development/GI at Dartmouth 
109  Medical School, and the Obesity, Metabolism and Nutrition Institute at Massachusetts 
110  General Hospital co-sponsored a two-day workshop, Device Development in 
111  Obesity and Metabolic Disease (DDOMD).  
112    On May 10-11, 2012, the Gastroenterology-Urology Devices Panel of the Medical 
113  Devices Advisory Committee discussed general issues related to obesity treatment 
114  devices and provided clinical study design recommendations to better evaluate the 
115 safety and effectiveness of obesity treatment devices.6
116  In 2013, FDA published a benefit-risk assessment paradigm that could provide an a 
117 priori tool for systematic assessment of the risks associated with the devices intended 
118 for treatment of obesity and to suggest appropriate levels of benefit for devices with 
119 different risk levels.7
3See Docket No. FDA-2019-N-4060 (https://www.regulations.gov/docket?D=FDA-2019-N-4060).
4See also https://www.fda.gov/medical-devices/weight-loss-and-weight-management-devices/fda-activities-weight-
loss-and-weight-management-devices.
5FDA Pediatric Advisory Committee, Development of Trials to Assess the Safety and Efficacy Relevant to Scientific 
and Ethical Issues Surrounding Trials for Pediatric Devices for Weight Loss. Gaithersburg, MD. Meeting materials 
can be accessed at https://wayback.archive-it.org/7993/20170403222257/https://www.fda.gov/ohrms/dockets/
ac/oc05.html#Pediatric.
62012 Materials of the Gastroenterology-Urology Devices Panel can be accessed at https://wayback.archive-
it.org/7993/20170113191551/http:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevic
es/MedicalDevicesAdvisoryCommittee/Gastroenterology-UrologyDevicesPanel/ucm286235.htm.
7Lerner, H., Whang, J., & Nipper, R. (2013). Benefit-risk paradigm for clinical trial design of obesity devices: FDA 
proposal. Surgical endoscopy, 27(3), 702-707.
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120   In 2015, FDA worked with the Research Triangle Institute Health Solutions (RTIHS) 
121  to conduct the first national benefitrisk patient preference study to provide 
122  information on patient risk tolerance for weight loss devices.8 
123    On June 28, 2018, FDA held a listening session with patients who have used FDA-
124  approved devices with indications associated with weight loss. 
125   
126  FDA refers the reader to the Q-Submission Program throughout this guidance document. For 
127  details on the Q-Submission Program, refer to the guidance Requests for Feedback and 
128  Meetings for Medical Device Submissions: The Q-Submission Program.9 
129   
III.  Scope 
130 
131  The scope of this document is limited to devices with indications for use associated with weight 
132  loss, including weight loss, weight reduction, weight management, or obesity treatment in 
133 patients who are overweight or have obesity. This includes the existing product codes listed in 
134 Table 1below:
135
136 Table 1. Existing product codes within the scope of this guidance
Product  Product Code Name Regulation Number
Code
LTI Intragastricimplant for morbid obesity Not applicable10
OYF Aspiration therapy system Not applicable11
PIM Neuromodulator for obesity Not applicable12
ONY Oral removable retainer for weight  21 CFR 876.598113
management
QFQ Ingested, Transient, Space Occupying  21 CFR 876.598214
Device For Weight Management 
And/Or Weight Loss
QTD Endoscopic Suturing Device For  21 CFR 876.598315
Altering Gastric Anatomy For Weight 
Loss
8Ho, M. P., Gonzalez, J. M., Lerner, H. P., Neuland, C. Y., Whang, J. M., McMurry-Heath, M., Hauber, A.B. & 
Irony, T. (2015). Incorporating patient-preference evidence into regulatory decision making. Surgical endoscopy, 
29(10), 2984-2993.
9https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-
medical-device-submissions-q-submission-program.
10This is a postamendments class III device.
11Ibid.
12Ibid.
13This classification regulation includes special controls. See 21 CFR 876.5981(b).
14This classification regulation includes special controls. See 21 CFR 876.5982(b).
15This classification regulation includes special controls established in the reclassification order, available at 
https://www.accessdata.fda.gov/cdrh_docs/pdf21/DEN210045.pdf. The publication of this classification in the 
Federal Register and codification in the Code of Federal Regulations are currently pending.
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137 
138  Although the product codes listed above are current as of the date of issuance of this draft 
139  guidance, new product codes or classification regulations may be created over time and could 
140  fall within the scope of this guidance.  We recommend that you reference the product code 
141  database (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm) or 
142  contact OHT3: Office of Gastro-Renal, ObGyn, General Hospital, and Urology Devices if you 
143  are uncertain whether this guidance applies to your device and the product code for your device 
144  is not already captured in this guidance. 
145   
146  Some of the recommendations in this guidance may assist in complying with some of the 
147  special controls for devices with indications associated with weight loss. For information 
148  regarding special controls for oral removable retainers for weight management, see 21 CFR 
149  876.5981(b).  For information regarding special controls for ingested, transient, space 
150  occupying devices for weight management and/or weight loss, see 21 CFR 876.5982(b). For 
151  information regarding special controls for endoscopic suturing devices for altering gastric 
152  anatomy for weight loss, see FDAs website.16 
153   
154  This draft guidance should be viewed as a complement to FDAs draft guidance entitled, 
155  Medical Devices with Indications Associated with Weight Loss - Non-Clinical 
156  Recommendations,17 which, once finalized, will provide recommendations for the non-clinical 
157  testing to support marketing submissions for these devices. 
158   
IV.  Clinical Performance Testing Considerations 
159 
160  Generally, non-clinical evaluation does not fully characterize all clinical experience, outcomes, 
161  and risks for these devices. We recommend submitters conduct in vivo (i.e., clinical) studies to 
162  evaluate device safety and effectiveness for new or significantly modified devices with 
163  indications associated with weight loss. For novel device designs, feasibility clinical studies can 
164  provide important safety and some effectiveness data that can be used to support a pivotal study. 
165  Pivotal studies can provide important safety and effectiveness data used to support marketing 
166  authorization. 
167   
168  Devices within the scope of this guidance document are generally considered significant risk 
169  devices and subject to all requirements of the Investigational Device Exemptions (IDE) 
170 regulation, 21 CFR part 812, for studies conducted in the UnitedStates (U.S.). See the FDA 
171 guidance titled, Significant Risk and Nonsignificant Risk Medical Device Studies.18 In 
172 addition to the requirements of 21 CFR part 812, sponsors of such trials of a device conducted in 
173 the U.S. generally must comply with the regulations governing institutional review boards (21 
174 CFR part 56) and informed consent (21 CFR part 50).
16See reclassification order, available at https://www.accessdata.fda.gov/cdrh_docs/pdf21/DEN210045.pdf. 
17When final, this guidance will represent FDAs current thinking on non-clinical testing for medical devices with 
indications associated with weight loss. Available at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/medical-devices-indications-associated-weight-loss-non-clinical-recommendations. 
18https://www.fda.gov/regulatory-information/search-fda-guidance-documents/significant-risk-and-nonsignificant-
risk-medical-device-studies.
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175 
176  Obesity represents a heterogeneous disease impacted by demographic, clinical and behavioral 
177  factors.19 Additionally, culture and public health policy can impact weight loss.20 Thus, FDA has 
178  encountered challenges about the applicability of foreign effectiveness data to the U.S. 
179  population for devices with indications associated with weight loss. Therefore, we recommend 
180  that pivotal studies be conducted in the U.S. If foreign data is collected, we recommend that no 
181  more than 50% of the pivotal study data be collected from outside the United States (O.U.S.). 
182  We also recommend that no more than 20% of the total enrollment population be from one site 
183  to avoid the study outcome being dominated by sites with large enrollment. 
184   
185  When data from clinical investigations conducted O.U.S. are submitted to FDA, the requirements 
186  of 21 CFR 812.28 may apply.21 21 CFR 812.28 outlines the conditions for FDA acceptance of 
187  clinical data from investigations conducted O.U.S. when submitted to support a premarket 
188  submission. For more information, see the FDA guidance Acceptance of Clinical Data to 
189  Support Medical Device Applications and Submissions: Frequently Asked Questions.22 
190   
  Study Design  
191 
192  We recommend that pivotal studies to support a weight loss indication be double-blinded, 
193  randomized, controlled trials (RCTs). We recommend that additional study staff remain blinded 
194  throughout the study (e.g., dieticians, personnel collecting study data). 
195   
196  We recommend a sham-controlled study as a placebo effect is anticipated. A sham control in a 
197  clinical study can provide an important comparator from which to determine the effectiveness of 
198  device therapy in comparison to the placebo effect. Therefore, a sham control is beneficial to 
199  reduce the uncertainty regarding the treatment effects of the device. We recommend the sham 
200  device and/or sham procedure be designed in a way to minimize the subjects ability to 
201  determine whether they have the study device or the sham device. We recommend that 
202  submitters consider how blinding will be assessed if using a sham control. We appreciate that a 
203  sham control may not be appropriate in all circumstances. If a sham device or sham procedure is 
204  not appropriate for a clinical trial design, we recommend a concurrent control arm where the 
205 control and treatment groups follow the same lifestyle programs. For all study designs, we 
206 recommend standardized dietary and behavioral study aspects between study arms and among 
207 centers involved in the study, and that these study aspects be representative of real-world diet 
208 and behavior regimens.
209
19Jimenez, M. P., Green, M. A., Subramanian, S. V., & Razak, F. (2018). A demographic, clinical, and behavioral 
typology of obesity in the United States: an analysis of National Health and Nutrition Examination Survey 2011-
2012. Annals of epidemiology, 28(3), 175181.e4.
20Waxman A. WHO Global Strategy on Diet, Physical Activity and Health. Food and Nutrition Bulletin. 
2004;25(3):292-302.
21This applies to data from clinical investigations that began on or after February 21, 2019 and are submitted to 
support a premarket submission, including IDEs, PMAs, and 510(k)s.
22https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-clinical-data-support-
medical-device-applications-and-submissions-frequently-asked.
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210  For additional information on principles for the design of premarket clinical studies, refer to 
211  FDAs guidance Design Considerations for Pivotal Clinical Investigations for Medical 
212  Devices.23 
213   
  Study Duration and Followup Schedule 
214 
215  The study should be designed to include adequate follow up to support the indications for use. 
216  The follow-up period should also account for the risk posed by device use.  
217   
218  To support device effectiveness, study duration and the follow-up schedule should be selected 
219  with the proposed indication in mind. 
220    For a proposed indication of weight loss, the duration of device use and primary 
221  endpoint should typically demonstrate weight loss at 12 months or more. 
222    A proposed indication of short term weight loss can typically be supported with a 
223  duration of device use and primary endpoint demonstrating weight loss at six months 
224  or more, but less than 12 months. 
225    Weight loss measured at, or a device that is used for, less than six months could be 
226  supportive of a proposed weight management indication. 
227    Additional follow-up may also be warranted to understand the durability of weight 
228  loss. Sometimes a supplemental marketing submission is submitted after these 
229  additional follow-up data are collected, for example, to update labeling. 
230  Consequently, we recommend consenting patients long enough for any anticipated 
231  additional follow-up which may be necessary to support such labeling (or other) 
232  modifications. 
233   
234  To support device safety, study duration and follow-up should be adequate to collect sufficient 
235  adverse event information depending on the device design and how it is used. The duration of 
236  follow-up needed to support device safety may be longer than that to support effectiveness if 
237  warranted due to the risk that the device may pose to patients. 
238   
  Inclusion/Exclusion Criteria 
239 
240 As body mass index (BMI) increases, risk of weight-related morbidity and mortality increases. 
241 The BMI range for inclusion in a clinical study should be the result of a risk-based decision to 
242 ensure that study patients will have an appropriate level of anticipated benefit to offset the risks 
243 associated with the device. 
244
245 In general, clinical trials of implanted or surgically-placed devices should enroll individuals with 
246 a BMI greater than or equal to 35 kg/m2,or greater than or equal to 30 kg/m2 if accompanied by 
23https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-considerations-pivotal-
clinical-investigations-medical-devices.
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247  weight-related comorbidities (e.g., type 2 diabetes mellitus (T2DM)).24 In studies of lower risk 
248  devices, patients with a BMI of 27 kg/m2 with weight-related comorbidities may be included. 
249  Higher-risk device studies may warrant additional specification of the BMI range and/or weight-
250  related comorbidities, to ensure that the anticipated benefit outweighs the probable risks.  
251   
252  Given the risks associated with implanted or surgically-placed devices, patients in studies of such 
253  devices should have failed more conservative, first-line weight loss methods such as diet, 
254  exercise, and behavior modification.  
255   
256  Treatment with these medical devices in a clinical study may not be appropriate for certain 
257  patients. We recommend that submitters consider the following for the exclusion criteria as 
258  applicable: 
259    Patients who are unable or unwilling to followthe dietary restrictions specified by the 
260  clinical protocol; 
261    Altered anatomy (e.g., sleeve gastrectomy); 
262    History of dysmotility or delayed gastric emptying; 
263    Pregnancy or breastfeeding; 
264    Current smokers, because of the contribution of smoking to obesity-linked 
265  comorbidities and increased risk of complications; 
266    Persons with a history of eating disorder(s), or a serious or uncontrolled psychiatric 
267  illness that could compromise understanding or compliance with visits and device 
268  maintenance/removal; 
269    Active substance abuse; 
270    Untreated endocrine or metabolic cause for obesity; 
271    Previous gastrointestinal surgery (e.g., bowel resection); and 
272    Older patients for whom the risks of the procedure are not acceptable and/or the 
273 anticipated lifespan conflicts with the expected period of benefit.
274
Patient Demographics
275
276 We recommendthat submitters include in theirstudy a representative sample of patients from 
277 various demographic groups (e.g., sex, gender, age, ethnic, andracial)in which the prevalence of 
278 obesity is highest. FDA recommends that clinical studies for these devices enroll participants that 
279 reflect the demographics for clinically relevant populations. 
280
24This recommendation is consistent with the 2018 position statement of the American Society of Metabolic and 
Bariatric Surgery (ASMBS): Aminian, A., Chang, J., Brethauer, S. A., Kim, J. J. (2018). ASMBS updated position 
statement on bariatric surgery in class I obesity (BMI 3035 kg/m2), Surgery for Obesity and Related Diseases, 
14(8), 1071-1087.
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281  For more information regarding the evaluation and reporting of age, race, ethnicity and sex-
282  specific data in medical device clinical studies, see FDAs guidances Evaluation of Sex-
283  Specific Data in Medical Device Clinical Studies25 and Evaluation and Reporting of Age-, 
284  Race-, and Ethnicity-Specific Data in Medical Device Clinical Studies.26 
285   
  Treatment Parameters/Protocol 
286 
287  The study-specific treatment protocol should minimize risk to patients. The protocol should not 
288  only consider the risks associated with the device and device placement, but any additional risk 
289  that may be applicable to all patient populations included in the study. For example, if submitters 
290  choose to include patients with certain comorbidities (e.g., T2DM), the protocol should explain 
291  how these patients will be protected from complications that may arise due to their disease.  
292   
293  Specifically, when designing trials that include patients with T2DM, we recommend that a safety 
294  monitoring plan be included in the protocol to detect and manage hypoglycemia or continued 
295 uncontrolled hyperglycemia. The management plan should consider an algorithm for the 
296  lowering or elimination of oral hypoglycemics or insulin based on fasting glucose levels and/or 
297  glycated hemoglobin (HbA1c)27 (for patients who lose clinically significant amounts of weight). 
298   
299  For a device with novel technology and/or with an undefined risk profile, it may also be 
300  appropriate to prospectively define stopping rules in the study protocol and/or initially enroll a 
301  limited number of patients in a phased manner to better manage risk.  
302   
303  If the device is a permanent implant, the study design should include considerations for how a 
304  device should be explanted if warranted or requested during or at termination of the study. 
305  Considerations should include, at a minimum, removal instructions and a plan for tracking 
306  reasons for device explant, including association with any adverse events as noted in Section 
307  IV.F below. There should also be evidence that removal instructions in device labeling are 
308  sufficient to safely remove the device if explant is warranted. Removal instructions should be 
309  evaluated during the course of the clinical study if devices are explanted from patients.  
310   
311 Throughout the study, participants should receive the standard of care, including medication and 
312 monitoring for comorbidities such as hypertension, dyslipidemia, and glycemic control. 
313
 Safety Endpoints and Data
314
315 The primary safety endpoint should be reporting of all device-and procedure-related adverse 
316 events,as FDA intends to consider all adverse events in our assessment of thepremarket 
25https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-sex-specific-data-
medical-device-clinical-studies-guidance-industry-and-food-and-drug.
26https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-and-reporting-age-race-
and-ethnicity-specific-data-medical-device-clinical-studies.
27HbA1c (glycated hemoglobin) is a term commonly used in relation to diabetes - the higher the HbA1c, the greater 
the risk of developing diabetes-related complications.
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317  submission. Additional safety assessments may be warranted based on the design and principles 
318  of operation of the specific device. 
319   
  Effectiveness Endpoints and Data 
320 
321  Demonstrated weight loss should be based on percent total body weight loss (% TBWL),28 which 
322  is typically captured in a clinical study with co-primary effectiveness endpoints that include:  
323    a hypothesis with a pre-specified superiority margin of the mean % TBWL over 
324  control; and  
325    a performance goal for a responder rate based on individual subject success. 
326   
327  FDA recommends a pre-specified superiority margin for mean % TBWL be included in the 
328  clinical protocol depending on the indication being sought in the premarket submission: 
329    For an indication of weight loss, we recommend at least a 5% superiority margin of 
330  the mean % TBWL over the control. However, the minimum value over the control 
331  arm should be appropriate for the risk associated with device use and any device-
332  related procedures. 
333    For an indication of limited weight loss, we recommend at least a 2% superiority 
334  margin of the mean % TBWL over the control. However, the minimum value over the 
335  control arm should be appropriate for the risk associated with device use and any 
336  device-related procedures. 
337    For an indication of weight management, a superiority margin of less than 2% may 
338  be supportive if additional benefit is measured (i.e., responder rate endpoint is met). 
339  However, the benefit should be appropriate for the risk associated with device use and 
340  any device-related procedures. 
341   
342  For the responder rate, we recommend that at least 50% of treated patients achieve at least 5% 
343  TBWL for any indication associated with weight loss (i.e., weight loss, limited weight loss, 
344  weight reduction, weight management, or obesity treatment).
345   
346 For an indication of obesity treatment, we recommend endpoint(s) demonstrating clinical 
347 benefits in addition to weight loss alone. Support for additional benefits should be appropriately 
348 powered in the study design.
349
350 We recommend submitters consider the following secondary effectiveness endpoints:
351  Percent excess weight loss (%EWL);29
352  Change in weight;
28For the purposes of this guidance, FDA defines % TBWL=[(initial weight final weight)initial weight]
100%. 
29 For the purposes of this guidance, FDA defines % EWL=
[(initial weight weight to be at a BMI of 25)initial weight]100%.
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353   Change in BMI; and
354    Change in waist circumference. 
355   
356  We also recommend that submitters consider including patient-reported outcomes (PROs)30 and 
357  patient preference information (PPI)31. The value patients associate with the treatment, their 
358  willingness to accept the risk of this treatment to achieve the benefit, the treatments ability to 
359  improve the patients overall quality of life, and the patients ability to understand the benefits 
360  and risks of the treatments are important factors in evaluating device benefit. 
361   
362  Changes in common weight-related comorbidities are often secondary endpoints in studies of 
363  devices with indications associated with weight loss. If any of the secondary endpoint analyses 
364  are intended to support the indications for use or to describe device performance in the labeling 
365  (e.g., comparing treatment and control groups using p-values or confidence intervals), we 
366  recommend pre-specifying this intention in the study protocol and providing a detailed 
367  description of the statistical methods plannedto follow. The study should be powered 
368  appropriately to evaluate such changes, if comparative statements are intended to be made in the 
369  labeling. 
370   
  Adverse Events 
371 
372  We recommend that all adverse event data be collected during the study and that events be 
373  adjudicated as to whether they are device- and/or procedure- related. In general, we recommend 
374  that studies have a data safety monitoring board (DSMB) and establish an endpoint 
375  assessment/adjudication committee. We refer the submitter to the FDA guidance Establishment 
376  and Operation of Clinical Trial Data Monitoring Committees32 for more information. 
377  Independent data monitoring committees help to ensure the safety of enrolled participants as 
378  follows: 
379   The committee can provide a comparative assessment of accumulating safety and 
380 effectiveness data to inform recommendations to the study sponsor whether to 
381 continue, modify, or stop the study;
382  Potential complications may warrant robust study oversight from a third party that is 
383 advisory to the study sponsor; and
30See FDA guidances Principles for Selecting, Developing, Modifying, and Adapting Patient-Reported Outcome 
Instruments for Use in Medical Device Evaluation available at https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/principles-selecting-developing-modifying-and-adapting-patient-reported-outcome-
instruments-use, and Patient-Reported Outcome Measures: Use in Medical Product Development to Support 
Labeling Claims, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-
reported-outcome-measures-use-medical-product-development-support-labeling-claims. 
31See FDA guidance Patient Preference Information - Voluntary Submission, Review in Premarket Approval 
Applications, Humanitarian Device Exemption Applications, and De Novo Requests, and Inclusion in Decision 
Summaries and Device Labeling, available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/patient-preference-information-voluntary-submission-review-premarket-approval-applications.
32https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishment-and-operation-
clinical-trial-data-monitoring-committees.
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384   Unbiased adjudication of adverse events reduces the uncertainty in study safety 
385  outcome data. 
386   
387  We recommend an adverse event classification modeled after the Clavien-Dindo Classification 
388  of Surgical Complications,33 shown in Table 2, where the severity of each adverse event is 
389  graded based on the treatment used to address the event.  
390   
391  Table 2. Adverse event classification for clinical studies 
Grade  Definition 
Any deviation from the normal treatment course without the need for surgical, endoscopic, 
and radiological interventions. Includes all over-the-counter pharmacological interventions 
Grade I 
and non-narcotic prescription pain medications (including anti-emetics, antipyretics, 
analgesics, diuretics, electrolytes, physiotherapy, and bedside wound care) 
Requiring pharmacological treatment with prescription drugs (excluding non-narcotic pain 
Grade II  medications in Grade I), the administration of intravenous fluids, blood transfusions, or 
total parenteral nutrition 
Grade 
Requiring surgical, endoscopic, or radiological interventions 
III 
Grade  Life-threatening complications requiring intensive care/intensive care unit management 
IV  (including single and multiorgan dysfunction, and central nervous system complications) 
Grade V  Death  
392   
393  The classification scheme identified in Table 2 focuses on deviations from the normal treatment 
394  course for a device. For example, the normal treatment course for a device may include use of 
395  concomitant medications, and additional therapy (e.g., anti-emetics, pain medication) typically 
396  provided as part of the practicing physicians treatment plan. While concomitant medications are 
397  not considered as adverse events per this classification scheme, FDA does consider such as part 
398  of the overall benefit-risk determination for a device, as described in Table 4 in Section V.A.  
399   
400 A single type of adverse event can be categorized into different grades, depending on the 
401 treatment required for resolution. For example, vomiting can be resolved with over-the-counter 
402 medication (Grade I), or vomiting can require administration of intravenous fluids (Grade II). 
403 The grades are to be considered mutually exclusive, and together the grades should cover all 
404 event outcomes. All events that fit into a single grade are of approximately equal severity/risk to 
405 the patient. 
406
33Dindo, 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. Annals of surgery, 240(2), 205.
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407  We recommend submitters present adverse event information to FDA in their premarket 
408  submission as follows:34 
409    Tabulate all adverse events and categorize as device-related, procedure-related, or not 
410  related to the device or procedure and categorize all adverse events as explained in 
411  Table 2; 
412    Tabulate all serious adverse events (SAEs) and categorize as device-related, 
413  procedure-related, or not related to the device or procedure and categorize all SAEs as 
414  explained in Table 2; 
415    Identify any and all unanticipated adverse device effects; 
416    Provide the time to onset as well as duration for all gastrointestinal-associated device- 
417  and/or procedure-related adverse events, including resolution status; and 
418    Tabulate all unanticipated device removals and the reason for removal. 
419   
420  We recommend the use of PRO instruments to assess non-serious adverse events using validated 
421  tools such as the gastrointestinal symptom scales included in the National Institutes of Health 
422  (NIH) PROMeasurement Information System (PROMIS).35  
423   
  Statistical Analysis Considerations 
424 
425  (1)  Sample Size 
426  For pivotal studies, we recommend that co-primary effectiveness endpoints include a hypothesis 
427  with a pre-specified superiority margin for percent total body weight loss and a performance goal 
428  for a responder rate. The number of patients should be the maximum of sample sizes calculated 
429  based on the co-primary endpoints considering anticipated loss to follow-up; however, additional 
430  patients should be enrolled to assess device safety to support premarket submission. In general, 
431  calculations should be based on two-sided tests of significance at the 5% level and at least 80% 
432  power. Effect sizes for the calculations should represent clinically meaningful differences.  
433   
434  (2)  Analysis Methods 
435 Endpoints should be analyzed based on the intent-to-treat (ITT)population, defined as patients
436 that were enrolledand randomized into the study,regardless of whether the patients received the 
437 treatment to which they were randomized.
438
34As described in Section III.B.(4), of FDAs draft guidance, Medical Devices with Indications Associated with 
Weight Loss - Non-Clinical Recommendations, FDA recommends that the adverse event information in this list 
also be included in the devices labeling. Available at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/medical-devices-indications-associated-weight-loss-non-clinical-recommendations.
35Spiegel, B. M., Hays, R. D., Bolus, R., Melmed, G. Y., Chang, L., Whitman, C., ... & Khanna, D. (2014). 
Development of the NIH patient-reported outcomes measurement information system (PROMIS) gastrointestinal 
symptom scales. The American journal of gastroenterology, 109(11), 1804.
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439  The analysis of % TBWL should use analysis of variance (ANOVA) or analysis of covariance 
440  (ANCOVA) with baseline weight as a covariate in the model.   
441   
442  Response rates should be compared between the treatment and control groups using statistical 
443  methods appropriate for categorical data. A sensitivity analysis should be conducted that 
444  considers patients who are treated, drop out, and do not have complete post-baseline data as 
445  treatment failures. Additionally, a tipping point analysis for binary response variables should be 
446  considered.  
447   
448  Type I error should be controlled across all clinically relevant secondary effectiveness endpoints 
449  intended for product labeling. 
450   
451  (3)  Missing Data 
452  a.  Efforts to reduce missing data 
453  We recommend you describe the efforts that will be used during the course of the study to 
454  monitor and minimize the incidence of patient dropouts, such as monitoring activities, special 
455  incentives to patients for study compliance, methods to remind patients of scheduled visits, and 
456  specific efforts to contact patients who miss their visit (e.g., telephone calls, postcards, contact 
457  nextofkin). 
458   
459  b.  Document reasons for missing data 
460  We recommend you identify the steps to document: 
461    the reason for each missed visit, e.g., complications, difficulty getting transportation to 
462  the site; and 
463    the reason for each dropout, e.g., seeking alternate therapy, complications or intolerance 
464  to the device, dissatisfaction with the device, moved away. 
465   
466  To permit a complete and detailed accounting of all study patients, we recommend you collect 
467  complete information during the study because loss to followup jeopardizes the conclusions that 
468  can be made about the longterm safety and effectiveness of a device. 
469   
470  c.  Handling missing primary endpoint data 
471  To allow for a true ITT analysis, we recommend obtaining body weight measurements in all 
472  patients who prematurely withdraw from studies near the calendar date at which they were 
473  scheduled. This will reduce uncertainty in the ultimate outcome of the study by having a data 
474 measurement at the primary effectiveness endpoint rather than imputing the measurement. For 
475 example, a patient who withdraws from a 12-month study after six months of treatment should 
476 have a body weight measurement at the time he or she would have completed 12 months of study 
477 participation. If this is not possible, we recommend conducting sensitivity analyses to determine 
478 the best mechanism to account for missing data. 
479
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480 d. Sensitivity analyses 
481  Sensitivity analyses employing imputation strategies should assess the effect of dropouts on the 
482  results. The imputation strategy should be prespecified and should consider the expected dropout 
483  patterns and the time-course of weight changes in the treatment group. No imputation strategy 
484  will work for all situations, particularly when the dropout rate is high, so a primary study 
485  objective should be to keep missing values to a minimum. We recommend multiple imputation 
486  when a missing at random assumption is plausible. For early exit due to adverse events or 
487  ineffectiveness of the device, we recommend you use unfavorable clinical outcome to impute 
488  missing data. 
489   
490  (4)  Subgroup Analyses 
491  We recommend submitters conduct gender and sex-based subgroup analyses. We recommend 
492  submitters conduct subgroup analyses based on race and ethnicity as the prevalence of obesity 
493  varies among these groups in the U.S. population.36 If the study includes sites O.U.S. then we 
494  recommend conducting a U.S. subgroup analysis. 
495   
  Pediatric Studies 
496 
497  Planning clinical trials for pediatric patients includes additional considerations beyond those of 
498  adult patients, such as ethical issues of studying a more vulnerable patient population and an 
499  altered benefit-risk profile because of potential interference of a medical device with physical 
500  growth and maturation. Consistent with the FDA guidance Premarket Assessment of Pediatric 
501  Medical Devices,37 FDA considers patients below 22 years of age to be pediatric (that is, from 
502  birth up to but not including the 22nd birthday) for medical device studies. 
503   
504  The increased prevalence of children being overweight or having obesity, emphasizes an unmet 
505  need to provide therapy to children who have a disease that impacts their health, quality of life, 
506  and psychosocial factors. FDA remains open to considering risk-based clinical study designs and 
507  intends to consider both the benefits and risks to adolescent study participants when determining 
508 the amount of benefit-risk evidence needed before initiation of an adolescent weight-loss device 
509 study.
510
511 We recommend using the U.S. Centers for Disease Control and Prevention (CDC) National 
512 Center for Health Statistics definitions for classifying pediatric-aged patients as overweight or
36https://www.niddk.nih.gov/health-information/health-statistics/overweight-obesity.
37https://www.fda.gov/regulatory-information/search-fda-guidance-documents/premarket-assessment-pediatric-
medical-devices.
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513  obese and the American Heart Association recommendation for severe obesity based on age- and 
514  sex-matched BMI cutoffs as follows:38, 39, 40, 41 
515   BMI-for-age between the 85th and 95th percentile is overweight; 
516   BMI-for-age at or above the 95th percentile is obesity; and  
517    BMI 120% of the 95th percentile or an absolute BMI 35 kg/m2, whichever is lower 
518  based on age and sex is severe obesity. 
519   
520  FDA developed the following recommendations considering outcomes from the 2005 FDA 
521  Pediatric Advisory Committee (PAC) meeting on weight loss device clinical trial designs for 
522  pediatric patients,42 changes in the field of childhood obesity since the PACs 
523  recommendations,43 and input from external experts, including clinicians.  Additionally, the 
524  following recommendations are intended to supplement and not supersede those discussed in the 
525  FDA guidance Premarket Assessment of Pediatric Medical Devices.44 These recommendations 
526  are in addition to those discussed elsewhere in this document for adult patients. 
527  
528  Recommendations specific for pediatric patients include: 
529 1.  In general, the device should not be studied in the pediatric population until enough data 
530 has been obtained to show that the study does not involvegreater than minimal risk.45,46
531 Additionally, if the device is a permanent implant, sufficient data should exist to support 
532 anticipated benefit in the pediatric population.47Other sources of data, including animal 
38Kelly, A. S., Barlow, S. E., Rao, G., Inge, T. H., Hayman, L. L., Steinberger, J., ... & Daniels, S. R. (2013). Severe 
obesity in children and adolescents: identification, associated health risks, and treatment approaches: a scientific 
statement from the American Heart Association. Circulation, 128(15), 1689-1712.
39Gulati, A. K., Kaplan, D. W., & Daniels, S. R. (2012). Clinical tracking of severely obese children: a new growth 
chart. Pediatrics, 130(6), 1136-1140.
40Ogden, C. L., & Flegal, K. M. (2010). Changes in terminology for childhood overweight and obesity. Age, 12(12).
41Flegal, K. M., Wei, R., Ogden, C. L., Freedman, D. S., Johnson, C. L., & Curtin, L. R. (2009). Characterizing 
extreme values of body mass index-for-age by using the 2000 Centers for Disease Control and Prevention growth 
charts. The American journal of clinical nutrition, 90(5), 1314-1320.
42FDA Pediatric Advisory Committee, Development of Trials to Assess the Safety and Efficacy Relevant to 
Scientific and Ethical Issues Surrounding Trials for Pediatric Devices for Weight Loss. Gaithersburg, MD. Meeting 
materials can be accessed at https://wayback.archive-it.org/7993/20170403222257/https://www.fda.gov/ohrms/
dockets/ac/oc05.html#Pediatric.
43Marrone A.K., Venkataraman-Rao P., Gottschalk L. (2021). Food and Drug Administration insights on clinical 
study of weight-loss devices intended for adolescent patients. Pediatric Obesity, e12768.
44https://www.fda.gov/regulatory-information/search-fda-guidance-documents/premarket-assessment-pediatric-
medical-devices.
45In general, the 2005 FDA PAC recommended that devices, especially implants, should not be studied in the 
pediatric population until enough data has been gained from adult study and use. For more information, see 
https://wayback.archive-it.org/7993/20170404062450/https://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-
4179m_summary.pdf.
46In general, the 2005 FDA PAC recommended that A staged introduction should be used when studying devices 
for obesity in the pediatric population. Namely, after adequate information is available in adult populations, the 
device can be studied in the older adolescent group (12 or 14 to 17). Sufficient experience and data should be 
collected before studying the device in patients younger than this. Ibid.
47In general, the 2005 FDA PAC recommended that post-approval data should be collected through 5 years and 
parties should be encouraged to have registries for long-term implants, which follow patients for 5-10 years. Ibid.
15 Contains Nonbinding Recommendations
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533  or other relevant modeling and simulation data, may preclude or mitigate the need to 
534  preliminarily collect data on older populations. This may be especially relevant when 
535  designing clinical investigations to meet the more immediate needs of patients, such as 
536  younger adolescents, experiencing co-morbidities associated with the severe end of the 
537  obesity spectrum. 
538  2.  If the device is a permanent implant, risk associated with potential explantation of the 
539  permanent implant should be well defined. 
540  3.  Pediatric patients should have a documented history of failing to achieve weight-loss 
541  goals with lifestyle modification before enrollment into a clinical study for these devices. 
542  In general, patients should have participated in a comprehensive, multi-disciplinary 
543  pediatric weight management program for at least six months without adequate results. 
544  4.  Studies should have a lead-in period that allows for adequate time for the clinical team to 
545  get to know the patient, for the failure of adequate therapy programs to be documented, 
546  for the patient to understand the therapy and its impact, and for the patients ability to 
547  comply with diet, protocol, and other considerations (e.g., psychosocial comorbidities) to 
548  be assessed.48
549  5.  FDA considers the risk profile of the device for the appropriate study population in a 
550  pediatric clinical study. Table 3 illustrates recommended percentiles for BMI-for-age for 
551  inclusion of adolescent patients into a study for a device with indications associated with 
552  weight loss. Generally, higher risk devices should have the potential for greater benefit, 
553  as indicated by the percentiles for BMI-for-age in Table 3. If the submitter believes that 
554  the device is low-risk, FDA encourages discussion of a risk-based justification for 
555  inclusion of study patients with lower BMI-for-age percentiles. 
556   
557 Table 3. Recommended percentiles (%ile) for BMI-for-age values for inclusion of adolescent 
558 patients into a study for a device with an indication associated with weight loss.Risk-dependent 
559 valueshould fall within specified ranges.
Comorbidity No comorbidity
Temporary49 device 85th %ileBMI 95th %ileBMI
85th %ileto 120% of the 95th 95th %ileto 140% of the 95th
Permanent50 device
%ileBMI %ileBMI
560
48In general, the 2005 FDA PAC recommended that studies should have a lead-in period during which the 
physician team got to know the patient and it could be documented that the patient had failed adequate conservative 
therapy programs and to ensure the patients ability to comply with diet, protocol, etc. Ibid.
49For the purposes of interpreting this table, a temporary device is intended to be implanted or used for a pre-
determined, limited amount of time (for example: a six-month intragastric balloon). A permanent device is one that 
is implanted without intention to remove or one that permanently alters the patients anatomy and/or physiology. For 
the purposes of device classification procedures, the definition of an implant is provided in 21 CFR 860.3.
50Ibid.
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561  6.  A study endpoint of less than 12 months is likely not appropriate to evaluate a permanent 
562  device in the pediatric population, as these patients are still growing and maturing.51  
563  7.  Obesity-related comorbidities that should be considered for inclusion include:52  
564   Obstructive sleep apnea; 
565    Prediabetes; 
566    T2DM; 
567    Uncontrolled hypertension; 
568    Orthopedic complications; 
569    Pseudotumor cerebri; 
570    Non-alcoholic steatohepatitis (NASH); 
571    Polycystic ovary syndrome (PCOS); and 
572    Hyperlipidemia/dyslipidemia. 
573  8.  Exclusion criteria should include:  
574    Uncontrolled psychiatric conditions; 
575    Patients that are ill-equipped or unwilling to change behavior; 
576    Patients who are unwilling to undergo the intervention themselves; 
577    Patients with anatomical issues that may put them at unreasonable risk; 
578    Patients with connective tissue disorders that may result in tissue breakdown, if the 
579  device is an implant or changes anatomy; and 
580    Developmentally disabled patients who cannot follow recommendations. 
581 9.  To determine suitability for participating in a clinical study, maturity level and 
582 psychosocial comorbidities should be assessed by a specialist trained in psychologyand 
583 in discussing mental health issues, stigma, bias, bullying, binge-purge behaviors, 
584 readiness for change, and other related considerations.
585 10.Patients should be screened for known genetic causes of obesity such as Prader-Willi 
586 Syndrome.53 For these patients, as well as those with hypothalamic obesity related to 
51In general, the 2005 FDA PAC recommended that Premarket data should be collected for 2 years although 
patients should be consented/assented for 5 years.  For more information, see https://wayback.archive-
it.org/7993/20170404062450/https://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4179m_summary.pdf.
52Obesity-related comorbidities listed are also applicable to adult study populations. These comorbidities are listed 
in this section of this guidance document due to the relevant general recommendations from the 2005 FDA PAC: 
1) Long-term implant devices should be studied in patients with significant disease, i.e., those who are in the 99th 
percentile for BMI-for-age, and have at least one significant comorbidity, such as sleep apnea, diabetes, 
pseudotumor cerebri, or NASH (Non-Alcoholic Steatohepatitis); and 2) Comorbidity reduction or resolution would 
be an important secondary effectiveness endpoint although the study would need to be powered appropriately to 
evaluate such changes.  Ibid.
53In general, the 2005 FDA PAC recommended that patients should be screened for known genetic causes of 
obesity and for Prader Willi, and if included in the study, should be evaluated separately. Ibid.
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587  craniopharyngioma surgery that are about eight years old and above, inclusion into a 
588  study could be considered, though FDA recommends that the submitter consider 
589  separately evaluating the data for this subpopulation. 
590  11. As for adult studies, clinically meaningful weight loss may be defined by % TBWL that 
591  should be linked to the health risk in the desired pediatric patient population. Consistent 
592  with clinical guidelines based on cardiometabolic risk,54 we consider at least a 5-10 % 
593  TBWL clinically meaningful, and these values could be applicable to the pediatric 
594  population. However, linear growth should be considered when assessing changes in 
595  body weight of children and adolescents. Thus, the primary effectiveness parameter could 
596  be a function of the change in %BMI-for-age and/or % TBWL. This should depend on 
597  what is most clinically meaningful in the desired patient population considering age, BMI 
598  range, and any additional disease factors (e.g., associated comorbidities). Additionally, 
599  endpoint(s) should be able to demonstrate a positive outcome on the disease status (e.g., 
600  change in class of obesity). 
601  12. If applicable, comorbidity reduction or resolution should be a secondary effectiveness 
602  endpoint.  
603  13. The overall clinical study duration and follow-up should be justified considering the 
604  anticipated benefit and device risk. However, for devices that result in the modification of 
605  anatomy or involve a permanent implant, we recommend that premarket evaluation 
606  include follow-up for two years to account for weight loss durability. Patients should be 
607  consented or assented, as applicable, for five years to allow for longer-term follow-up 
608  post-marketing. Parental permission should be obtained when applicable. 
609  14. For a device that is temporary, durability of device-effect should be measured at least six 
610  months post device use unless a shorter assessment period is justified. 
611  15. Height measurements should be obtained from a wall-mounted stadiometer by study 
612  personnel trained in its use. A bone age study to obtain radiographic imaging of the 
613  growth plates can also be considered. 
614   
615  Other clinically relevant issues to consider when designing a pediatric study include 
616 endocrinologic causes of obesity, assessing neuropsychiatric symptoms and/or psychosocial 
617 environment, compliance, nutritional issues, and reproduction issues. We recommend addressing
618 and/or monitoring these issues as appropriate. 
619
620 We encourage submitters to utilize FDAs Q-Submission Program to ensure that thepediatric 
621 study protocol addresses safety concernsdepending on the facts and circumstances of the device 
622 and study.
623
54Jensen, M. D., Ryan, D. H., Apovian, C. M., Ard, J. D., Comuzzie, A. G., Donato, K. A., & Yanovski, M. (2014). 
AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American 
College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. 
Circulation, 129(25 Suppl 2), S102-138.
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V. BenefitRisk Considerations  
624
BenefitRisk 
625
626  FDA evaluates whether a device has a reasonable assurance of safety and effectiveness during 
627  the PMA review, or whether general or general and special controls provide such assurance for a 
628  device in a De Novo classification, or whether it is substantially equivalent to a valid predicate in 
629  510(k) review, by weighing any probable benefit to health from the use of the device against any 
630  probable risk of injury or illness from such use,55 or assessing the benefit-risk profile of a device 
631  as compared to a valid predicate,56 among other relevant factors. To aid in this process, 
632  submitters include valid scientific evidence, including one or more clinical investigations, where 
633  appropriate, and/or non-clinical information, which FDA reviews to determine, among other 
634  things, whether the device will have the effect it purports or is represented to have under the 
635  conditions of use prescribed, recommended, or suggested in the labeling of the device.57 
636   
637  When assessing the benefits of devices, FDA considers the types of benefits, the magnitude of 
638  benefits, the probability of patients experiencing one or more benefits, and the duration of 
639  effects.58 When assessing the risks of devices, FDA considers severity, type, number, and rate of 
640  harmful events associated with use of the device or procedure associated with the device, 
641  probability of harmful events, and duration of harmful events. Additional factors considered 
642  when assessing the probable benefits and risks of devices include uncertainty59 surrounding the 
643  benefit and risk, patient-centric assessments and PROs, characterization of the disease or 
644 condition, patient preferences,60 availability of alternate treatments, risk mitigation, device-type 
645 post-market data, and novel technology for addressing unmet medical needs.
646
647 Specific to devices with indications associated with weight loss, important considerations include 
648 the factors listed in Table 4.
649
55The criteria for determining the safety and effectiveness of a device are set forth in section 513(a) of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 860.7.
56See FDA guidance Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket 
Notifications (510(k)) with Different Technological Characteristics, available at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/benefit-risk-factors-consider-when-determining-substantial-
equivalence-premarket-notifications-510k. 
57Section 513(a)(3)(A) of the FD&C Act.
58See FDA guidance Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket 
Approval and De Novo Classifications, available at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/factors-consider-when-making-benefit-risk-determinations-medical-device-premarket-
approval-and-de.
59See FDA guidance Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device 
Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions, available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/consideration-uncertainty-making-
benefit-risk-determinations-medical-device-premarket-approvals-de.
60See FDA guidance Patient Preference Information - Voluntary Submission, Review in Premarket Approval 
Applications, Humanitarian Device Exemption Applications, and De Novo Requests, and Inclusion in Decision 
Summaries and Device Labeling, available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/patient-preference-information-voluntary-submission-review-premarket-approval-applications.
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650 
651  Table 4. Factors considered as part of the benefit-risk evaluation for devices with indications 
652  associated with weight loss 
Factor  Example(s)
Assessment of Benefits from a Clinical Study 
amount of weight loss attributed to the device, proportion of patients
Weight loss 
experiencing weight loss, and durability of weight loss 
improvements in cardiometabolic risk factors, as well as other 
obesity-related comorbidities (e.g., clinically significant reduction in 
Changes in comorbidities 
HbA1c, hypertension, and/or dyslipidemia), reduction in 
medication(s) 
Other benefit  improvement in quality of life 
Assessment of Risks from a Clinical Study 
Device- and procedure-related  seriousness, severity, types, numbers, rates, duration, resolution of 
adverse events  adverse events and exacerbation of pre-existing conditions 
permanent implantation, anatomic changes, restriction of future 
Effects of the device  treatment options, reversibility limitations, effect on drug and/or 
nutrient absorption 
risk associated with expected concomitant medications or therapies, 
Clinical  rate of early device removal due to patient request, risks related to 
treatments/procedures related  placement/removal procedures, risks related to procedures necessary 
to the device  to diagnose adverse events, hospitalization (need, duration, and 
reason for) 
Additional Factors 
Evaluation matrices decision  extent of weight loss and duration of device use versus prevalence 
aid61  and severity of adverse events reported in a clinical study 
uncertainty resulting from study design, study conduct, potential for 
Uncertainty 
sham effect, and range of confidence intervals 
studies from outside the United States, feasibility studies, real-world 
Additional clinical data  
evidence, use of the device repeatedly or in sequence 
availability of alternative therapies, risk mitigation measures, patient 
Additional considerations 
preferences
653
654 There is a wide range of technology and techniques being attempted for devices with indications 
655 associated with weight loss. These different approaches can translate into different impacts or 
656 outcomes, such as duration of device implantation, adverse event profiles, and different amounts 
657 of weight loss. As innovators conceive and develop the next generation of devices with plans to 
658 market such devices in the U.S.,the recommendations below explain how FDA intends to 
61The evaluation matrices are applicable to devices with indications outlined in Table 5.
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659  consider, in the context of premarket submission decision, adverse events in light of varying 
660  degrees of benefit (specifically extent of weight loss and duration of device use). 
661   
  Use of Modified ClavienDindo to Assess Risk 
662 
663  As described in Section IV.HH, we recommend an adverse event classification modeled after the 
664  Clavien-Dindo Classification of Surgical Complications,62 where the severity of each device- and 
665  procedure-related adverse event is graded based on the treatment used to address the event (See 
666  Table 2). The Clavien-Dindo Classification was chosen due to its wide use among physicians as 
667  a reliable and reproducible system for reporting surgical complications. Modifications to the 
668  Classification system were adapted to make it more relevant for weight loss device-related 
669  complications. 
670   
671 We highlight the differences from the original Clavien-Dindo Classification as well as relevant 
672  considerations in the following summation: 
673    Grade I was adapted to include over-the-counter medications and non-narcotic 
674  prescription pain medications. 
675    Grade II includes all other prescription medications and the administration of 
676  intravenous fluids.  
677    Like the original Clavien-Dindo Classification scheme, length of hospital stay is not 
678  included, since practices vary between medical centers and unexpected 
679  hospitalization typically occurs in combination with other therapies that are captured 
680  by the classification. However, FDA intends to consider seriousness and the need, 
681  duration of, and reason for hospitalization when making our overall benefit-risk 
682  determination for these devices. 
683    Diagnostic procedures, such as diagnostic endoscopies, are not included, because an 
684  adverse event discovered by a diagnostic procedure would be classified by the 
685  treatment needed for the adverse event. However, FDA intends to consider the risk of 
686  diagnostic procedures that may be used to diagnose device- or procedure-related 
687  adverse events when making our overall benefit-risk determination for these devices. 
688    Regarding Grade II, a patients need for blood transfusions and total parenteral 
689  nutrition (TPN) would be indicative of more serious adverse events in comparison to 
690  prescription medication use; however, the associated adverse events are likely to 
691  include additional treatments defined as Grade III or Grade IV, and the grades of 
692  those additional treatments would also be captured. 
693   Devices can electively be removed prior to the end of their intended course of therapy 
694 for reasons other than adverse events included in the Adverse Event Classification 
695 described in Table 2. These reasons could be at patient request. These events are not 
696 captured in the Adverse Event Classification, but FDA intends to consider early 
697 device removal when making our overall benefit-risk determination for these devices.
62Dindo, 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.
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698
Balancing Weight Loss and Adverse Events for an 
699 
Indication of Weight Loss 
700 
701  FDAs assessment of tolerability of adverse events in light of varying degrees of weight loss for 
702  devices specifically with a weight loss indication have been developed considering:  
703    Outcomes from the 2012 Gastroenterology-Urology Devices Panel on general issues 
704  related to obesity treatment devices;63 
705    Feedback from external experts, including clinicians; and 
706    The public comments submitted to Docket No. FDA-2019-N-4060 in response to a 
707  discussion paper outlining concepts discussed below. 
708   
709  As described in Sections IV.GB and IV.G, indications for weight loss depend on the extent and 
710  duration of weight loss demonstrated in a clinical study. For devices used for less than six 
711  months, or having less benefit than that outlined in Table 5, a weight management indication 
712  may be appropriate. An obesity treatment indication should be supported by clinical benefits in 
713  addition to weight loss alone.  
714   
715 Table 5 summarizes four weight loss indication categories based on the amount of weight loss 
716 observed in a clinical study and the duration of device use.
717
718 Table 5. Weight loss indication categories
Demonstrated Weight Loss
Superiority  Responder Rate
Indication Margin  % patientsachieving  Duration of Device Use
% TBWL Over  5% TBWL
Control
Short-Term Limited Weight Loss 2% and <5% 50% 6 months to <12 months
Limited Weight Loss 2% and <5% 50% 12 months
Short-Term Weight Loss 5% 50% 6 months to <12 months
Weight Loss 5% 50% 12 months
719
720 For the categories in Table 5, the duration of device use depends on the characteristics of device 
721 use. It may depend on the time period over which the device is used and/or the time period over 
722 which weight loss is measured, as follows:
632012 Materials of the Gastroenterology-Urology Devices Panel can be accessed at https://wayback.archive-
it.org/7993/20170113191551/http:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevic
es/MedicalDevicesAdvisoryCommittee/Gastroenterology-UrologyDevicesPanel/ucm286235.htm.
  
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723   For an implantable device, the duration of device use is the total time that the device 
724  is inside the body. For example, for an intragastric balloon that is in the stomach for 6 
725  months and then removed, the duration of device use would be 6 months.  
726    If the device is used transiently and results in changes to the anatomy and/or 
727  physiology that persist after use, the duration of device use is the terminal time point 
728  at which weight loss is measured. For example, for a device that is used temporarily 
729  but permanently reduces the size of the stomach, if the change in total body weight 
730  was assessed at 12 months post-device use, then the duration would be 12 months. 
731    For devices that are used on a recurring basis, the duration of device use is the course 
732  of time the device is used before measuring the results. For example, for a device that 
733  is used daily, if the change in total body weight is assessed after eight months of daily 
734  use, then the duration would be eight months.  
735   
736  In a hypothetical example, a device was temporarily placed in the stomach. A clinical 
737  investigation included two groups: a treatment group that had the device placed via an 
738  endoscopic procedure; and a sham group for the control arm, which underwent an endoscopic 
739  procedure, but no device was placed. After six months, devices were removed from the treatment 
740  group and the change in weight was measured for both groups, so the duration of this device use 
741  is six months. The results showed that at least half (50%) of the treatment group lost at least 5% 
742  of their starting body weight. The results also showed that the treatment group lost more of their 
743  starting body weight than the sham group did, with a superiority margin of 3% more weight lost. 
744  Thus, the device successfully met co-primary effectiveness endpoints of 50% responder rate and 
745 at least 2% TBWL over sham when measured at device removal 6 months post implant. Based 
746  on the recommendations in Table 5, this weight loss would be considered short-term limited 
747  weight loss. 
748   
749  FDA intends to use the weight loss indication categories (Table 5), the Adverse Event 
750  classification (Table 2), and the Evaluation Matrices decision aid (Figure 1) to compare the 
751  weight loss demonstrated with the adverse event classification profile as part of the benefit-risk 
752  assessment of a weight loss device (Table 4). 
753   
754  1.  There are four proposed Evaluation Matrices (numbered 1-4 in Figure 1). There is one 
755  Evaluation Matrix corresponding with each of the four weight loss indication categories 
756  described in Table 5. An Evaluation Matrix is selected for a device based on the amount 
757  of weight loss demonstrated in a clinical study and the duration of device use, consistent 
758  with Table 5.  
759  2.  Within each Evaluation Matrix, there are five columns for the five grades of adverse 
760  events described in Table 2. For each grade of adverse event, if there is a patient in the 
761  clinical study with that adverse event, then a lettered cell is intended to be selected based 
762 on the percentage of patients who experienced that grade of adverse event. The letter of 
763 the cells is for reference purposes only.
764 3. The shading of each cell indicates the possible consideration for the device based on the 
765 corresponding grade of adverse events (the column the cell is in). White indicates that the 
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766  weight loss to adverse event profile appears favorable. Light gray shading indicates that 
767  the weight loss to adverse event profile is uncertain. Dark gray shading indicates that the 
768  weight loss to adverse event profile appears unfavorable.  
769  4.  The Evaluation Matrix for a specific device may include some combination of cells with 
770  different shading. The overall risk of the device depends on the cell of greatest risk; thus, 
771  the cell with the darkest shading suggests the outcome of the decision aid. 
772  5.  The outcome from the Evaluation Matrix is considered as part of the totality of the 
773  benefit-risk determination (Table 4). 
774  6.  The matrices are provided as a decision aid, which is only one part of FDAs assessment 
775 when evaluating whether probable benefit outweighs probable risk for the device for its 
776 conditions of use.
777
778
779
780 Figure 1. Evaluation Matrices for comparing weight loss indication categories (Table 5) and 
781 adverse events classification.64
64Lettering within the matrices is included for reference purposes only. For example, the cell corresponding to a 
Grade IV adverse event occurring at a rate of more than 25% of the time is lettered P.
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782 
783  In a hypothetical example, suppose that in a clinical investigation, a device successfully met co-
784  primary effectiveness endpoints of 50% responder rate and a superiority margin of 3% TBWL 
785  over sham control when measured at device removal six months post implant. Based on Table 5, 
786  the weight loss indication category would be short-term limited weight loss, so the device 
787  would be evaluated via Evaluation Matrix 1 in Figure 1. In the assessment of the clinical study: 
788    50% of patients had Grade I adverse events, which corresponds to the light gray cell 
789  A in Matrix 1 of Figure 1;  
790    3% of patients had Grade II adverse events, which corresponds to the white cell I in 
791  Matrix 1 of Figure 1;  
792    0% of patients had Grade III adverse events; and 
793    1% of patients had Grade IV adverse events, which corresponds to the dark gray cell 
794  S in Matrix 1 of Figure 1.  
795   
796  Overall, the risk of the device is characterized by the prevalence of greatest risk observed in the 
797  study, i.e., the 1% Grade IV adverse event rate, where the dark gray cell indicates that the weight 
798  loss to adverse event profile may not be favorable for the given amount of weight loss as part of 
799  the overall benefit-risk assessment. The low rate of adverse events in Grade II (the white cell) 
800  and Grade I (the light gray cell) may not negate the risk associated with the rate of adverse 
801  events in Grade IV (the dark gray cell). 
802   
803  In another hypothetical example, suppose that in a clinical investigation, a device successfully 
804  met co-primary effectiveness endpoints of 50% responder rate and a superiority margin of 10% 
805  TBWL over sham control when measured at device removal 12 months post implant. Based on 
806  Table 5, the weight loss indication category would be weight loss, so the device would be 
807  evaluated via Evaluation Matrix 4 in Figure 1. In the assessment of the clinical study: 
808    70% of patients had Grade I adverse events, which corresponds to the light gray cell 
809  A in Matrix 4 of Figure 1; 
810    10% of patients had Grade II adverse events, which corresponds to the white cell G in 
811  Matrix 4 of Figure 1; 
812    0.5% of patients had Grade III adverse events, which corresponds to the white cell O 
813  in Matrix 4 of Figure 1; and 
814    2% of patients had Grade IV adverse events, which corresponds to the light gray cell 
815  S in Matrix 4 of Figure 1.  
816   
817  Overall, the risk of the device is characterized by the prevalence of greatest risk observed in the 
818 study, i.e., the 2% Grade IV adverse event rate and 70% Grade I adverse event rate, where the 
819 light gray cells indicate that the weight loss to adverse event profile is uncertain given the 
820 amount of weight loss as part of the overall benefit-risk assessment. The low rate of adverse 
821 events in Grade IIand Grade III(the white cells) may not negate the risk associated with the rate 
822 of adverse events in Grade Iand Grade IV (the light gray cells).
823
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824  During the review of a marketing submission, FDA intends to consider information from the 
825  proposed Evaluation Matrices, along with all other applicable factors identified in Table 4, to 
826  make a final determination regarding whether the probable benefits of the device outweigh the 
827 probable risks of the device.
26