Obesity and Overweight: Developing Drugs and Biological Products for Weight Reduction

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Obesity and Overweight:
Developing Drugs and
Biological Products for
Weight Reduction
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact John Sharretts at 240-402-4678.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2025
Clinical/Medical
Revision 2

Obesity and Overweight:
Developing Drugs and
Biological Products for
Weight Reduction
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4 th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2025
Clinical/Medical
Revision 2

Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	CLINICAL BACKGROUND: OVERWEIGHT AND OBESITY ............................... 2
A. 	The Adult Population .................................................................................................................... 2
B. 	The Pediatric Population ............................................................................................................... 4
III. 	CLINICAL ASSESSMENT OF WEIGHT-REDUCTION DRUGS IN ADULT
PATIENTS......................................................................................................................... 5
A. 	Phase 1 and Phase 2 Trials ............................................................................................................ 5
B. 	Phase 3 Clinical Trials ................................................................................................................... 6
1. Trial Design and Patient Populations ............................................................................................. 6
2. Trial Size and Duration ................................................................................................................... 7
3. Efficacy Endpoints ........................................................................................................................... 8
a. 	Primary efficacy endpoint ......................................................................................................... 8
b. 	Secondary efficacy endpoints ................................................................................................... 8
c. 	Efficacy benchmarks ................................................................................................................. 9
4. Standard of Care and Concomitant Medication .............................................................................. 9
5. Subjects With Type 2 Diabetes ......................................................................................................... 9
6. Metabolic Syndrome ...................................................................................................................... 10
7. Delay or Prevention of Type 2 Diabetes ........................................................................................ 11
C. 	General Safety Assessment of Weight-Reduction Drugs.......................................................... 11
D. 	Weight-Reduction Drugs Used in Combination ........................................................................ 12
E. 	Weight-Reduction Drugs for Patients With Medication-Induced Weight Gain .................... 13
IV. 	CLINICAL ASSESSMENT OF WEIGHT-REDUCTION DRUGS IN PEDIATRIC
PATIENTS....................................................................................................................... 14
V. 	STATISTICAL CONSIDERATIONS .......................................................................... 16
A. 	Estimands ..................................................................................................................................... 16
B. 	Minimizing Missing Data From Premature Study Withdrawal or Loss to Follow-Up ......... 16
C. 	Estimators ..................................................................................................................................... 17
D. 	Sensitivity Analyses...................................................................................................................... 17
E. 	Sample Size ................................................................................................................................... 18
F. 	Analysis Methods ......................................................................................................................... 18
G. 	Graphical Methods ...................................................................................................................... 18
REFERENCES............................................................................................................................ 19

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1
Obesity and Overweight:	1
Developing Drugs and Biological Products for Weight Reduction	2
Guidance for Industry1
3
4
5
6
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	7
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	8
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	9
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	10
for this guidance as listed on the title page.	11
12
13
14
I. 	INTRODUCTION	15
16
This guidance provides recommendations to industry regarding the development of drugs and	17
biological products2 regulated within the Center for Drug Evaluation and Research in the Food	18
and Drug Administration (FDA) intended for reduction and long-term maintenance of body	19
weight in patients with obesity and those with body mass index (BMI) classified as overweight	20
who also have weight-related comorbidities (hereafter, patients with overweight).	21
22
This guidance focuses on the design of trials to demonstrate sustained weight reduction in	23
patients with obesity or overweight. Weight reduction is defined herein as a long-term reduction	24
in excess adiposity (body fat) with a goal of reduced morbidity and mortality. The expression	25
long-term describes the course of body weight observed over a period of at least 1 year on the	26
maintenance dose of the drug.	27
28
Although FDA encourages assessment of the effect of drugs on the manifestations of obesity or	29
overweight beyond excess adiposity (e.g., obstructive sleep apnea, osteoarthritis), this guidance	30
focuses on study designs and endpoints to assess the effectiveness of drugs on sustained weight	31
reduction itself in patients with obesity or overweight. Sponsors should consult with the Agency	32
regarding trial design features and endpoints to evaluate other manifestations of obesity or	33
overweight.	34
35
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	36
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	37
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	38
1 This guidance has been prepared by the Division of Diabetes, Lipid Disorders and Obesity in the Center for Drug
Evaluation and Research at the Food and Drug Administration.
2 For the purposes of this guidance, the term drug or drugs includes both human drugs and therapeutic biological
products unless otherwise specified.

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the word should in Agency guidances means that something is suggested or recommended, but	39
not required.	40
41
II. 	CLINICAL BACKGROUND: OVERWEIGHT AND OBESITY	42
43
A. 	The Adult Population	44
45
Obesity is a chronic disease characterized by excess adiposity. Excess adiposity is associated	46
with an increased risk of death and major comorbidities such as type 2 diabetes mellitus,	47
hypertension, dyslipidemia, cardiovascular disease, nonalcoholic steatohepatitis, gallbladder	48
disease, osteoarthritis of the knee, sleep apnea, and some cancers (Guh et al. 2009; Wang et al.	49
2011; Diehl and Day 2017). The pathogenesis of obesity involves the interaction of genetic,	50
environmental, and behavioral factors. Patients with overweight (i.e., those who have	51
comorbidities indicating metabolic dysfunction) also represent a patient population at increased	52
health risk from excess adiposity.	53
54
BMI, expressed as kilograms of weight divided by height in meters squared (kg/m2
), is	55
commonly used to identify patients with obesity or overweight in the clinical setting. BMI is	56
widely used in both clinical and research settings and has a long history of use for regulatory	57
purposes.	58
59
• 	BMI is inexpensive, universally available, easy to calculate, reproducible, and correlates	60
strongly with total body fat in nonelderly adults.	61
62
• 	The relationship between BMI and risk for death varies by age, sex, race, and other	63
factors, such as smoking status, but generally, the annual incidence of all-cause mortality:	64
65
– 	Is lowest in individuals with BMIs of 22.5 kg/m2 to 24.9 kg/m2 and	66
67
– 	Increases with BMIs from 25 kg/m2 to greater than 40 kg/m2 (Prospective Studies	68
Collaboration 2009)	69
70
• 	Change in BMI from baseline is correlated with changes in body fat in patients with	71
obesity or overweight. Mean percentage change in BMI is an effective method to assess	72
change in adiposity in a population with obesity or overweight, adjusted for baseline	73
BMI.	74
75
Based on data relating BMI to mortality risk, the World Health Organization in 1995 and the	76
National Institutes of Health in 1998 adopted the weight classifications by BMI that are shown in	77
Table 1 (NHLBI Obesity Education Initiative Expert Panel on the Identification, Evaluation, and	78
Treatment of Overweight and Obesity in Adults 1998).	79
80

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Table 1. Weight Classification Guidelines	81
Classification 	BMI
Underweight 	< 18.5 kg/m2
Normal weight 	18.5 kg/m2 – 24.9 kg/m2
Overweight 	25 kg/m2 – 29.9 kg/m2
Obesity (Class 1) 	30 kg/m2 – 34.9 kg/m2
Obesity (Class 2) 	35 kg/m2 – 39.9 kg/m2
Extreme3 obesity (Class 3) 	> 40 kg/m2
82
BMI has several limitations. Although higher BMI is strongly associated with increased body fat,	83
BMI is not a direct measure of body fat, and it does not inform the distribution of excess body	84
fat. In clinical practice, supplementing BMI with other anthropometric measures, such as waist	85
circumference, may be appropriate in certain individuals.	86
87
Other methods to evaluate adiposity have important limitations as well. Assessment of skinfold	88
thickness is operator dependent and has relatively poor reproducibility. Bioelectrical impedance	89
may vary depending on the hydration status of the individual. Imaging modalities, such as dual	90
x-ray absorptiometry (DXA) or magnetic resonance imaging, may provide more precise	91
measures of body fat but are expensive and require use of multiple blinded, central readers for	92
implementation in a trial. Trial results based on imaging changes may not be generalizable to	93
clinical care of patients, whereas baseline BMI and percentage change in weight or BMI are	94
available in any office or clinic. Additionally, change in fat mass based on imaging or other	95
modalities is not as clearly tied to clinical outcomes as change in BMI.	96
97
In patients with obesity or overweight, particularly patients with comorbidities such as	98
hypertension, dyslipidemia, and type 2 diabetes, long-term weight reduction greater than or	99
equal to 5% of baseline body weight or BMI4 following diet, exercise, and some, but not all,	100
drug therapies, is associated with improvement in various metabolic and cardiovascular risk	101
factors (Douketis et al. 2005; Jensen et al. 2014.).	102
103
Some, but not all, observational studies suggest that modest intentional weight loss in	104
individuals with obesity or overweight can reduce the incidence of some cancers,	105
cardiovascular disease, and all-cause mortality (Parker et al. 2003; Eilat-Adar et al. 2005; Gregg	106
et al. 2003; Ma et al. 2017; Carlsson et al. 2022; Sjöholm et al. 2022). Furthermore,	107
pharmacological weight reduction has been associated with reduced risk of cardiovascular	108
events for at least one agent (Lincoff et. al. 2023).	109
110
Although weight loss is associated with the aforementioned clinical benefits, some prospective	111
trials of pharmacological weight-reduction interventions have failed to show benefit on certain	112
clinical outcomes (Nissen et al. 2016; Bohula et al. 2018), and some products have been	113
3 The U.S. Centers for Disease Control and Prevention uses the term severe rather than extreme as a synonym for
Class 3 obesity in adults.
4 For adults of stable height, percentage change from baseline body weight is equal to percentage change from
baseline BMI.

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associated with potential harm (Connolly et al. 1997; James et al. 2010, Sharretts et al. 2020).	114
For this reason, claims for drug intended for reduction and long-term maintenance of body	115
weight in patients with obesity or overweight will generally be limited to weight reduction	116
unless other benefits related to complications (e.g., improvement in sleep apnea) have also been	117
demonstrated.	118
119
B. 	The Pediatric Population	120
121
BMI is used as an inexpensive and simple parameter that correlates with direct methods of	122
measuring body fat, particularly at higher levels of body fat, to estimate adiposity in children	123
and adolescents (Hampl et al. 2023; Barlow and Dietz 1998; Dietz and Robinson 2005; Speiser	124
et al. 2005; Whitlock et al. 2010). Additionally, BMI correlates with obesity-related	125
comorbidities, such as hypertension, dyslipidemia, type 2 diabetes mellitus, and nonalcoholic	126
steatohepatitis in pediatric patients (Krebs et al. 2003; Skinner et al. 2015; Anderson et al. 2015;	127
Cote et al. 2013). A child’s BMI category (e.g., healthy weight, overweight) is determined using	128
an age- and sex-specific percentile for BMI rather than the BMI cut-points used for adult	129
categories.	130
131
Accepted classifications of pediatric obesity are based on the 2000 U.S. Centers for Disease	132
Control and Prevention growth charts for children and adolescents ages 2 years and older and	133
are defined as the following:	134
135
• 	Overweight: BMI at or above the 85th percentile for age and sex	136
137
• 	Obesity: BMI at or above the 95th percentile for age and sex	138
139
• 	Severe obesity: BMI at or above 120% of the 95th percentile for age and sex (or greater	140
than or equal to 35 kg/m2 ) (Kelly et al. 2013; Styne et al. 2017)	141
142
If indicated, pediatric patients with obesity or overweight should be evaluated for genetic,	143
endocrine, or other causes.	144
145
• 	Genetic obesity syndromes (e.g., Prader-Willi syndrome, Bardet-Biedl syndrome)	146
typically present with severe, early-onset obesity (before 5 years of age) and	147
characteristic phenotypic features.	148
149
• 	Endocrine disorders (e.g., Cushing’s syndrome) may present as mild obesity or	150
overweight accompanied by short stature (or decreased linear growth) or other	151
hormone deficiencies, such as hypogonadism.	152
153
154

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III. 	CLINICAL ASSESSMENT OF WEIGHT-REDUCTION DRUGS IN ADULT	155
PATIENTS	156
157
A. 	Phase 1 and Phase 2 Trials	158
159
Before a sponsor initiates phase 3 clinical trials, the pharmacokinetics (PK), pharmacodynamics	160
(PD), and dose-response profiles of a new weight-reduction drug should be adequately	161
characterized.	162
163
• 	The safety and tolerability of a wide range of doses should be studied in early phase trials.	164
Because excess adiposity may influence a drug’s metabolism and disposition (Hanley et	165
al. 2010; Smit et al. 2018; Cheymol 2000), phase 1 trials should examine the PK and PD	166
profile of a weight-reduction drug across a broad range of BMIs that adequately covers	167
the population likely to receive the drug.	168
169
• 	Other clinical pharmacology studies, including assessment of drug interactions5 and the	170
impact of intrinsic and extrinsic factors on the PK and PD of the investigational drug,	171
should be conducted early in drug development to aid in the design of later phase trials.	172
173
• 	Phase 2 trials should include a range of doses and identify the appropriate dosing	174
regimen(s) to take into phase 3 trials. The duration of the phase 2 trials should be	175
sufficient to capture the maximal or near-maximal weight-reduction effects of the active	176
dosing regimen(s).	177
178
– 	The trial design, size, and duration should account for dosing considerations, such as	179
whether the drug will be ultimately used in a fixed-dose or dose-titration regimen, or	180
whether a period of dose-escalation to achieve the target dose is needed to improve	181
tolerability.	182
183
– 	Phase 2 trials should also examine the effects by dose of the weight-reduction drug on	184
common weight-related comorbidities (e.g., type 2 diabetes mellitus, hypertension,	185
dyslipidemia), and a sponsor should consider these dose-response data when choosing	186
the most appropriate dosing regimen(s) for phase 3 trials.	187
188
• 	Subjects included in phase 2 efficacy and safety studies generally should be adults who	189
have BMIs greater than or equal to 30 kg/m2 or greater than or equal to 27 kg/m2 if	190
accompanied by at least one comorbidity.	191
192
• 	The primary efficacy endpoint should be a comparison of the mean percentage change in	193
body weight between the group assigned to the investigational drug and the group	194
assigned to the control.	195
196
5 See the ICH guidance for industry M12 Drug Interaction Studies (August 2024). We update guidances
periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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• 	If a sponsor intends to use one or more clinical outcome assessments (COAs) to support	197
labeling claims, the sponsor should seek FDA input as early as possible and at important	198
milestones throughout the drug development process to ensure the inclusion of fit-for-	199
purpose COAs in phase 3 trials. The sponsor should also discuss with the Agency early	200
in the development program the endpoints, analyses, and anchors to ensure that the	201
COA results are both clinically meaningful and interpretable.	202
203
B. 	Phase 3 Clinical Trials	204
205
1. 	Trial Design and Patient Populations	206
207
In general, phase 3 clinical trials examining the efficacy and safety of weight-reduction drugs	208
should be randomized, double-blind, and placebo-controlled, with the investigational drug used	209
as an add-on to standardized recommendations for diet and physical activity in all randomized	210
subjects.	211
212
• 	The lifestyle-modification programs used in the preapproval trials should be applicable to	213
patients who would be prescribed the drug after approval.	214
215
– 	At least one phase 3 trial should incorporate a standard-of-care diet and physical	216
activity program (i.e., a program that strikes an appropriate balance between	217
effectiveness and simplicity that could be implemented in a primary care setting).	218
219
• 	To ensure that trial subjects have or are at significant risk for weight-related morbidity	220
and mortality, trials should include subjects with the following characteristics:	221
222
– 	BMI greater than or equal to 30 kg/m 2 , including a representative sample of subjects	223
with Class 3 or severe obesity (BMI greater than 40 kg/m 2
).	224
225
– 	BMI greater than or equal to 27 kg/m 2 in the presence of at least one weight-related	226
comorbidity (e.g., type 2 diabetes, hypertension, dyslipidemia, sleep apnea, or	227
cardiovascular disease)	228
229
• 	Because the observed treatment effect of a drug might be substantially different in	230
subjects taking concomitant glucose-lowering medications, it may be reasonable to	231
conduct one or more trials that enroll only subjects with diabetes at baseline (see item 5,	232
Subjects With Type 2 Diabetes, in this section for more details).	233
234
• 	The development program should include subjects with comorbidities, such as	235
cardiovascular disease, heart failure, liver disease, and chronic kidney disease.	236
237
• 	Subjects are expected to reflect the patient populations likely to use the drug in clinical	238
practice, with regard to age, sex, race, and ethnicity in the U.S. population. Sponsors	239

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should implement a diversity plan6 that accounts for the higher prevalence of obesity and	240
its comorbidities in certain racial and ethnic groups in the United States, such as	241
American Indian or Alaska Native, Asian, Black or African American, Hispanic or	242
Latino, Middle Eastern or North African, Native Hawaiian or Pacific Islander.	243
244
2. 	Trial Size and Duration	245
246
To ensure a thorough assessment of a weight-reduction drug, the size of the safety database for a	247
weight-reduction program should exceed the subject exposures outlined in the ICH guidance for	248
industry E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended	249
for Long-term Treatment of Non-Life-Threatening Conditions (March 1995). Given the	250
prevalence of obesity and overweight, substantial patient exposure can be expected after a	251
weight-reduction drug is approved. Patients with obesity or overweight have a significant	252
background rate of morbidity and mortality, so evaluation of this population represents a	253
circumstance where the harmonized general standard for the safety evaluation is not applicable.	254
255
• 	The general recommendation for a sample size to assess the safety of a weight-reduction	256
drug is 3,000 subjects randomized to the investigational drug within the to-be-	257
recommended dosage range and no fewer than 1,500 subjects randomized to placebo for	258
at least 1 year of treatment at the maintenance dosage. A sponsor developing multiple	259
dosing regimens should consider a randomization scheme that assigns more subjects to	260
the higher doses and should discuss the overall size of the safety database with the	261
Agency at or before the end of phase 2.	262
263
– 	The recommended sample size will provide 80% power to detect, with 95%	264
confidence, an approximately 50% increase in the incidence of an adverse event that	265
occurs at a rate of 3% in the placebo group (i.e., 4.5% versus 3%).	266
267
– 	This sample size also would allow for efficacy and safety analyses to be conducted	268
within important subgroups such as age, sex, race, ethnicity, and baseline BMI,	269
provided that a sufficient number are enrolled in each of these groups.	270
271
• 	As the number of subjects necessary to demonstrate the efficacy of a weight-reduction	272
drug in each individual trial is generally smaller than the number needed to adequately	273
assess safety, sponsors can either increase the sample size of the two adequate and	274
well-controlled trials necessary to support approval, or the safety analysis could be	275
based on integrated data from multiple adequate and well-controlled trials, including	276
the efficacy and safety studies (see section VI for more details).	277
278
6 See the draft guidance for industry Diversity Action Plans to Improve Enrollment of Participants from
Underrepresented Populations in Clinical Studies (June 2024). When final, this guidance will represent FDA’s
current thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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3. 	Efficacy Endpoints	279
280
a. 	Primary efficacy endpoint	281
282
The efficacy of a weight-reduction drug in adults should be assessed by analyses of mean	283
percentage change from baseline body weight in the investigational drug group versus the	284
control group. Note that in subjects with stable height (i.e., adults who have achieved terminal	285
height) percentage change in body weight equals percentage change in BMI.	286
287
b. 	Secondary efficacy endpoints	288
289
Secondary efficacy endpoints should include, but are not limited to, changes in the following	290
metabolic parameters:	291
292
• 	Blood pressure	293
• 	Lipoprotein lipids	294
• 	Fasting glucose	295
• 	A1C (in subjects with type 2 diabetes)	296
297
Assessments of clinical outcomes from fit-for-purpose COA measures could also be appropriate	298
secondary endpoints to support a labeling claim. For example, if a sponsor seeks to demonstrate	299
clinical benefit on a particular set of functional impacts (e.g., physical functioning), we	300
recommend that the sponsor do the following:	301
302
• 	Specify and define functional impacts that are relevant and important to patients with	303
obesity or overweight and that are likely to demonstrate meaningful and interpretable	304
changes in the planned clinical trial(s).	305
306
• 	Consider whether the target population will have sufficient limitation in their physical	307
functioning and how the extent of limitation in the population at baseline may affect the	308
instruments’ ability to observe a clinically meaningful within-patient score change.	309
310
• 	If all randomized subjects do not have sufficient limitation in physical functions, we	311
recommend prespecifying a subgroup to be analyzed and providing details of the	312
proposed analyses. The proposed analysis plan should be submitted to FDA for review	313
and agreement before conducting the trial.	314
315
In clinical practice, waist circumference is sometimes used as an indirect measure of visceral fat,	316
as it is easy and inexpensive to measure; but for regulatory purposes, it is not considered a	317
surrogate for visceral fat content or metabolic abnormalities because the procedure is not	318
standardized, the measurement is impacted by the extent of non-visceral fat, and the accuracy is	319
reduced in patients with BMI greater than 35 kg/m 2 . Nevertheless, change in waist circumference	320
may be evaluated as a secondary endpoint. Acceptability for labeling would depend on the	321
quality of the data.	322
323

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Because changes in major weight-related comorbidities are informative to prescribers, it may be	324
appropriate to present secondary endpoints from adequate and well-controlled trials in the	325
CLINICAL STUDIES section of labeling upon review of the data. Results suitable for labeling	326
generally would include clinically meaningful and statistically significant treatment effects	327
demonstrated on prespecified endpoints controlled for type 1 error and consistent across trials.	328
Statistical robustness alone is generally necessary, but not sufficient, to support inclusion of an	329
endpoint in labeling.	330
331
Responder analyses on continuous variables (i.e., the proportion of subjects achieving	332
prespecified thresholds of weight reduction compared with the control arm; for example, greater	333
than or equal to 5%, 10%, or 15% of baseline body weight or BMI) should be interpreted with	334
caution. Specifically, responder analyses may inappropriately exaggerate treatment effects	335
(Abugov et al. 2023). For example, consider a hypothetical case in which treatment benefit	336
exceeds risk if the mean treatment effect is 5% or greater reduction in weight, and in which the	337
means of normally distributed percentage reductions in weight for treatment and control are 6%	338
and 4%, respectively, each with a standard deviation of 1%. Analysis on the continuous	339
outcomes would indicate an inadequate treatment effect equal to 2% weight reduction, while	340
analysis based on a responder threshold of 5% would suggest a large treatment effect, with the	341
difference in response rate between treatment and control equal to 68%. For this reason,	342
responder analyses for the evaluation of weight reduction are generally not recommended. A	343
sponsor intending to pursue a responder analysis as an endpoint should consult with the Agency.	344
345
c. 	Efficacy benchmarks	346
347
In general, a drug is considered effective for weight reduction and maintenance in patients with	348
obesity or overweight with comorbidities if, after 1 year of treatment at the maintenance dosage,	349
the difference in mean percentage weight reduction between the investigational drug and control-	350
treated groups is at least 5% and the difference is statistically significant.	351
352
4. 	Standard of Care and Concomitant Medication	353
354
Subjects with obesity or overweight enrolled in clinical trials of investigational weight-reduction	355
drugs should receive standard-of-care treatment, including medication, for comorbidities such as	356
hypertension, dyslipidemia, and glycemic control. Data should be collected on initiation and/or	357
discontinuation or dose reduction of medications for these comorbidities to support evidence of	358
the drug effect on blood pressure or glycemic control.	359
360
5. 	Subjects With Type 2 Diabetes	361
362
Compared with their effects in patients without diabetes, weight-reduction drugs are typically	363
less efficacious at reducing weight in patients with concomitant type 2 diabetes. Furthermore,	364
patients with type 2 diabetes may face unique safety issues such as a risk for hypoglycemia,	365
because of either improved glycemia following weight reduction or a direct glucose-lowering	366
effect of the weight-reduction drug. Because patients with type 2 diabetes represent an important	367
subgroup of patients with obesity or overweight, it is expected that sponsors evaluate sufficient	368
subjects with type 2 diabetes to assess the efficacy and safety in this subgroup, either in	369

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dedicated trials of subjects with type 2 diabetes (with concomitant obesity or overweight) or in	370
adequately powered subgroups of larger weight-reduction trials that also include subjects without	371
diabetes.	372
373
• 	Subjects with diabetes should be on a stable regimen of medications intended for glycemic	374
control before enrollment in a weight-reduction trial.	375
376
• 	Trials should generally exclude subjects with poor glycemic control at baseline (e.g., A1C	377
greater than 10% or fasting glucose levels greater than 270 mg/dL).	378
379
• 	Subject randomization should be stratified by the effect of common baseline	380
glucose-lowering medications on weight (i.e., weight gain promoting, weight loss	381
promoting, weight neutral) and baseline A1C (e.g., less than or equal to 8% versus	382
greater than 8%).	383
384
• 	Protocols should include rescue criteria for subjects who experience worsening glycemic	385
control during the trial. Increased dose or initiation of new glucose-lowering medication	386
should be documented.	387
388
• 	Because weight reduction may result in improved insulin sensitivity or glycemic	389
control, sponsors should consider including an algorithm for the lowering or	390
elimination of glucose-lowering medications or reduction of insulin dose based on	391
glucose levels or A1C in clinical protocols.	392
393
• 	Hypoglycemia safety should be monitored and reported consistent with published	394
guidelines (International Hypoglycaemia Study Group 2017; Abraham et al. 2018).	395
396
6. 	Metabolic Syndrome	397
398
The term metabolic syndrome represents a cluster of laboratory and clinical findings that serve as	399
markers for increased risk for cardiovascular disease and type 2 diabetes. Approval of a	400
metabolic syndrome indication would most likely require demonstrating a reduction in the risk of	401
cardiovascular morbidity or mortality in persons with metabolic syndrome—or some other	402
clinically meaningful benefit that outweighs the potential risks of treatment—associated with	403
improvement in most or all components of the syndrome.	404
405
Issues related to seeking a metabolic syndrome indication include the following:	406
407
• 	Depending on the definition used, the thresholds defining the individual parameters that	408
constitute metabolic syndrome, including increased visceral adiposity, lipid parameters,	409
blood pressure, and insulin resistance, may not define disease states.	410
411
• 	Available pharmacological therapies targeting the individual components may already be	412
indicated in the subset of patients diagnosed with a recognized disease or condition (e.g.,	413
triglyceride lowering in patients with severe hypertriglyceridemia, blood pressure	414

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reduction in patients with hypertension, glycemic control in patients with diabetes	415
mellitus, or low-density lipoprotein cholesterol (LDL-C) lowering in patients with	416
cardiovascular disease or increased cardiovascular risk).	417
418
• 	Demonstration of improvement in one or more of the individual parameters in individuals	419
meeting the definition of metabolic syndrome but without a disease diagnosis (i.e., severe	420
hypertriglyceridemia, hypertension, type 2 diabetes, or cardiovascular disease) is not	421
clearly linked to improvement in clinical outcomes and thus could not be considered	422
substantial evidence of effectiveness to support a metabolic syndrome indication.	423
424
7. 	Delay or Prevention of Type 2 Diabetes	425
426
Obesity is a risk factor for the onset of type 2 diabetes. Although there is evidence that weight	427
loss in individuals with obesity or overweight can reduce the incidence of type 2 diabetes	428
diagnosis, delayed biochemical diagnosis of type 2 diabetes has not been shown to improve	429
microvascular outcomes (Diabetes Prevention Program Research Group 2015). For a drug	430
intended for weight reduction and maintenance, an additional indication for the delay of onset of	431
type 2 diabetes would need to be supported by the establishment of clinical benefit(s) of the	432
delay; trials demonstrating delayed biochemical diagnosis of type 2 diabetes alone would most	433
likely not be sufficient. Benefits on quality of life, disease management burden, or psychosocial	434
functioning could be considered. It is unclear what would constitute a minimum trial duration for	435
a delay or prevention of type 2 diabetes claim, but the magnitude of the benefit of any delay in	436
the onset must be clinically meaningful. Because some drugs intended for weight reduction may	437
have glycemic effects, how a trial would demonstrate that diabetes diagnosis is delayed or	438
prevented, rather than concealed by early antihyperglycemic treatment initiation, would need to	439
be clarified.	440
441
C. 	General Safety Assessment of Weight-Reduction Drugs	442
443
Safety assessment of drugs intended for weight reduction should include evaluation of	444
cardiometabolic parameters as part of routine safety monitoring (including but not limited to	445
assessment of blood pressure, heart rate, plasma lipids, glycemic control parameters, and	446
electrocardiography).	447
448
In addition to routine safety monitoring, additional specialized safety assessments may be	449
appropriate for some weight-reduction development programs. For example:	450
451
• 	Programs should include a comprehensive cardiovascular assessment, which should	452
generally include features such as ambulatory blood pressure monitoring.7 A	453
cardiovascular outcomes trial may be necessary if a signal for CV risk is identified during	454
development. Whether such a trial would be needed premarket or could be conducted	455
postmarket would depend on the nature of the signal(s); we recommend early	456
consultation with FDA if early phase trials demonstrate such a signal.	457
7 See the draft guidance for industry Assessment of Pressor Effects of Drugs (February 2022). When final, this
guidance will represent the FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation
12
458
• 	Programs for drugs that directly interact with the serotonin (5-HT) receptor system,	459
specifically the 5-HT2 receptor subtypes, should include evaluation of risk for cardiac	460
valvulopathy using serial echocardiography.	461
462
• 	The development plans for centrally acting weight-reduction drugs generally should	463
include fit-for-purpose assessments of neuropsychiatric function, such as the Patient	464
Health Questionnaire-9 (PHQ-9) and Columbia Suicide Severity Rating Scale (C-SSRS).	465
Additionally, sponsors should anticipate the need to conduct nonclinical and clinical	466
studies to assess abuse liability8 and discuss the design of these studies with FDA during	467
the early phases of drug development.	468
469
• 	Assessment of the immunogenic potential of therapeutic proteins (or related biological	470
entities, such as peptides) should be consistent with published FDA guidance.9	
471
472
Loss of lean mass is observed after weight reduction in patients with obesity or overweight	473
regardless of intervention type (lifestyle, bariatric surgery, or pharmacotherapy). Patients with	474
obesity or overweight have greater lean mass than lean individuals, including greater muscle	475
mass, higher bone density, increased organ weight (i.e., liver, kidneys, and pancreas), and greater	476
absolute total body water (despite lower percentage body water). In pharmacological trials,	477
reduction of fat mass has typically accounted for 60% to 90% of weight reduction, and the	478
accompanying reduction in lean mass has not been considered adverse. To ensure that drug-	479
induced or biologic-induced weight reduction is caused primarily by a reduction in fat content,	480
not lean-body mass, a representative sample of trial subjects should have a baseline and follow-	481
up measurement of body composition by DXA or a suitable alternative. Sponsors seeking an	482
efficacy claim related to changes in body composition would need to consult with FDA early in	483
development to align on the clinical condition being treated. Trial design, including appropriate	484
choice of population and selection of endpoints that measure how a patient feels, functions, or	485
survives, to potentially support such a claim is beyond the scope of this guidance.	486
487
The need for and details of specific safety monitoring may change as new data emerge. Sponsors	488
are encouraged to discuss their plans for specific safety monitoring with the division during the	489
early stages of drug development and at the end of phase 2.	490
491
D. 	Weight-Reduction Drugs Used in Combination	492
493
Two or more drugs may be combined into a single dosage form when each component makes a	494
contribution to the claimed effects and the dosage of each component is such that the	495
combination is safe and effective for a significant patient population requiring such concurrent	496
therapy as defined in the labeling for the drug:10	
497
8 See the guidance for industry Assessment of Abuse Potential of Drugs (January 2017).
9 See the guidance for industry Immunogenicity Testing of Therapeutic Protein Products — Developing and
Validating Assays for Anti-Drug Antibody Detection (January 2019).
10 See 21 CFR 300.50(a).

Contains Nonbinding Recommendations
Draft — Not for Implementation
13
498
• 	Before initiating long-term clinical studies with a fixed-combination drug product	499
(FCDP),11 a sponsor should conduct the appropriate nonclinical and PK studies.12	
500
501
• 	Sponsors should compare the efficacy and safety of an FCDP with the individual	502
components of the combination in trials of sufficient duration to capture the maximal or	503
near-maximal weight-reduction effects.	504
505
E. 	Weight-Reduction Drugs for Patients With Medication-Induced Weight	506
Gain	507
508
This section addresses development of drugs intended for weight reduction in patients with	509
obesity or overweight caused by or exacerbated by medication-induced weight gain. It is not	510
intended to address development of drugs for the prevention of weight gain in patients with a	511
normal BMI, which is outside the scope of this guidance.	512
513
Certain drugs, notably some psychotropic and anticonvulsant agents, are associated with	514
moderate-to-marked weight gain. In addition to increasing the risk for adverse health outcomes,	515
medication-induced weight gain may reduce adherence with the drug responsible for the	516
increased body weight.	517
518
• 	Before initiating long-term clinical studies in patients with medication-induced weight	519
gain, a sponsor should evaluate potential clinically significant drug-drug interactions and	520
perform appropriate nonclinical toxicological studies.13	
521
522
• 	Participants in trials examining the efficacy and safety of drugs for the treatment of	523
medication-induced weight gain should have a documented increase in body weight of at	524
least 5% temporally associated with starting a drug known to cause weight gain.	525
526
• 	Generally, patients should have BMIs greater than or equal to 27 kg/m 2 with one or more	527
weight-related comorbidities or greater than or equal to 30 kg/m 2 with or without	528
comorbidities at the time of screening.	529
530
• 	The efficacy of a drug for the treatment of medication-induced weight gain generally	531
should be assessed using the same factors as those for weight reduction, as defined in	532
section III.B.3 of this guidance.	533
11 For the purposes of this guidance, an FCDP is one in which two or more active ingredients are combined at a
fixed dosage in a single dosage form.
12 For details, see the guidance for industry Nonclinical Safety Evaluation of Drug or Biologic Combinations (March
2006) and the draft guidance for industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs —
General Considerations (March 2014). When final, this guidance will represent the FDA’s current thinking on this
topic.
13 For details, see ICH M12 and the guidance for industry Nonclinical Safety Evaluation of Drug or Biologic
Combinations.

Contains Nonbinding Recommendations
Draft — Not for Implementation
14
534
• 	The design of the clinical program may need to consider unique efficacy or safety issues	535
with drugs used to treat medication-induced weight gain and should consider the specific	536
indication sought. For example, approval of a drug for weight reduction in patients with	537
medication-induced weight gain generally would most likely be limited to the weight-	538
inducing drug(s) studied and not the entire drug class of which the compound is a	539
member or other drug classes. In addition, the development program for a weight-	540
reduction drug with a central nervous system mechanism of action should evaluate	541
whether the drug changes the efficacy or safety of a central nervous system–acting	542
medication causing the weight gain.	543
544
545
IV. 	CLINICAL ASSESSMENT OF WEIGHT-REDUCTION DRUGS IN PEDIATRIC	546
PATIENTS	547
548
Under the Pediatric Research Equity Act, pediatric assessments are required in certain drugs and	549
biological products developed for diseases and/or conditions that occur in both the adult and	550
pediatric populations unless an exception, waiver or deferral is applicable. Studies must use	551
appropriate formulations for each age group.14 Plans for pediatric studies should be submitted	552
early in the drug development process, no later than 60 calendar days after the end-of-phase 2	553
meeting or such other time as agreed upon between FDA and the sponsor.15 Generally, efficacy	554
and safety data in adults should be available before a new drug is studied in children to support	555
the prospect of direct benefit and the potential for a favorable benefit-risk profile in this	556
population.	557
558
• 	In some cases, PK characterization in pediatric patients may be appropriate before	559
initiation of long-term pediatric clinical trials. PK and dose-ranging studies generally	560
should include subjects with age-matched and sex-matched BMIs greater than or equal to	561
the 95th percentile (see http://www.cdc.gov/growthcharts).	562
563
Phase 3 trials examining the efficacy and safety of a weight-reduction drug in pediatric subjects	564
should be randomized, double-blind, placebo-controlled, and at least 1 year in duration at the	565
target dosage.	566
567
• 	Pediatric trials should include subjects aged 6 years and older. Separate trials or cohorts	568
are generally recommended for adolescents (aged 12 years and older) and younger	569
pediatric subjects (aged 6 to 11 years).	570
571
• 	Eligible subjects should have age-matched and sex-matched BMIs greater than or equal	572
to the 95th percentile (or 85th percentile in the presence of one or more weight-related	573
14 See the draft guidance for industry Pediatric Drug Development: Regulatory Considerations — Complying With
the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for
Children Act (May 2023). When final, this guidance will represent the FDA’s current thinking on this topic.
15 See the guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study
Plans and Amended Initial Pediatric Study Plans (July 2020).

Contains Nonbinding Recommendations
Draft — Not for Implementation
15
comorbidities—that is, type 2 diabetes, hypertension, or dyslipidemia—in adolescents)	574
and a documented history of failure to lose sufficient weight with lifestyle modification.	575
576
• 	Trials should target equal proportions of males and females and representative samples of	577
subjects from racial or ethnic groups in which the prevalence of obesity and its	578
comorbidities is high in the U.S. population.	579
580
• 	Trials should include a substantial proportion of subjects (30% or greater recommended)	581
who meet BMI criteria for severe obesity.	582
583
• 	The lifestyle-modification program should continue following randomization and its	584
importance emphasized at appropriate intervals throughout the trials.	585
586
• 	Because linear growth should be considered when assessing changes in the body weight	587
of children and adolescents, the primary efficacy parameter in weight-reduction trials of	588
pediatric subjects should be a function of the change in BMI (e.g., the mean percentage	589
change in BMI). Height measurements should be obtained at all study visits using a wall-	590
mounted stadiometer and following appropriate procedures16 specified in the protocol.	591
592
• 	As in adults, demonstration of adequate safety may necessitate a larger sample size than	593
demonstration of efficacy. Sponsors should justify their proposed sample size and obtain	594
FDA agreement before initiating the trial(s).	595
596
• 	Baseline and follow-up measurement of body composition by DXA or suitable	597
alternative should be obtained in pediatric subjects.	598
599
In addition to standard safety evaluations specific to growing children (e.g., assessing Tanner	600
stage and bone age at baseline and endpoint), trials of centrally acting weight-reduction drugs in	601
pediatric subjects also should include fit-for-purpose assessments of depression, suicidality, and	602
neuropsychiatric function. Other specialized safety assessments may be appropriate depending	603
on the drug’s mechanism of action and its safety profile in adults.	604
605
606
16 See the draft guidance for industry Measuring Growth and Evaluating Pubertal Development in Pediatric Clinical
Trials (November 2022). When final, this guidance will represent the FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation
16
V. 	STATISTICAL CONSIDERATIONS	607
608
A. 	Estimands	609
610
Study protocols and statistical analysis plans should clearly prespecify how intercurrent events17	
611
and missing data18 will be handled during the trial and how they will be accounted for in the	612
statistical analyses. Sponsors should consult with FDA regarding these issues during trial design.	613
Although we are open to considering alternative estimands, we generally recommend inclusion	614
of analyses using the treatment policy estimand, in which all subjects, regardless of intercurrent	615
events, continue to be measured at each prespecified clinical visit unless consent to collect such	616
data is explicitly withdrawn, and in which all such measurements are included in the statistical	617
analyses. For other strategies to address specific intercurrent events, sponsors should justify that	618
the estimand addresses a meaningful clinical question of interest and can be estimated with	619
plausible assumptions.	620
621
B. 	Minimizing Missing Data From Premature Study Withdrawal or Loss to	622
Follow-Up	623
624
To help minimize the uncertainty associated with imputation of missing data, we recommend the	625
following:	626
627
• 	The protocol and informed consent form should clearly differentiate between treatment	628
discontinuation (i.e., discontinuation of intervention) and study withdrawal (i.e.,	629
withdrawal of consent to continued participation in study procedures, including data	630
collection).	631
632
• 	To help inform the imputation process, medical reasons for treatment discontinuation or	633
study withdrawal should be recorded on the case report forms and data sets (e.g.,	634
“nausea” rather than “patient decision” or “investigator decision”).	635
636
• 	The only grounds for study withdrawal (discontinuing the collection of outcome	637
information) should be withdrawal of subject consent to continued collection of data.	638
639
• 	To help ensure collection of data after early treatment discontinuation, the patient consent	640
form and investigator training should include material emphasizing the scientific	641
importance of data recorded after treatment discontinuation.	642
643
17 Intercurrent events are events occurring after treatment initiation that affect either the interpretation or the
existence of the measurements associated with the clinical question of interest, for example, discontinuation of
assigned treatment, use of prohibited medications, use of alternative or additional medications, and corrective
surgery. See the ICH guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands
and Sensitivity Analysis in Clinical Trials (May 2021).
18 Missing data include withdrawal of informed consent for collection of additional data, missed clinical visits, and
loss to follow-up.

Contains Nonbinding Recommendations
Draft — Not for Implementation
17
• 	The study protocols should establish systematic plans to avoid or minimize loss to	644
follow-up of subjects who do not actively maintain contact with the investigator (e.g.,	645
timing and number of telephone calls from investigator staff to the subject and subject’s	646
relatives, calls to the subject both at work and at home, offers of transportation to the	647
clinic).	648
649
• 	The protocol should include options to ascertain key outcome information in subjects	650
who discontinue study treatment and are unable or unwilling to continue all study visits,	651
including returns only for the visit at which primary and key secondary endpoints are	652
evaluated.	653
654
C. 	Estimators	655
656
Despite the best precautions, some data will inevitably be missing. How the statistical analyses	657
will account for missing data should be prespecified in the statistical analysis plan. Missing data	658
should be imputed in a fashion consistent with what the values, with their corresponding	659
uncertainty, would likely have been had they been collected.	660
661
We recommend the multiple imputation of missing data based on data retrieved from subjects	662
who discontinued treatment (i.e., retrieved dropout), calculated according to study treatment and	663
study month of an intercurrent event. For continuous endpoints, multiple imputations can be	664
aggregated using Rubin’s method. For categorical endpoints, particular imputation models	665
should be discussed with FDA during study planning.	666
667
D. 	Sensitivity Analyses	668
669
The use of retrieved data to impute missing data adds uncertainty because the outcomes of	670
subjects who support continued collection of data after intercurrent events may differ from	671
outcomes of subjects who withdraw from study. To assess the sensitivity of results to such	672
uncertainty, tipping point analyses should be conducted that vary assumptions about the missing	673
data. The tipping point analyses should be two-dimensional (i.e., should allow assumptions about	674
the missing outcomes on the two treatment arms to vary independently) and should include	675
scenarios where dropouts on treatment have worse outcomes than dropouts on placebo. The goal	676
is to evaluate the plausibility of the assumed expected values for missing outcomes in each	677
treatment arm under which the conclusions change (i.e., under which there is no longer evidence	678
of a treatment effect). In the tipping point analyses, all observed data should be included as	679
nonmissing, regardless of adherence to treatment or use of prohibited medications. For	680
continuous data, we recommend centering the tipping point analysis around the analysis that	681
most appropriately addresses missing data.	682
683
Sensitivity analyses are distinct from supplementary analyses, which target a different estimand	684
or different estimator of the same estimand. Supplementary analyses may be useful to provide	685
additional insights into the evidence of treatment effect but do not directly test the missing data	686
assumptions of the primary analysis.	687
688

Contains Nonbinding Recommendations
Draft — Not for Implementation
18
E. 	Sample Size	689
690
The number of subjects in trials designed to provide substantial evidence of effectiveness should	691
provide adequate power (e.g., 90%) to evaluate the primary endpoint.	692
693
F. 	Analysis Methods	694
695
The analysis of percentage weight change from baseline should use analysis of variance or	696
analysis of covariance with baseline weight as a covariate in the model. The statistical model	697
should incorporate as factors prognostic covariates as well as any variables used to stratify the	698
randomization. If statistical significance is achieved on the primary endpoint, the type 1 error	699
rate should be controlled across all clinically relevant secondary efficacy endpoints intended for	700
drug labeling.	701
702
Because the number of safety events in any one trial may be limited, safety data are commonly	703
integrated across studies. Integrated analyses of safety data should generally be stratified by trial.	704
Stratification is important to prevent confounding (e.g., Simpson’s paradox) that can occur when	705
pooling trials with different randomization ratios and populations with different risks of adverse	706
events. In addition, sponsors should consider the impact of the following differences across	707
studies:	708
709
• 	Different treatment durations.	710
711
• 	Different trial populations: Trial populations may have different risks of certain adverse	712
events that occur spontaneously as background events or different susceptibility to	713
adverse reactions to the drug (e.g., older adults or participants with particular	714
comorbidities).	715
716
• 	Different methods of adverse event ascertainment (e.g., questionnaire versus general	717
inquiry, different frequencies of querying, or substantial differences in reporting	718
patterns).	719
720
• 	Incompatible trial designs: It is not generally appropriate to integrate safety data collected	721
from controlled and uncontrolled trials to assess the impact of treatment on common	722
adverse events because between-group comparisons of event incidence will no longer be	723
possible.	724
725
To facilitate the assessment of integrated trial results, we recommend inclusion of forest plots,	726
with estimates of treatment effects from the individual trials as well as from the integrated	727
analysis.	728
729
G. 	Graphical Methods	730
731
Sponsors should provide graphs showing treatment effects over time for completers, with	732
additional graphs to illustrate the effect of the drug, such as cumulative distribution functions,	733
histograms, or waterfall plots.	734

Contains Nonbinding Recommendations
Draft — Not for Implementation
19
735
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737
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Contains Nonbinding Recommendations
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20
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Contains Nonbinding Recommendations
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21
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Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in	826
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Clinical Trial, JAMA, 315(10):990–1004.	828
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