Guidance for Industry 
Developing Products for 
Weight Management  
 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit comments to the Division of Dockets Management (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 Eric Colman at 301-796-1190.  
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2007 
Clinical/Medical 
 
Revision 1 
 
I:\7544dft.doc 
01/31/07   
Guidance for Industry 
Developing Products for 
Weight Management 
 
 
 
 
Additional copies are available from: 
 
Office of Training and Communications 
Division of Drug Information, HFD-240 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5600 Fishers Lane 
Rockville, MD  20857 
(Tel) 301-827-4573 
http://www.fda.gov/cder/guidance/index.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2007 
Clinical/Medical 
 
Revision 1 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  OVERWEIGHT AND OBESITY CLINICAL BACKGROUND................................2 
A.  The Adult Population....................................................................................................................2 
B.  The Pediatric Population...............................................................................................................4 
IV.  CLINICAL ASSESSMENT OF WEIGHT-MANAGEMENT PRODUCTS IN 
ADULT PATIENTS.........................................................................................................5 
A.  Phase 1 and Phase 2 Trials............................................................................................................5 
B.  Phase 3 Clinical Trials...................................................................................................................5 
1. Trial Design and Patient Populations.............................................................................................5 
2. Trial Size and Duration...................................................................................................................6 
3. Efficacy Endpoints...........................................................................................................................6 
a.  Primary efficacy endpoint.........................................................................................................6 
b.  Secondary efficacy endpoints...................................................................................................6 
c.  Efficacy benchmarks.................................................................................................................7 
4. Standard of Care and Concomitant Medication..............................................................................7 
5. Patients with Type 2 Diabetes..........................................................................................................7 
C.  General Safety Assessment of Weight-Management Products..................................................8 
D.  Weight-Management Products Used in Combination................................................................9 
E.  Weight-Management Products for Patients with Medication-Induced Weight Gain.............9 
V.  CLINICAL ASSESSMENT OF LONG-TERM WEIGHT-MANAGEMENT 
PRODUCTS IN PEDIATRIC PATIENTS...................................................................11 
VI.  STATISTICAL CONSIDERATIONS..........................................................................12 
A.  Sample Size...................................................................................................................................12 
B.  Preventing Missing Data from Premature Subject Withdrawal.............................................12 
C.  Analysis Methods.........................................................................................................................12 
D.  Graphical Methods......................................................................................................................13 
VII.  LABELING CONSIDERATIONS................................................................................13 
VIII.  STAND-ALONE INDICATIONS FOR THE PREVENTION OR TREATMENT 
OF WEIGHT-RELATED COMORBIDITIES............................................................13 
IX.  METABOLIC SYNDROME.........................................................................................14 
REFERENCES............................................................................................................................15 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1
Guidance for Industry
1 
Developing Products for Weight Management 
2 
3   
4   
5   
6   
7  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
8  thinking on this topic.  It does not create or confer any rights for or on any person and does not operate to 
9  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
10  the applicable statutes and regulations.  If you want to discuss an alternative approach, contact the FDA 
11  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
12  the appropriate number listed on the title page of this guidance. 
13   
14   
15   
16   
17  I.  INTRODUCTION  
18   
19  This guidance provides recommendations to industry regarding the development of drugs and 
20  therapeutic biologics (hereafter products) regulated within the Center for Drug Evaluation and 
21  Research (CDER) in the Food and Drug Administration (FDA) for the indication of weight 
22  management.  This guidance applies to products intended to be used for medical weight loss, 
23  which can be defined as a long-term reduction in fat mass with a goal of reduced morbidity and 
24  mortality through quantifiable improvements in biomarkers such as blood pressure, lipids, and 
25  HbA1c.  This guidance revises the draft Guidance for the Clinical Evaluation of Weight-Control 
26  Drugs that issued in September 1996.  When finalized, this guidance will replace the September 
27  1996 draft guidance.   
28   
29  The September 1996 draft guidance is being revised to provide advice on conducting studies to 
30  evaluate the efficacy and safety of products for weight management in patients with medication-
31  induced weight gain and weight management in obese pediatric patients.  Recommendations on 
32  the design of studies evaluating the efficacy and safety of combinations of weight-management 
33  products are also provided.   
34   
35  This guidance does not explicitly discuss indications for weight loss or maintenance of lost 
36  weight (which also can be described as prevention of weight regain); however, weight loss and 
37  weight maintenance should be demonstrated over the course of at least 1 year before a product 
38  can be considered effective for weight management.  Thus, the weight management indication 
39  incorporates and signifies weight loss and weight maintenance.    
40   
                                                 
1 This guidance has been prepared by the Division of Metabolism and Endocrinology Products in the Center for 
Drug Evaluation and Research (CDER) at the Food and Drug Administration.  
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41  This guidance also does not discuss the general issues of clinical trial design or statistical 
42  analysis.  Those topics are addressed in the ICH guidances for industry E8 General 
43  Considerations for Clinical Trials and E9 Statistical Principles for Clinical Trials.2
44   
45  FDAs guidance documents, including this guidance, do not establish legally enforceable 
46  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
47  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
48  cited.  The use of the word should in Agency guidances means that something is suggested or 
49  recommended, but not required.  
50   
51   
52  II.  BACKGROUND 
53   
54  In January 2004, the FDA issued a notice in the Federal Register requesting public comment on 
55  the September 1996 draft guidance for the purpose of incorporating the latest scientific and 
56  clinical advances in weight management drug development.  In September 2004, the FDA 
57  convened an advisory committee meeting to discuss the public comments received and to 
58  identify specific scientific, clinical, and regulatory issues that should be included in an updated 
59  guidance.  
60   
61  As a result, this revised guidance discusses several key areas of interest that are not covered in 
62  the September 1996 draft guidance.  These areas include recommendations on the development 
63  of products for weight management in pediatric patients and in patients with medication-induced 
64  weight gain, and recommendations on the development of combinations of weight-management 
65  products.  
66   
67   
68  III.  OVERWEIGHT AND OBESITY CLINICAL BACKGROUND 
69   
70  A.  The Adult Population 
71   
72  Obesity is a chronic, relapsing health risk defined by excess body fat.  The pathogenesis of 
73  obesity involves the interaction of genetic, environmental, and behavioral factors.  Total body fat 
74  can be accurately measured using hydrodensitometry and dual-energy x-ray absorptiometry 
75  (DEXA).  Because body mass index (BMI), expressed as kilograms of weight divided by height 
76  in meters squared (kg/m2), is simple and inexpensive to calculate, and correlates strongly with 
77  total body fat in non-elderly adults, it is commonly used as a surrogate for total body fat.   
78   
79  Excess body fat increases the risk of death and major comorbidities such as type 2 diabetes, 
80  hypertension, dyslipidemia, cardiovascular disease, osteoarthritis of the knee, sleep apnea, and 
81  some cancers (Caterson and Hubbard et al. 2004; Calle and Thun et al. 1999).  The relationships 
82  between BMI and risks for death and major comorbidities vary by age, sex, race, and smoking 
83  status, but, in general, are lowest in individuals with BMIs of 18.5 kg/m2 to 24.9 kg/m2 and 
84  increase in a curvilinear or linear manner with BMIs of 25 kg/m2 to approximately 40 kg/m2.  
                                                 
2 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the CDER 
guidance Web page at http://www.fda.gov/cder/guidance/index.htm. 
  2 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
85   
86  Based on data relating BMI to mortality risk, the World Health Organization in 1995 and the 
87  National Institutes of Health in 1998 adopted the weight classifications by BMI that are shown in 
88  Table 1 (Clinical Guidelines on the Identification and Treatment of Overweight and Obesity in 
89  Adults 1998).  
90   
91  Table 1.  Weight Classification Guidelines 
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
Extreme obesity (class 3)  > 40 kg/m2
92   
93  An increased level of visceral or intra-abdominal adiposity, independent of BMI, increases the 
94  risk for metabolic derangements and perhaps cardiovascular disease (Janssen and Katzmarzyk et 
95  al. 2004; Rexrode and Carey et al. 1998; Zhu and Wang et al. 2002).  Visceral fat content can be 
96  accurately measured with computed tomography (CT) or magnetic resonance imaging (MRI).  
97  Waist circumference, like BMI, is inexpensive and easy to measure and correlates with CT- and 
98  MRI-derived measurements of visceral fat content (Pi-Sunyer 2004).  In general, a waist 
99  circumference greater than 40 inches (greater than 102 cm) in men and greater than 35 inches 
100  (greater than 88 cm) in women is accepted as indicating increased visceral adiposity (The 
101  Practical Guide. Identification, Evaluation, and Treatment of Overweight and Obesity in Adults 
102  2000).  
103   
104  In overweight and obese individuals, particularly individuals with comorbidities such as 
105  hypertension, dyslipidemia, and type 2 diabetes, long-term weight loss greater than or equal to 5 
106  percent following diet, exercise, and in some cases, drug treatment, is associated with 
107  improvement in various metabolic and cardiovascular risk factors (Douketis and Macie et al. 
108  2005).  
109   
110  Although some, but not all, observational studies suggest that modest degrees of intentional 
111  weight loss in overweight and obese individuals can reduce the incidence of some cancers, 
112  cardiovascular disease, and all-cause mortality, at the time of this writing, there are no data from 
113  randomized, controlled trials on the effects of drug-induced weight loss on these clinical 
114  outcomes (Parker and Folsom 2003; Eilat-Adar and Eldar et al. 2004; Gregg and Gerzoff et al. 
115  2003).    
116   
117  Lifestyle modification, consisting of changes in patterns of dietary intake, exercise, and other 
118  behaviors, is considered the cornerstone of overweight and obesity management.  Because all 
119  drug and biological therapies impose some risk for adverse events, the use of a weight-
120  management product should be contemplated only after a sufficient trial of lifestyle modification 
121  has failed and the risks of excess adiposity and the anticipated benefits of weight loss are 
122  expected to outweigh the known and unknown risks of treatment with a particular weight-
123  management product.  
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124   
125  Patients with BMIs greater than or equal to 30 kg/m2 or greater than or equal to 27 kg/m2 if 
126  accompanied by weight-related comorbidities historically have been considered appropriate 
127  populations for treatment with weight-management medications (Clinical Guidelines on the 
128  Identification and Treatment of Overweight and Obesity in Adults 1998).  Although these 
129  patient-selection criteria are to a degree arbitrary, and an argument may be made for criteria that 
130  are more or less restrictive, we believe that individuals with BMIs greater than or equal to 30 
131  kg/m2 or greater than or equal to 27 kg/m2 if accompanied by weight-related comorbidities 
132  represent patient groups with sufficient baseline risk to justify inclusion in studies of 
133  investigational weight-management products.  
134   
135  B.  The Pediatric Population 
136   
137  As in adults, BMI correlates with more direct measures of adiposity in children and adolescents 
138  (American Academy of Pediatrics 2003; Barlow and Dietz 1998; Dietz and Robinson 2005; 
139  Speiser and Rudolf et al. 2005).  Also similar to adults, BMI correlates with obesity-related 
140  comorbidities such as hypertension, dyslipidemia, and type 2 diabetes mellitus in pediatric 
141  patients.  
142   
143  In contrast to adults, the terms overweight and obese are used synonymously in pediatric patients 
144  (American Academy of Pediatrics 2003).  The American Academy of Pediatrics (AAP) defines a 
145  pediatric-aged patient with an age- and sex-matched BMI of greater than or equal to 95th 
146  percentile as overweight or obese.  
147   
148  For patients aged 2 to 7 years, the AAP recommends weight loss through lifestyle modification if 
149  the BMI is greater than or equal to the 95th percentile for age and sex with the presence of one or 
150  more comorbidities.  For patients who are 7 years of age or older, weight loss through lifestyle 
151  modification is recommended if the BMI is between the 85th and 95th percentile for age and sex 
152  with the presence of one or more comorbidities or if the BMI is greater than or equal to the 95th 
153  percentile for age and sex regardless of the presence of comorbidities. 
154   
155  Before therapeutic intervention, pediatric patients should receive a medical assessment to 
156  identify genetic (e.g., Prader-Willi syndrome) or endocrinologic (e.g., Cushings syndrome) 
157  causes of their obesity.  Patients also should be screened for the presence of comorbidities such 
158  as hypertension, glucose intolerance, and dyslipidemia.    
159   
160  The use of weight-management products in pediatric patients, as in adults, should be 
161  contemplated only after a sufficient trial of lifestyle modification has failed and the risks of 
162  excess adiposity and the expected benefits of weight loss are believed to outweigh the known 
163  and unknown risks of treatment with a particular weight-management product.  Such a 
164  population might include obese pediatric patients with weight-related comorbidites.  
165   
166   
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167  IV.  CLINICAL ASSESSMENT OF WEIGHT-MANAGEMENT PRODUCTS IN 
168  ADULT PATIENTS 
169   
170  A.  Phase 1 and Phase 2 Trials 
171   
172  Before initiating phase 3 clinical trials, the pharmacokinetics and dose-response profiles of a new 
173  weight-management product should be well-characterized.  Because excess adiposity may 
174  influence a products metabolism and disposition, the pharmacokinetics profile of a weight-
175  management product should be examined in patients with a broad range of BMIs (e.g., 27 kg/m2 
176  to 35 kg/m2) (Cheymol 2000).  To increase the likelihood of identifying the most appropriate 
177  dose for the pivotal clinical trials, early phase clinical studies should include a range of doses and 
178  be designed to identify no-effect and maximally tolerated doses.  Studies should be designed to 
179  differentiate the efficacy of all the active doses versus placebo.  The duration of the phase 2 trials 
180  should be sufficient to capture the maximal or near-maximal weight loss effects of the active 
181  doses.  Forethought should be given to whether the product will be ultimately used in a fixed-
182  dose or dose-titration scheme, as this dosing decision will also influence the size and duration of 
183  the studies.   
184   
185  Patients included in the early phase efficacy and safety studies generally should have BMIs 
186  greater than or equal to 30 kg/m2 or greater than or equal to 27 kg/m2 if accompanied by 
187  comorbidities.  The primary efficacy endpoints should be a comparison of the mean absolute or 
188  percent change in body weight between the active-product and placebo-treated groups and the 
189  proportion of patients in each treatment group who lose greater than or equal to 5 percent of 
190  baseline weight.  The effects by dose of the weight-management product on common weight-
191  related comorbidities also should be examined and taken into account when choosing the most 
192  appropriate dose for the phase 3 studies.  
193   
194  B.  Phase 3 Clinical Trials 
195   
196  1.  Trial Design and Patient Populations 
197   
198  In general, phase 3 clinical trials examining the efficacy and safety of weight-management 
199  products should be randomized, double-blind, and placebo-controlled.  The lifestyle modification 
200  programs used in the preapproval trials should be applicable to individual patients prescribed the 
201  product post-approval (i.e., programs should strike an appropriate balance between effectiveness 
202  and simplicity).     
203   
204  In general, patients should have or be at significant risk for weight-related morbidity and 
205  mortality.  Such patients include those with BMIs greater than or equal to 30 kg/m2 or greater 
206  than or equal to 27 kg/m2 in the presence of comorbidities (e.g., type 2 diabetes, hypertension, 
207  dyslipidemia, sleep apnea, cardiovascular disease).   
208   
209  Effort should be made to include in the studies a representative sample of patients from the 
210  various demographic, ethnic, and racial groups in which the prevalence of obesity is highest.  
211  Development programs also should include a representative sample of patients with extreme 
212  obesity (BMI greater than 40 kg/m2).  
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213   
214  2.  Trial Size and Duration 
215   
216  The number of subjects necessary to demonstrate the efficacy of a weight-management product 
217  will be smaller than the number needed to adequately assess safety.  A reasonable estimation of 
218  the safety of a weight-management product upon which to base approval generally can be made 
219  when a total of approximately 3,000 subjects are randomized to active doses of the product and 
220  no fewer than 1,500 subjects are randomized to placebo for 1 year of treatment.  
221   
222  For example, the above sample size will provide 80 percent power to rule out with 95 percent 
223  confidence an approximately 50 percent increase in the incidence of an adverse event that occurs 
224  at a rate of 3 percent in the placebo group (i.e., 4.5 percent versus 3 percent).  This sample size 
225  also should allow for efficacy and safety analyses to be conducted within important subgroups 
226  such as sex, ethnicity, and baseline BMI.  
227   
228  3.  Efficacy Endpoints 
229   
230  a.  Primary efficacy endpoint 
231   
232  The efficacy of a weight-management product should be assessed by analyses of both mean and 
233  categorical changes in body weight.  
234   
235    Mean: The difference in mean percent loss of baseline body weight in the active-product 
236  versus placebo-treated group.  
237   
238    Categorical: The proportion of subjects who lose at least 5 percent of baseline body 
239  weight in the active-product versus placebo-treated group.      
240   
241  b.  Secondary efficacy endpoints 
242   
243  Secondary efficacy endpoints should include, but are not limited to, changes in the following 
244  metabolic parameters: 
245   
246    Blood pressure and pulse 
247    Lipoprotein lipids 
248    Fasting glucose and insulin 
249    HbA1c (in type 2 diabetics) 
250    Waist circumference 
251   
252  In clinical practice, waist circumference is used as an indirect measure of visceral fat content, 
253  which when increased is associated with an elevated risk for metabolic abnormalities such as 
254  dyslipidemia and diabetes.  Because the evaluation of investigational weight-management 
255  products routinely includes assessment of changes in patients metabolic profiles, and in some 
256  cases may involve measurement of visceral fat content by CT or MRI, waist circumference 
257  should not serve as a surrogate for visceral fat content when measured in a clinical trial 
258  investigating the efficacy of a product for weight loss.  Rather, it can be a means to confirm that 
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259  reductions in waist circumference following treatment with a weight-management product are 
260  associated with the expected improvements in metabolic parameters.    
261   
262  It is likely that a large portion of study subjects will be taking concomitant medications to treat 
263  weight-related comorbidities such as hypertension, type 2 diabetes, and dyslipidemia.  Since 
264  weight loss is expected to improve these comorbidities, an important secondary efficacy 
265  endpoint should be the proportion of subjects treated with the weight-management product 
266  compared with placebo who have a meaningful dose-reduction or complete withdrawal of their 
267  concomitant medication.  Algorithms that direct dose reduction or withdrawal of concomitant 
268  medications based on changes in levels of blood pressure, lipids, or glycemia should be included 
269  in the study protocols.  
270   
271  Measures of quality of life from validated instruments also can be appropriate secondary efficacy 
272  endpoints.  
273   
274  c.  Efficacy benchmarks 
275   
276  In general, a product can be considered effective for weight management if after 1 year of 
277  treatment either of the following occurs: 
278   
279    The difference in mean weight loss between the active-product and placebo-treated 
280  groups is at least 5 percent and the difference is statistically significant 
281   
282    The proportion of subjects who lose greater than or equal to 5 percent of baseline body 
283  weight in the active-product group is at least 35 percent, is approximately double the 
284  proportion in the placebo-treated group, and the difference between groups is statistically 
285  significant  
286   
287  Improvements in blood pressure, lipids, glycemia, or other areas commensurate with the degree 
288  of weight lost are expected in patients treated with an effective weight-management product.  
289  Therefore, changes in common weight-related comorbidites should be factored into the efficacy 
290  assessment of investigational weight-management products.  
291   
292  4.  Standard of Care and Concomitant Medication 
293   
294  Overweight and obese patients enrolled in clinical studies of investigational weight-management 
295  products should receive standard of care, including medication, for comorbidities such as 
296  hypertension, dyslipidemia, and glycemic control.  
297   
298  5.  Patients with Type 2 Diabetes 
299   
300  Compared with nondiabetic patients, overweight and obese patients with type 2 diabetes often 
301  respond less favorably to weight-management products and may face unique safety issues such 
302  as risk for sulfonylurea-induced hypoglycemia following weight loss (if the dose of sulfonylurea 
303  is not appropriately lowered or the drug discontinued).  Therefore, sponsors should consider 
304  examining the efficacy and safety of weight-management products in trials dedicated to patients 
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305  with type 2 diabetes.  The following recommendations should be considered when designing 
306  such trials: 
307   
308    In general, patients should have baseline HbA1c levels between 8 percent and 10 percent. 
309    Patients should be excluded if they have fasting glucose levels greater than 270 mg/dl. 
310    Protocols should include escape criteria for poor glycemic control. 
311    Protocols should include an algorithm for the lowering or elimination of oral 
312  hypoglycemia or insulin dose based on fasting glucose levels and/or HbA1c (for patients 
313  who lose clinically significant amounts of weight). 
314    Patient randomization should be stratified by baseline antidiabetic medication (e.g., 
315  metformin versus sulfonylurea versus a thiazolidinedione versus insulin) and baseline 
316  HbA1c level (e.g., less than or equal to 9 percent versus greater than 9 percent). 
317    Hypoglycemia safety should be monitored.3   
318   
319  C.  General Safety Assessment of Weight-Management Products  
320   
321  To ensure that drug or biologic-induced weight loss is caused primarily by a reduction in fat 
322  content, not lean-body mass, a representative sample of study subjects should have a baseline 
323  and follow-up measurement of body composition by DEXA, or a suitable alternative.  
324   
325  In addition to routine safety monitoring, it may be appropriate for the development programs of 
326  some weight-management products to have specialized safety assessments.  For example, 
327  products that directly interact with the 5HT receptor system, specifically the 5HT  receptor 
2
328  subtypes, probably should include evaluation of risk for cardiac valvulopathy using serial 
329  echocardiography.  The development plans for centrally acting weight-management products 
330  generally should include validated assessments of neuropsychiatric function.  
331   
332  Assessment of the immunogenic potential of therapeutic proteins should be performed over a 
333  period of at least 6 to 12 months.  If adverse events characteristic of allergic or immunologic 
334  reactions are identified, the FDA may ask for additional studies, with durations longer than 12 
335  months.  These additional studies may need to be conducted before submission of an application 
336  for registration or may be conducted after approval as a postmarketing commitment, based on the 
337  overall analysis of the products risks and benefits.  The appropriate timing of such studies can 
338  be discussed with the FDA at a pre-biologics license application meeting or other similar advice 
339  meeting. 
340   
341  For centrally acting weight-management products, sponsors should anticipate the need to 
342  conduct preclinical and clinical studies of abuse liability.  Sponsors are encouraged to discuss the 
343  design of these studies with members of CDERs Controlled Substance Staff during the early 
344  phases of product development.  
345   
                                                 
3 Defining and Reporting Hypoglycemia in Diabetes: A Report from the American Diabetes Association Workgroup 
on Hypoglycemia, 2005, Diabetes Care, 28(5): 1245-9.  
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346  The need for and details of specific safety monitoring may change as new data emerge.  
347  Sponsors are encouraged to discuss their plans for specific safety monitoring with the division 
348  during the early stages of product development. 
349   
350  D.  Weight-Management Products Used in Combination  
351   
352  Two or more products may be combined into a single fixed-dosed combination when each 
353  component makes a contribution to the claimed effect or effects (21 CFR 300.50).  
354   
355  Before initiating long-term clinical studies with fixed-dose combinations, sponsors should 
356  conduct the appropriate preclinical and pharmacokinetics studies.  (See the guidances for 
357  industry Nonclinical Safety Evaluation of Drug or Biologic Combinations and Bioavailability 
358  and Bioequivalence Studies for Orally Administered Drug Products  General Considerations.) 
359   
360  We recommend that the efficacy and safety of fixed-dose combinations be compared with the 
361  individual product components of the combination and placebo in phase 2 trials of sufficient 
362  duration to capture the maximal or near-maximal weight-management effects of the products.  
363  We have not defined a minimum difference in weight loss between a fixed-dose combination and 
364  its individual component products that should be achieved for the combination to be considered 
365  more efficacious than either of its components when used alone.  However, a fixed-dose 
366  combination that is associated with at least twice the weight loss observed with that of each of 
367  the individual components will be viewed more favorably than combinations that do not achieve 
368  this degree of relative weight loss.  
369   
370  Once a fixed-dose combination has been deemed more effective than its individual components, 
371  the combination can then be examined versus placebo in phase 3 trials.  This approach may 
372  preclude the need to include treatment groups for the individual components of the fixed-dose 
373  combination product in late-stage preapproval trials. 
374   
375  The efficacy of a product combination for weight management generally will be assessed using 
376  the same factors as those applied to a single product, as defined in section IV.B.3. 
377   
378  E.  Weight-Management Products for Patients with Medication-Induced Weight 
379  Gain  
380   
381  A number of drugs, notably psychotropic and some anticonvulsant agents, are associated with 
382  moderate-to-marked weight gain (Baptista and Zarate et al. 2004; Pierre and Picard 2001).  In 
383  addition to increasing the risk for adverse health outcomes, medication-induced weight gain may 
384  reduce compliance with the drug responsible for the increased body weight.  
385   
386  Before initiating long-term clinical studies in patients with medication-induced weight gain, 
387  sponsors should rule out clinically significant drug-drug interactions and perform appropriate 
388  preclinical toxicological studies of the subject products.  For details, see the guidances for 
389  industry Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies 
390  In Vitro, In Vivo Drug Metabolism/Drug Interaction Studies  Study Design, Data Analysis, and 
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391  Recommendations for Dosing and Labeling, and Nonclinical Safety Evaluation of Drug or 
392  Biologic Combinations.   
393   
394  Patients eligible for participation in trials examining the efficacy and safety of products for the 
395  treatment of medication-induced weight gain should have a documented increase in body weight 
396  of at least 5 percent within 6 months of starting a drug known to cause weight gain.  Patients 
397  should have BMIs greater than or equal to 27 kg/m2 with comorbidities or greater than or equal 
398  to 30 kg/m2 with or without comorbidities at the time of screening.  
399   
400  Because most weight-management products act within the central nervous system (CNS) and 
401  many of the drugs commonly associated with moderate-to-marked weight gain are used to treat 
402  psychiatric or neurological disorders, unique issues of efficacy and safety may arise in studies of 
403  products used to treat medication-induced weight gain.  For example, it would be important to 
404  demonstrate that the efficacy and safety of the medication causing the weight gain (e.g., atypical 
405  antipsychotic) was not adversely affected by a weight-management product with a CNS 
406  mechanism of action, and vice versa.  These and similar issues should be taken into account 
407  when designing and determining the sample size of trials for the treatment of medication-induced 
408  weight gain.  
409   
410  The efficacy of a product for the treatment of medication-induced weight gain generally will be 
411  assessed using the same factors as those for weight management, as defined in section IV.B.3. 
412   
413  Serotonin syndrome, a potentially life-threatening condition characterized by akathisia, tremor, 
414  altered mental status, clonus, muscular hypertonicity, and hyperthermia (Boyer and Shannon 
415  2005), has been observed in patients exposed to a single or two or more proserotonergic agents 
416  used in combination.  Therefore, in general, weight-management products that act as agonists at 
417  serotonin receptors, particularly the 5-HT2  subtype, should not be studied in combination with 
A
418  proserotonergic medications associated with weight gain.   
419   
420  Because of issues related to safety and possibly efficacy that are unique to the particular 
421  combinations of drugs studied, approval of a product for weight management in patients with 
422  medication-induced weight gain generally will be limited to the weight-inducing drug studied 
423  and will not apply to the drug class in which the compound is a member.  For example, if a 
424  weight-management product is shown to be effective and reasonably safe in the treatment of 
425  clozapine-induced weight gain, the approved indication would be limited to clozapine-induced 
426  weight gain and would not necessarily apply to the entire class of atypical or second generation 
427  antipsychotics.   
428   
429   
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430  V.  CLINICAL ASSESSMENT OF LONG-TERM WEIGHT-MANAGEMENT 
431  PRODUCTS IN PEDIATRIC PATIENTS4  
432   
433  Because the benefit of weight-management products should be carefully weighed against 
434  potential toxicity, particularly in the pediatric population, we anticipate that phase 3 data in 
435  adults generally will be available before a new product is studied in children. 
436   
437  To ensure that the most appropriate dose or doses are studied in phase 3 trials, an assessment of 
438  the pharmacokinetics of a weight-management product in pediatric patients may be appropriate 
439  before initiation of long-term clinical studies.  Pharmacokinetics and dose-ranging studies 
440  generally should include patients with age- and sex-matched BMIs greater than or equal to the 
441  95th percentile.  
442   
443  Trials examining the efficacy and safety of a weight-management product in pediatric patients 
444  should be randomized, double-blind, placebo-controlled, and 1 year in duration.  We suggest that 
445  initial pediatric studies be limited to adolescents (i.e., 12 to 16 year olds).  Eligible patients 
446  should have age- and sex-matched BMIs greater than or equal to the 95th percentile (see 
447  http://www.cdc.gov/growthcharts).  Patients should have a documented history of failing to lose 
448  sufficient weight with lifestyle modification before enrollment into studies of a weight-
449  management product.   
450   
451  We recommend that initial clinical studies include patients with one or more weight-related 
452  comorbidities such as type 2 diabetes, dyslipidemia, or hypertension.  Once a satisfactory risk-
453  benefit profile has been established in this high-risk group of patients, studies of lower risk 
454  patients can be considered.  Effort should be made to recruit equal numbers of males and females 
455  and representative samples of patients from ethnic groups in which the prevalence of obesity is 
456  high.  
457   
458  The lifestyle modification program should continue following randomization to product or 
459  placebo and its importance emphasized at appropriate intervals throughout the trials.    
460   
461  Because linear growth should be taken into account when assessing changes in the body weight 
462  of children and adolescents, the primary efficacy parameter in weight-management trials of 
463  pediatric patients should be a function of the change in BMI (e.g., the mean percent change in 
464  BMI and the proportion of patients who lose greater than or equal to 5 percent of baseline BMI).  
465  Height measurements should be obtained from a wall-mounted stadiometer.  
466   
467  Since demonstration of adequate safety necessitates a larger sample size than demonstration of 
468  efficacy, we anticipate that the sample size of the long-term pediatric weight-management 
469  studies will be determined by considerations of the products mechanism of action and safety 
470  profile in adults.  Sponsors should discuss and justify their proposed sample size with the 
471  division before initiating the study.   
472   
                                                 
4 For details on preclinical and pharmacokinetic evaluations for pediatric product development, see the ICH 
guidances for industry M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceutics 
and E11 Clinical Investigation of Medicinal Products in the Pediatric Population. 
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473  In addition to standard safety evaluations specific to growing children (e.g., assessing Tanner 
474  stage at baseline and endpoint), studies of centrally acting weight-management products in 
475  pediatric patients also should include validated assessments of neuropsychiatric function.  Other 
476  specialized safety assessments may be appropriate depending on the products mechanism of 
477  action and its safety profile in adults.  
478   
479  The efficacy assessment of a weight-management product in pediatric patients will take into 
480  account the products effectiveness in overweight and obese adults as well as the magnitude of 
481  the difference in the mean and categorical (greater than or equal to 5 percent) changes in BMI 
482  from baseline to Year 1 in pediatric patients treated with active product versus placebo.  
483   
484   
485  VI.  STATISTICAL CONSIDERATIONS 
486   
487  A.  Sample Size  
488   
489  The number of subjects in a placebo-controlled trial should be the maximum of sample sizes 
490  calculated based on the co-primary endpoints of categorical response defined as greater than or 
491  equal to 5 percent reduction in baseline body weight after 1 year, and change from baseline 
492  weight.  Calculations should be based on two-sided tests of significance at the 5 percent level 
493  and at least 80 percent power.  Effect sizes for the calculations should represent clinically 
494  meaningful differences.  
495   
496  B.  Preventing Missing Data from Premature Subject Withdrawal 
497   
498  Historically, there have been high rates of premature subject withdrawal in long-term trials of 
499  weight-management products.  To allow for a true intent-to-treat (ITT) analysis, we encourage 
500  sponsors to obtain body weight measurements in all subjects who prematurely withdraw from 
501  late-stage preapproval trials near the calendar date at which they were scheduled to complete the 
502  trial (Simons-Morton and Obarzanek et al. 2006).  For example, a subject who withdraws from a 
503  12-month study after 6 months of treatment should have a body weight measurement at the time 
504  he or she would have completed 12 months of study participation. 
505   
506  C.  Analysis Methods 
507   
508  Response rates should be compared between treatment groups using statistical methods 
509  appropriate for categorical data.  A sensitivity analysis should be conducted that considers 
510  subjects who are treated, drop out, and do not have complete post-baseline data as treatment 
511  failures.  
512   
513  The analysis of (percentage) weight change from baseline should use ANOVA or ANCOVA 
514  with baseline weight as a covariate in the model.  The analysis should be applied to the last 
515  observation carried forward on treatment in the modified ITT population defined as subjects who 
516  received at least one dose of study drug and have at least one post-baseline assessment of body 
517  weight.  Sensitivity analyses employing other imputation strategies should assess the effect of 
518  dropouts on the results.  The imputation strategy should always be prespecified and should 
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519  consider the expected dropout patterns and the time-course of weight changes in the treatment 
520  groups.  No imputation strategy will work for all situations, particularly when the dropout rate is 
521  high, so a primary study objective should be to keep missing values to a minimum.  Repeated 
522  measures analyses can be used to analyze longitudinal weight measurements but should estimate 
523  the treatment effect at the final time point.  Statistical models should incorporate as factors any 
524  variables used to stratify the randomization.  As important as assessing statistical significance is 
525  estimating the size of the treatment effect.  If statistical significance is achieved on the co-
526  primary endpoints, type 1 error should be controlled across all clinically relevant secondary 
527  efficacy endpoints intended for product labeling. 
528   
529  D.  Graphical Methods 
530   
531  Graphical methods showing treatment effects over time for completers should be presented.  
532  Cumulative distribution plots can be useful for showing response rates for different definitions of 
533  response based on the percentage of subjects with a change value equal to or less than the value 
534  on the x-axis selected to define the positive response.  Additional graphical presentations of the 
535  data to illustrate the effect of the drug are encouraged.  For examples, see the guidance for 
536  industry Clinical Studies Section of Labeling for Human Prescription Drug and Biological 
537  Products  Content and Format. 
538   
539   
540  VII.  LABELING CONSIDERATIONS 
541   
542  Data on the changes in the major weight-related comorbidities are important in assessing the 
543  overall risk-benefit profile of a new weight-management product and can be included in the 
544  Clinical Studies section of the products labeling.  However, it is important to recognize that 
545  even though secondary efficacy endpoints are prespecified and the overall type 1 error rate is 
546  controlled for, that does not necessarily guarantee that all secondary endpoints will be included 
547  in labeling if the differences between active-product and placebo-treated groups are of nominal 
548  statistical significance.  The clinical significance and consistency across studies of any observed 
549  differences will be important in determining whether the secondary efficacy data merit inclusion 
550  in the Clinical Studies section of the labeling.   
551   
552   
553  VIII.  STAND-ALONE INDICATIONS FOR THE PREVENTION OR TREATMENT 
554  OF WEIGHT-RELATED COMORBIDITIES 
555   
556  As mentioned earlier, weight loss through lifestyle modification is associated with improvements 
557  in blood pressure, lipid levels, glucose and insulin metabolism, and other physiometabolic 
558  endpoints.  Improvements in these comorbidites are expected following drug or biologic-induced 
559  weight loss, and from a regulatory perspective, they are considered part of the weight-
560  management indication.  Thus, for a weight-management product to obtain a stand-alone 
561  indication for the prevention or treatment of type 2 diabetes, dyslipidemia, hypertension, or any 
562  other weight-related comorbidity, it should be shown that the product effectively prevents or 
563  treats the comorbidity through a mechanism that is independent of weight loss.  
564   
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565   
566  IX.  METABOLIC SYNDROME 
567   
568  The term metabolic syndrome represents a cluster of laboratory and clinical findings that serve as 
569  markers for increased risk for cardiovascular disease and type 2 diabetes, and, depending upon 
570  the definition used, is prevalent in as much as 25 percent of the adult American population.  The 
571  FDA does not necessarily consider the metabolic syndrome to represent a distinct disease entity.  
572  At present, there is no single etiological factor or central pathogenetic abnormality identified as 
573  mediating the constellation of excess visceral adiposity, abnormal lipids, elevated blood pressure, 
574  and insulin resistance that comprise the metabolic syndrome.  Nonetheless, in addition to 
575  lifestyle modification, a host of drug therapies now exist to address individual or multiple 
576  components of the syndrome (e.g., lipid altering agents, antihypertensives, insulin sensitizers).  
577  Ideally, a therapeutic product intended to treat metabolic syndrome should normalize or improve 
578  all components of the syndrome, independent of weight loss (see section VIII), and ultimately be 
579  shown to prevent the development of type 2 diabetes and reduce cardiovascular morbidity and 
580  mortality.   
581   
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582  REFERENCES 
583   
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591  Barlow, SE and WH Dietz, 1998, Obesity Evaluation and Treatment: Expert Committee 
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628  Janssen, I, PT Katzmarzyk, and R Ross, 2004, Waist Circumference and not Body Mass Index 
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640  The Practical Guide. Identification, Evaluation, and Treatment of Overweight and Obesity in 
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647  Simons-Morton, D, E Obarzanek, and J Cutler, 2006, Obesity Research-Limitations of Methods, 
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649   
650  Speiser, P, M Rudolf, H Anhalt, C Camacho-Hubner, F Chiarelli et al., 2005, Childhood Obesity, 
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652   
653  Zhu, S, Z Wang, S Heshka, M Heo, MS Faith et al., 2002, Waist Circumference and Obesity-
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656   
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