Major Depressive 

Disorder:  Developing 

Drugs for Treatment 

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DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only.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 60 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Javier Muniz, Jean Kim, or Juliette Toure at 
301-796-2260. 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
June 2018 

Clinical/Medical 

 
Revision 1 

15071dft.docx  
 
05/31/18   
Major Depressive 

Disorder:  Developing 

Drugs for Treatment 

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., 4th 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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
  
 
June 2018 

Clinical/Medical 

 
Revision 1 

 
   
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION..................................................................................................1
  
II.   BACKGROUND ....................................................................................................2
  
III.   DEVELOPMENT PROGRAM ............................................................................2
  
A.   General Considerations ....................................................................................................2 
 
B.   General Pharmacological and Clinical Safety Considerations ......................................3 
 
1.  Nonclinical Safety Considerations ......................................................................................3
  
2.  Clinical Pharmacology Considerations ..............................................................................3 
 
C.   Specific Efficacy Trial Considerations ............................................................................4
  
1.  Study Design........................................................................................................................ 4
  
a.   Short-term treatment of a depressive episode ...............................................................4
  
b.   Maintenance treatment .................................................................................................5
  
c.   Noninferiority design ....................................................................................................5 
 
d.   Partial response and treatment-resistant depression .....................................................5 
 
2.  Study Population and Entry Criteria ...................................................................................6 
 
3.  Selection and Adjudication of Efficacy Endpoints ..............................................................6 
 
4.  Statistical Considerations.................................................................................................... 7 
 
5.  Phase 3 or 4 (Postmarketing) Safety Considerations ..........................................................7 
 
a.   Long-term safety data ...................................................................................................7 
 
b.   Pregnancy ..................................................................................................................... 7 
 
6.  Additional Considerations for Special Populations  ............................................................7 
 
a.   Pediatrics ...................................................................................................................... 7 
 
b.   Other special populations  .............................................................................................8 
 
D.   Biomarker Considerations................................................................................................8 
 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
Major Depressive Disorder:    
1 
Developing Drugs for Treatment 
2 
Guidance for Industry1  
3 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations. To  discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION  
18   
19  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
20  monotherapeutic, combination, and adjunctive treatment of major depressive disorder (MDD).2   
21  Specifically, this guidance addresses the FDAs current thinking regarding the overall 
22  development program and clinical trial designs for antidepressant drug products.  This draft 
23  guidance is intended to serve as a focus for continued discussions among the Division of 
24  Psychiatry Products (the Division), pharmaceutical sponsors, the academic community, and the 
25  public.3   
26   
27  This guidance does not address bipolar depression.  This guidance also does not address the 
28  development of nonpharmacologic treatments for depression. 
29   
30  This guidance does not contain discussion of the general issues of statistical analysis or clinical 
31  trial design. Those topics are addressed in the ICH guidances for industry E9  Statistical 
32  Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
33  Trials, respectively.4  
34   
                                                 
1 This  guidance has been  prepared by the Division of Psychiatry Products in  the Center for  Drug Evaluation and  
Research at the Food and Drug  Administration.  
 
2 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  unless otherwise specified.  
 
3 In addition to consulting  guidances, sponsors are encouraged to contact the Division to  discuss specific issues that 
arise during the development of antidepressant drug products.  
 
4 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page  
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
1 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
35  This guidance revises the guidance for industry Guidelines for the Clinical Evaluation of 
36  Antidepressant Drugs issued in September 1977.  Major revisions were made to the 1977 
37  guidance to align it with the FDAs current thinking on this topic. After it has been finalized, 
38  this guidance will replace the 1977 guidance.   
39   
40  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
41  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
42  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
43  the word should in Agency guidances means that something is suggested or recommended, but 
44  not required. 
45   
46   
47  II.  BACKGROUND 
48   
49  MDD is a debilitating and chronic illness. According to a 2018 World Health Organization 
50  (WHO) Fact Sheet, depression is a common illness worldwide, with more than 300 million 
51  people affected.5   
52   
53  The symptoms of MDD are defined in the most recent Diagnostic and Statistical Manual of 
54  Mental Disorders (DSM).6  The DSM also lists several other depressive disorders distinguished 
55  by differences in severity, chronicity, etiology, and time course of symptoms.  Although this 
56  guidance focuses on MDD, some of the principles described here may be applicable to clinical 
57  trials of drugs intended to treat other forms of depression.  Sponsors should seek FDA feedback 
58  on development programs for non-MDD depression treatments.  
59   
60   
61  III.  DEVELOPMENT PROGRAM 
62   
63  A.  General Considerations 
64   
65  Traditional clinical trial designs for antidepressant drugs have been based on an expected 4- to 8
66  week onset of action. All conventional classes of antidepressants have been oral medications for 
67  chronic daily administration, including tricyclic antidepressants, monoamine oxidase inhibitors, 
68  selective serotonin-reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors 
69  (SNRIs), and others. Their FDA-approved indications have included treatment of MDD (in adult 
70  and pediatric patients), adjunctive therapy to existing MDD treatment, and treatment-resistant 
71  depression. 
72   
73  MDD treatment indications may be divided into two phases:  short-term (i.e., treatment of a 
74  depressive episode) and maintenance (i.e., relapse prevention).  The regulatory issues for these 
75  phases depend on the particular characteristics of each antidepressant.   
                                                 
5 WHO, 2018, Depression Fact Sheet, accessed April 10, 2018, 
http://www.who.int/mediacentre/factsheets/fs369/en/. 
 
6 American Psychiatric Association, editor, 2013, Diagnostic and Statistical Manual  of Mental Disorders, 5th 
edition.   
2 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
76   
77  Rapid-acting antidepressant drugs are in development, and their clinical trial design issues and 
78  regulatory considerations may differ from those of previously approved antidepressant drugs, 
79  which generally take 4 to 6 weeks to show their effect. 
80   
81  B.  General Pharmacological and Clinical Safety Considerations 
82   
83  1.  Nonclinical Safety Considerations 
84   
85  In addition to the usual animal toxicology studies needed for any new molecular entity, sponsors 
86  should consider the drugs intended duration of treatment, mechanism of action, and known 
87  pharmacodynamic and/or pharmacokinetic interactions with other coadministered drugs when 
88  determining the types of nonclinical safety studies needed.  As sponsors explore drugs with new 
89  mechanisms of action, they should be aware that there could be specific nonclinical safety 
90  studies needed based on mechanism-specific concerns.  
91   
92  For example, N-methyl-d-aspartate (NMDA) receptor antagonists have been found to cause 
93  Olney lesions, which are vacuoles that may precede the onset of permanent injury in the form of 
94  neuronal cell death in the brain.  For the NMDA receptor antagonist drug class, a study 
95  evaluating the acute neurotoxic effect of the drug is expected before the first human use.  The 
96  protocol for this study should be submitted for review and feedback before initiating the study.   
97   
98  We recommend that all general toxicology studies contain a thorough histopathology evaluation 
99  of at least seven slices of the brain as described in Bolon et al., 2013.7  Use of alternate slices can 
100  be justified based on the predicted sensitivity of the drug.  If the drug is intended for chronic use, 
101  the duration of nonclinical studies should conform to the ICH guidance for industry M3(R2)  
102  Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
103  Authorization for Pharmaceuticals. Sponsors are encouraged to request a pre-investigational 
104  new drug application meeting with the FDA to discuss the specific requirements of the 
105  nonclinical program and the need for special toxicity studies.   
106    
107  2.  Clinical Pharmacology Considerations 
108   
109  Characterization of a drugs pharmacokinetics and pharmacodynamics in early phase 
110  development is critical to assist identification of rational doses and dosing intervals for the phase 
111  3 trials, and to develop drug switching strategies.  Different types of antidepressants, such as the 
112  rapid-acting drugs under development, are likely to have different pharmacokinetic and 
113  pharmacodynamic properties that may involve specific studies and methods of analysis. 
114   
115  For all antidepressants, sponsors should conduct pharmacodynamic studies, such as in vivo 
116  receptor binding studies or biomarker studies, to initially identify appropriate dosage ranges, and 
117  these should be followed by clinical endpoint dose-response studies.  Sponsors generally should 
118  include at least one dose-finding trial using a fixed-dose design with at least three doses.  
                                                 
7 Bolon, B, et al., 2013, STP Position Paper:  Recommended Practices for Sampling and Processing the Nervous 
System (Brain, Spinal Cord, Nerve, and Eye) During  Nonclinical General Toxicity Studies, Toxicol Pathol, 41, 
10281048. 
3 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
119  Sponsors can apply dose-response or exposure-response modeling and simulation to integrate the 
120  information obtained in early phase clinical trials and to inform dosing regimen selection for 
121  phase 3 trials. 
122   
123  To develop an antidepressant intended for adjunctive therapy, early assessment of 
124  pharmacokinetic interaction with the background therapy is highly recommended.  
125   
126  C.  Specific Efficacy Trial Considerations 
127   
128  Sponsors should consider the following recommendations concerning study design, study 
129  population criteria, efficacy endpoints, statistical considerations, and safety considerations.  
130   
131  1.  Study Design 
132   
133  a.  Short-term treatment of a depressive episode 
134   
135     Choice of control group  Substantial responses are typically seen in placebo groups in 
136  antidepressant trials, and these are often larger than the drug-placebo difference.  For that 
137  reason, trials of effective antidepressants have a high failure rate (about 50 percent).  
138  Therefore, it is not possible to identify a consistent drug effect that could be used as a 
139  noninferiority margin in comparative trials.  A placebo group is necessary to ensure that 
140  observed effects are not the result of spontaneous improvement, expectation bias, 
141  attention from health care professionals involved in the trial, regression to the mean, or 
142  other factors not related to the activity of the study drug.  Randomized, double-blind, 
143  placebo-controlled, parallel designs are the current standard for short-term efficacy trials 
144  in MDD.  A substantially earlier or larger effect could be demonstrated in an active
145  control superiority trial.  
146   
147     Timing of effect  Study duration and timing of assessment of primary endpoints 
148  depends on the mechanism of action of the antidepressant and the expected onset of the 
149  treatment effect.  Antidepressants in established classes (e.g., SSRIs, SNRIs) typically 
150  need studies of 6 to 8 weeks duration to demonstrate efficacy, with the effect first 
151  appearing after 3 to 4 weeks. Thus, we consider 6 to 8 weeks an appropriate study 
152  duration for short-term efficacy endpoints for these types of antidepressants.  
153   
154  For rapid-acting antidepressants, the timing of effect considerations include the 
155  following: 
156   
157    Efficacy generally should be demonstrated within 1 week for a rapid-acting 
158  antidepressant. Some novel antidepressants are thought to be effective within hours 
159  or days. In such cases, an earlier primary efficacy endpoint would be appropriate.  
160   
161    Durability of effect beyond the initial response should be characterized.  To  
162  demonstrate both early onset of action and durability of effect, a primary efficacy 
163  endpoint early in the course of treatment would be chosen, with continued 
164  observation of drug-placebo differences over time.  The precise studies depend on 
4 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
165  how the drug is intended to be used, for example as a predecessor to a conventional 
166  antidepressant or as a drug for repeated use.  In the latter case, the appropriate dosing 
167  interval could be determined by randomizing, after the initial dose, to several 
168  different dosing intervals. 
169   
170  Sponsors planning to employ novel trial designs should request a meeting with the FDA 
171  and seek early advice on relevant trial design and statistical considerations.   
172   
173  b.  Maintenance treatment 
174   
175  Because depression usually is a cyclical disease, maintenance studies of conventional 
176  antidepressants are actually assessments of the ability of the drug to reduce the rate of recurrence 
177  of depression. Thus, typical studies generally should be at least 6 months in duration, as most 
178  recurrences are delayed. To inform labeling regarding maintenance treatment, after approval of 
179  an antidepressant, the FDA typically requests a postmarketing commitment to conduct a double
180  blind randomized withdrawal trial.  To date, such trials have included an open-label stabilization 
181  period followed by randomization to either continued treatment or to placebo.  For rapid-acting 
182  antidepressants, there is interest in whether the rapid effect does in fact persist for the episode 
183  treated. Demonstration of maintenance effects usually has different study requirements 
184  depending on the drugs dosing schedule, long-term safety considerations, and whether long
185  term usage is feasible.  In general, long-term  safety assessments should be incorporated in the 
186  design of maintenance studies (see section III.C.5., Phase 3 or 4 (Postmarketing) Safety 
187  Considerations). 
188   
189  The FDA is interested in studies that explore whether treatment response can be maintained with 
190  a lower dose of the drug than is needed for short-term efficacy, and whether a lower dose may 
191  improve tolerability.  We may consider the results of such studies for labeling. 
192   
193  Of note, randomized withdrawal studies provide a useful opportunity to assess whether a 
194  treatment is associated with a discontinuation syndrome.  Sponsors should systematically assess 
195  adverse events that occur upon drug discontinuation.  
196   
197  c.  Noninferiority design 
198   
199  As noted above, noninferiority designs are not able to establish efficacy for antidepressants.  
200  High placebo response rates and small magnitude of treatment effect (relative to placebo) are of 
201  concern in most conventional antidepressant trials, which makes defining the active control 
202  effect and choosing a noninferiority margin difficult. 
203   
204  d.  Partial response and treatment-resistant depression  
205   
206  Although it is reasonable to distinguish between adjunctive therapy for partial responders versus 
207  monotherapy for nonresponders based on intended use, the distinction is somewhat arbitrary.  
208  Response, partial response, and nonresponse exist on a continuum with no universally accepted 
209  definitions or cut points for differentiation.  Nevertheless, we distinguish between these 
210  conditions in considering indications for labeling, and the types of studies needed to demonstrate 
5 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
211  efficacy in adjunctive therapy versus treatment-resistant depression (TRD) are quite different.  
212  For adjunctive treatment, studies should include patients with partial responses to other 
213  antidepressant therapies; the investigational drug should be compared to placebo when added to 
214  the baseline antidepressant. Patients who have not responded to more than one prior 
215  antidepressant, administered at an adequate dose and duration, should be enrolled in TRD 
216  studies. Patients should be randomized to either the new treatment or to continue the 
217  antidepressant to which they had failed to respond. 
218    
219  Sponsors are encouraged to discuss their proposed study designs with the FDA before initiating 
220  trials intended to support a marketing application. 
221    
222  2.  Study Population and Entry Criteria 
223   
224  Trials designed to assess the efficacy of antidepressant drugs should include patients with DSM
225  defined MDD. The diagnosis should be confirmed via a semi-structured interview such as the 
226  current Structured Clinical Interview for DSM or MINI International Neuropsychiatric 
227  Interview.  
228   
229  Study populations should reflect a range of severities of MDD, although trials to date in patients 
230  with less-than-moderate depression have not been successful.  Investigators should seek 
231  demographically broad populations and avoid unnecessary restriction of study populations (e.g., 
232  by excluding patients with concomitant illness and concomitant therapy (although known or 
233  anticipated drug-drug interactions  should be avoided)).  Patients with a history of suicidal 
234  ideation and behavior need not be systematically excluded from trials.  See also section III.C.6., 
235  Additional Considerations for Special Populations.  Sponsors should provide the rationale for 
236  restrictive inclusion and exclusion criteria.   
237   
238  3.  Selection and Adjudication of Efficacy Endpoints 
239   
240  Clinician-rated outcome measures are the current standard for assessing efficacy in 
241  antidepressant trials.  To date, the FDA has accepted the following as primary endpoints in phase 
242  3 studies to support an MDD indication: 
243   
244     Hamilton Depression Rating Scale (typically the 17-item version)  
245     Montgomery Asberg Depression Rating Scale  
246     Childrens Depression Rating Scale 
247   
248  Other primary endpoints may be acceptable; however, sponsors planning to use a novel primary 
249  endpoint in phase 3 trials should seek advice before initiating studies.  
250   
251  Secondary endpoints assess other domains of symptom improvement relevant for labeling.  
252  Common endpoints for consideration include: 
253   
254     Clinical Global Impression (CGI)  
255     Sheehan Disability Scale  
256   
6 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
257  In the past, either CGI-Improvement (CGI-I) measured at the end of study or CGI-Severity 
258  (CGI-S) assessed as change from baseline have been acceptable.  However, the Division prefers 
259  CGI-S to CGI-I, given the potential influence of recall bias on CGI-I.  
260   
261  4.  Statistical Considerations 
262   
263  Because of high placebo response and dropout rates that are commonly observed, sponsors 
264  should consider these factors in sample size calculations to ensure that the trial has sufficient 
265  statistical power to detect the anticipated treatment effect.  In general, a detailed statistical  
266  analysis plan should be submitted before trial initiation to obtain timely feedback on the trial 
267  design and statistical concerns.  Any consideration of nontraditional designs or novel analyses 
268  should be preceded by a meeting with the FDA to review and reach agreement on the plan.  
269  Sponsors who submit the statistical analysis plan after enrollment of the first patient (but before 
270  data lock) should provide documentation that the analysis plan was not developed or altered with 
271  efficacy data in hand. 
272   
273  5.  Phase 3 or 4 (Postmarketing) Safety Considerations 
274   
275  a.  Long-term safety data 
276   
277  Conventional drugs for treatment of MDD are often taken long-term (defined as continuous or 
278  intermittent use for at least 6 months), given that MDD is a chronic condition requiring ongoing 
279  management to reduce the rate of recurrence.  Therefore, the safety database should meet the 
280  patient exposures outlined in the ICH guidance for industry E1A The Extent of Population 
281  Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term Treatment of Non-Life-
282  Threatening Conditions. Note that these are minimum patient exposures and that larger 
283  exposures may be needed for specific drugs depending on safety concerns identified during drug 
284  development.  
285   
286  b.  Pregnancy 
287   
288  Given that pregnant women typically are excluded from antidepressant trials but remain a 
289  population that sometimes requires depression treatment, sponsors should collect safety data in 
290  women who are inadvertently exposed in pregnancy during drug development trials and in 
291  pregnant women who use these drugs in the postmarketing setting.  Sponsors should use existing 
292  antidepressant pregnancy registries (e.g., National Pregnancy Registry for Psychiatric 
293  Medications) or establish their own registry.   
294   
295  6.  Additional Considerations for Special Populations 
296   
297  a.  Pediatrics  
298   
299  At present, data are insufficient to support extrapolation of adult efficacy data to support efficacy 
300  in pediatric MDD because pediatric studies of antidepressants effective in adults have frequently 
301  been unsuccessful. Even for antidepressants already approved in adult MDD, to obtain an initial 
302  short-term efficacy indication in pediatric MDD sponsors should conduct two independent, 
7 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
303  adequate and well-controlled clinical trials in pediatric patients, in addition to pharmacokinetic 
304  and safety information in the relevant pediatric age groups.  The Division may consider reliance 
305  on positive adult maintenance studies for a maintenance indication study waiver after studies 
306  have established short-term efficacy and long-term safety in the pediatric population.  
307   
308  For pediatric MDD, we consider the relevant age groups to be children (ages 7 through 12) and 
309  adolescents (ages 13 through 17). We consider these age groups to be unique populations with 
310  their own specific needs (e.g., different developmental physiology, different psychosocial 
311  concerns). Therefore, the traditional pediatric development program should consist of 
312  pharmacokinetic, efficacy, and safety studies that cover both age groups.  For patients aged 0 to 
313  6 years, including neonates, studies are considered impossible or highly impractical because of 
314  the low prevalence of MDD in this age range, and a study waiver is generally granted.  
315  Supplementary juvenile animal studies may be needed before the initiation of drug treatment in 
316  pediatric patients.  Protocols for clinical and nonclinical studies should be submitted for review 
317  and feedback before initiating the study. 
318   
319  b.  Other special populations 
320   
321  Geriatric patients and patients with renal insufficiency, cardiac disease, chronic pain, and hepatic 
322  impairment should be included in trials during drug development, if feasible.  Because patients 
323  with human immunodeficiency virus and hepatitis C can require treatment with antidepressants, 
324  these patients should not be excluded from trials during drug development.  Patients with a 
325  history of substance abuse should also be considered for inclusion in these studies, although such 
326  inclusions should be weighed against concerns about diagnostic and medication effect 
327  confounders, including substance abuse maintenance therapy.  Accordingly, patients whose 
328  substance use disorder is not at least in partial remission will likely be excluded from  
329  antidepressant trials depending on the level of particular confounding concerns.  
330   
331  D.  Biomarker Considerations 
332   
333  At present, there are no surrogate markers for assessment of antidepressant effectiveness.  
334  Biomarkers could be developed for disease subtyping, monitoring of disease progression, dose 
335  selection, and prediction of treatment response.  Sponsors seeking to include a biomarker in their 
336  clinical trials should request a guidance meeting with the Division early in the development 
337  program.  
8