Stimulant Use 
Disorders:  
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Matthew Sullivan at 301-796-1245.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
October 2023 
Clinical/Medical 
52473066dft.docx 
09/29/23   
Stimulant Use 
Disorders:  
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/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) 
 
October 2023 
Clinical/Medical
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND:  HETEROGENEITY OF STIMULANT USE DISORDERS AND 
POPULATIONS ................................................................................................................ 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 3 
A.  Early Phase Development Considerations ................................................................................... 3 
B.  Efficacy Trial Considerations ....................................................................................................... 4 
1. Population ........................................................................................................................................ 4 
2. Design and Duration........................................................................................................................ 5 
3. Measurements of Drug Use ............................................................................................................. 5 
4. Measurements of Drug Use to Assess Treatment Response............................................................. 6 
C.  Endpoints ........................................................................................................................................ 7 
1. Change in Pattern of Stimulant Use ................................................................................................ 7 
2. Change in Disease Status Using Diagnostic Criteria ...................................................................... 8 
3. Use of Other Clinical Outcome Assessments ................................................................................... 9 
IV.  BENEFIT-RISK CONSIDERATIONS ........................................................................ 10 
V.  LABELING ..................................................................................................................... 10 
VI.  EXPEDITED PROGRAMS ........................................................................................... 11 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Stimulant Use Disorders:  Developing Drugs for Treatment 
2  Guidance for Industry1 
3   
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
19  treatment of stimulant use disorders.2  Specifically, this guidance addresses the Food and Drug 
20  Administrations (FDAs or Agencys) current recommendations regarding the overall 
21  development program and clinical trial designs for the development of drugs to support 
22  indications for treatment of moderate to severe cocaine use disorder, treatment of moderate to 
23  severe methamphetamine use disorder, or treatment of moderate to severe prescription stimulant 
24  use disorder.3  This draft guidance is intended to serve as a focus for continued discussions 
25  among Center for Drug Evaluation and Research staff (particularly the Division of 
26  Anesthesiology, Addiction Medicine, and Pain Medicine, or the division), pharmaceutical 
27  sponsors, the academic community, and the public.4  This guidance does not address treatment of 
28  intoxication or poisoning with various stimulants or treatment of withdrawal from stimulants.  
29   
30  Because FDA has yet to approve any medication treatments for stimulant use disorder, this 
31  guidance reflects current recommendations based on a number of uncertainties about the best 
 
1 This guidance has been prepared by the Division of Anesthesiology, Addiction Medicine, and Pain Medicine 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 biological products unless 
otherwise specified. 
 
3 FDA understands that sponsors may also wish to consider the development of drugs to support indications for 
treatment of mild stimulant use disorders, though given past experience, it may be particularly challenging to 
demonstrate treatment is effective in individuals with mild stimulant use disorders.  There may also be practical and 
ethical concerns about identifying, recruiting, and enrolling subjects with mild stimulant use disorders if the benefit-
risk balance of the specific drug being studied is not appropriate for an individual with a mild stimulant use disorder. 
However, we encourage sponsors to contact FDA if this is of interest.  
 
4 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that 
arise during the development of these drugs.  
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
32  approaches for treating stimulant use disorder and the best approaches for evaluating responses 
33  to treatment.  This guidance also incorporates lessons learned about approaches for evaluating 
34  responses to treatment that are unlikely to be successful.  FDA is engaged in an ongoing process 
35  to learn more about stimulant use disorders and their treatments to provide the best possible 
36  advice to sponsors.5  As the evidence supporting the development of drugs for stimulant use 
37  disorder treatment evolves, the recommendations in this guidance and any recommendations 
38  given to sponsors at milestone meetings may change. 
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:  HETEROGENEITY OF STIMULANT USE DISORDERS AND 
48  POPULATIONS 
49   
50  The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (DSM-5) has a single 
51  diagnosis, stimulant use disorder, defined as a pattern of amphetamine-type substance, cocaine, 
52  or other stimulant use leading to clinically significant impairment or distress, ranging from mild 
53  to severe.6  The definition lists various symptoms of impairment or distress, but notably, it does 
54  not include any criteria related to amount or frequency of stimulant use.7  
55   
56  The group of individuals meeting DSM-5 criteria for stimulant use disorder is very 
57  heterogeneous, with individuals using different stimulants in a range of different settings and for 
58  different reasons.  This heterogeneity may contribute to the difficulty in identifying medications 
59  that are efficacious for the entire subset of patients diagnosed with cocaine use disorder or 
60  methamphetamine use disorder, and even more for all patients meeting the broader criteria for 
61  stimulant use disorder.  Cocaine, methamphetamine, and other stimulants have different 
62  mechanisms and effects, and this may lead to differences in clinical presentation and responses 
63  to treatment.   
64   
65   
 
5 A public workshop hosted by the Reagan-Udall Foundation for the FDA in October 2021 brought together experts 
from the patient community, academia, clinical care, FDA, the National Institute on Drug Abuse, pharmaceutical 
companies, and health insurance payers.  Those experts emphasized the need for continued investment in clinical 
research and for consensus around clinically meaningful and patient-centric endpoints for assessing treatments for 
stimulant use disorder.  The report can be found on the foundations website at 
https://reaganudall.org/programs/substance-use-disorders.  
 
6 American Psychiatric Association, 2013, Diagnostic and Statistical Manual of Mental Disorders, 5th edition, 
Arlington, VA: American Psychiatric Association, 561. 
 
7 The DSM-5 stimulant use disorder diagnostic criteria are available on pages 561 to 562 of the manual, which is 
available at https://dsm.psychiatryonline.org/doi/epdf/10.1176/appi.books.9780890425596. 
2  Contains Nonbinding Recommendations 
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66  III.  DEVELOPMENT PROGRAM 
67   
68  This section includes general considerations for development programs evaluating potential drug 
69  treatments for stimulant use disorder.  FDA is open to discussing various approaches to address 
70  these considerations; sponsors should engage the division early in the drug development process. 
71   
72  A.  Early Phase Development Considerations 
73   
74  To characterize the safety profile of the drug, sponsors should conduct first-in-human studies in 
75  healthy volunteers.  In addition to general phase 1 safety and pharmacokinetic studies, sponsors 
76  should address the potential for interactions between the investigational drug and the relevant 
77  stimulant in subjects who are experienced in taking stimulants.  Because stimulants have the 
78  potential for single-dose lethality, sponsors should establish that the investigational drug does not 
79  potentiate the toxicity of the stimulant (e.g., with adverse effects such as tachycardia, 
80  hypertension, and central nervous system (CNS) activation).  It should be expected that the 
81  subject with stimulant use disorder may be exposed to both the investigational drug and the 
82  stimulant concurrently.  For this reason, sponsors should ensure that there is no clinically 
83  relevant drug-stimulant interaction (either pharmacokinetic or enhancement of the 
84  pharmacodynamic or adverse effects of the stimulant leading to exaggerated adverse effects) 
85  early in drug development.   
86   
87    If there is a predicted interaction that may lead to an adverse event based upon the 
88  investigational drug and the stimulants mechanism of action, or if there are observations 
89  in nonclinical studies or phase 1 studies of the investigational drug alone (e.g., 
90  adrenergic-type observations, CNS activation, or lowered seizure threshold in animal 
91  toxicology studies) that suggest the potential for an interaction with the stimulant, animal 
92  toxicology interaction studies should precede clinical phase 1 interaction trials.  These 
93  toxicology studies should address risks such as acute cardiovascular effects, lowering of 
94  seizure threshold, or other specific predicted effects.8   
95   
96    If sponsors observe serious interactions leading to toxicity in nonclinical studies, or if 
97  sponsors observe potentially important adverse events likely resulting from an interaction 
98  in phase 1 trials, sponsors should consider discontinuing development or suspending 
99  development and assessing the benefit-risk of continued development.  Depending on the 
100  pharmacology of the investigational drug, sponsors should design animal toxicology 
101  studies and (if appropriate) phase 1 clinical trials in stimulant-experienced subjects to 
102  carefully assess any potential drug effect that may enhance the stimulants adverse effects 
103  (e.g., CNS activity, adrenergic activity including assessment of cardiovascular effects, 
104  seizure threshold). 
105   
 
8 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible.  We 
encourage sponsors to consult with us if it they wish to use a nonanimal testing method they believe is suitable, 
adequate, validated, and feasible.  We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.  
 
3  Contains Nonbinding Recommendations 
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106  After completing investigational drug-stimulant interaction nonclinical studies, as appropriate, 
107  sponsors should conduct initial investigational drug-stimulant interaction human trials in subjects 
108  who are experienced with the stimulant through the route of administration of interest, who are 
109  not seeking treatment for their stimulant use disorders, and who are otherwise medically healthy.  
110  These trials should be conducted in carefully monitored situations where stimulant-associated 
111  adverse events can be managed.  Sponsors should evaluate the effects of the investigational drug 
112  on the pharmacokinetics and pharmacodynamics (e.g., physiological effects) of the stimulant(s) 
113  of interest.  These initial investigational drug-stimulant interaction human trials may also be able 
114  to provide some preliminary data on the ability of the investigational drug to modify subjective 
115  responses to the stimulant of interest.  Additionally, FDA anticipates that the trials can provide 
116  information on how the investigational drug affects the detection of the stimulant in biological 
117  fluids.  This is important in interpreting the results of toxicology tests that are used to detect 
118  illicit stimulant use in efficacy trials. 
119   
120  B.  Efficacy Trial Considerations 
121   
122  1.  Population 
123   
124  To improve the chances of success, we recommend that sponsors of drug development programs 
125  evaluating potential treatments for stimulant use disorder give careful attention to the populations 
126  they select for study.  Thus, when evaluating the efficacy of a drug for the treatment of stimulant 
127  use disorder, the sponsor should consider studying people who use cocaine, methamphetamine, 
128  and prescription stimulants separately.  Initial clinical trial evidence that therapeutic response is 
129  similar across different stimulants could provide useful information for later clinical trials with 
130  broader populations. 
131   
132  Some additional considerations for sponsors of drugs for the treatment of stimulant use disorders 
133  could include route of administration (oral, smoked, intravenous, or intranasal) and/or motivation 
134  for use of a specific stimulant (e.g., work performance enhancement, club drug use, escape, 
135  sensation seeking, sexual performance enhancement).  Some subpopulations may be particularly 
136  responsive, or nonresponsive, to specific types of treatment.  Another factor sponsors may want 
137  to consider is mechanism of action: Some drugs proposed to treat stimulant use disorder might 
138  be more suitable for helping subjects actively using stimulants, while other drugs might be more 
139  suitable for preventing relapse in subjects who are abstinent at baseline. 
140   
141  To increase the chance of matching the investigational drug to the population likely to benefit, 
142  we recommend that sponsors incorporate early-stage clinical trials that evaluate response in 
143  different stimulant use disorder populations.  Based upon the results of the earlier trials, sponsors 
144  may determine whether it is appropriate to conduct later trials in broader populations or in 
145  narrower, more targeted ones.  Note that sponsors should not need to study their drugs in all 
146  conceivable populations before submitting marketing applications.  Sponsors are encouraged to 
147  contact the division to discuss the development of trials to ensure sufficient statistical power and 
148  sample size to adequately capture a representative segment of subjects with stimulant use 
149  disorder, while balancing the potential for success in matching the investigational drug to the 
150  population likely to benefit.  
151   
4  Contains Nonbinding Recommendations 
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152  Finally, sponsors should enroll subjects whose primary problem is their stimulant use disorder.  
153  Some individuals who use stimulants report using them to manage other problems, not because 
154  of a particular urge or desire to use stimulants.  For example, some patients with opioid use 
155  disorder report using methamphetamines to manage the effects of opioids (either to treat 
156  withdrawal or to prevent overdose).  These individuals may meet diagnostic criteria for a 
157  stimulant use disorder but would be unlikely to respond to a drug that addressed only that 
158  problem, and thus FDA does not recommend that such subjects be included in trials of drug 
159  treatments for stimulant use disorder. 
160   
161  2.  Design and Duration 
162   
163  Sponsors should conduct randomized, double-blind, and placebo-controlled efficacy trials.  FDA 
164  strongly recommends sponsors provide behavioral treatment to all trial subjects and that the 
165  behavioral treatment be standardized and described in the protocol.  
166   
167  Trials should also be of sufficient duration to achieve a meaningful change in stimulant use 
168  behavior and/or stimulant use disorder symptoms and to demonstrate that this effect is durable.  
169  Improvement may not occur immediately, given the nature of stimulant use disorder, and for this 
170  reason sponsors could consider a scientifically justifiable portion of the trial duration a grace 
171  period for analytic purposes.9  Because of the time period required to demonstrate a response to 
172  treatment, FDA typically recommends demonstrating improvement in the trial primary endpoint 
173  for 3 months or longer, which may involve a controlled period of 6 months of observation.  FDA 
174  encourages sponsors to discuss any questions about trial duration, such as the characteristics of 
175  the specific study sample and the anticipated effect of the intervention, with the division.  
176   
177  3.  Measurements of Drug Use 
178   
179  To bolster confidence in trial results, FDA suggests that sponsors propose and explain the 
180  rationale for a combination of self-report and biological testing.  FDAs recommended 
181  considerations for each are as follows: 
182   
183    Self-report:  For any endpoint involving a pattern of stimulant use, a certain amount of 
184  reliance on self-report will likely be necessary.  Sponsors can propose daily reports, staff-
185  assisted timeline followback reconstruction at visits,10 or other self-report tools.  Because 
186  self-report can be subject to issues related to recall, response bias, social desirability, and 
187  other factors, self-report of drug use may not provide persuasive data by itself. 
188   
189    Biological testing:  FDA recognizes that biological testing is often an important 
190  component of monitoring response to treatment.  However, FDA does not currently have 
 
9 Kiluk BD, Carroll KM, Duhig A, Falk DE, Kampman K, Lai S, Litten RZ, McCann DJ, Montoya ID, Preston KL, 
Skolnick P, Weisner C, Woody G, Chandler R, Detke MJ, Dunn K, Dworkin RH, Fertig J, Gewandter J, Moeller 
FG, and Strain EC, 2016, Measures of Outcome for Stimulant Trials: ACTTION Recommendations and Research 
Agenda, Drug Alcohol Depend, 158:17. 
 
10 Timeline followback is described on the National Institute on Drug Abuse Clinical Trials Networks Common 
Data Elements website at https://cde.drugabuse.gov/instrument/d89c8e23-16e5-625a-e040-bb89ad43465d.  
 
5  Contains Nonbinding Recommendations 
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191  evidence to support a recommendation on the optimal frequency of biological testing, 
192  including urine toxicology.  Sponsors should consider expected effects and any impact of 
193  the investigational drug on the biological detection window, striking a balance between 
194  minimizing subject burden and providing some degree of biological confirmation of self-
195  report.11 
196   
197  During nonclinical development or phase 1 trials, sponsors should determine any potential for 
198  the investigational drug to alter detection of the stimulant.  This could occur for various reasons, 
199  including interference with the assay for the stimulant or because of a drug-stimulant interaction 
200  with alteration in metabolism or clearance of the stimulant.  Sponsors should be aware that 
201  outcome measures based on detecting changes in day-to-day use, rather than more sustained 
202  periods of nonuse, must be carefully interpreted based upon a knowledge of the 
203  pharmacokinetics (detection in urine or other matrices) of the stimulant and any interactions 
204  between the investigational drug and the stimulant that alter urinary excretion of the stimulant or 
205  metabolites.  Note that some treatment approaches for stimulant use disorder (e.g., 
206  immunotherapy such as a monoclonal antibody directed at the drug, a vaccine leading to 
207  antibody developed to the drug) may both markedly reduce free drug, increase bound drug, and 
208  prolong detectable urinary excretion.  Trial designs, including the use of urine or biochemical 
209  testing in studies of such approaches, should be informed by such interactions.  
210   
211  4.  Measurements of Drug Use to Assess Treatment Response 
212   
213  Historically, clinical trials of treatments for stimulant use disorder have focused on the results of 
214  urine toxicology testing as a way to assess response to treatment; and as noted above, FDA 
215  recognizes the importance of urine toxicology testing for this purpose.  Urine toxicology results 
216  (e.g., in reflecting pattern of stimulant use) are a surrogate measure because they are not a 
217  reflection of how the subject feels, functions, or survives.12  We have previously advised that a 
218  sustained period of negative urine toxicology findings, indicating abstinence, could be a valid 
219  surrogate for clinical benefit.  However, FDA does not, and has not, advised that the only 
220  appropriate endpoint based on urine toxicology results is the number of subjects achieving 
221  complete abstinence.     
222   
223  FDA is open to other endpoints that reflect meaningful improvement in stimulant use disorder, 
224  noting that measuring other changes in pattern of stimulant use and establishing their clinical 
225  benefit may be more complex.  For example, capturing periods of nonuse, such as number of 
 
11 Many previous trials of drugs to treat cocaine use disorder incorporated thrice-weekly toxicology testing based on 
prior trials in other addictive disorders.  Quantitative assays were developed for the major metabolite of cocaine 
(benzoylecgonine) and an algorithm for distinguishing new use from previous use, minimizing false-positive urine 
tests caused by carryover when sampling thrice weekly.  Less is known about the detection of methamphetamines or 
other stimulants in urine and other body fluids.  However, prior research has suggested that thrice-weekly visits may 
be burdensome to subjects and, thus, contribute to missing data and trial drop out. 
 
12 See the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products (December 2019). When final, this guidance will represent the FDAs 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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226  days of nonuse per period (e.g., per week, per month), may be more practical.  Conversely, there 
227  is consensus that certain changes in pattern of stimulant use, such as fewer uses per day or 
228  reduced amount of drug used per occasion of use, are impractical to measure.13  They are also of 
229  uncertain significance when the stimulant used is illicit, and therefore of unknown and inherently 
230  variable potency.  Thus, some changes in pattern of stimulant use are likely unsuitable as clinical 
231  trial endpoints.  FDA encourages sponsors to discuss responder definition with the division. 
232   
233  Likewise, change from baseline analyses based on pattern of use is very challenging.  It is not 
234  possible to get a right now baseline measurement of a pattern of stimulant use, the way one can 
235  for blood pressure or pain score, or a snapshot that captures the overall level of use over a period 
236  of time (analogous to hemoglobin A1c).  However, the entry criteria may specify severity of use 
237  (e.g., moderate to severe cocaine use disorder), so use over time in the trial may be more useful 
238  than comparison to baseline, given the challenges of adequately evaluating the baseline. 
239   
240  C.  Endpoints 
241   
242  The subsections below lay out considerations for change in pattern of stimulant use, change in 
243  disease status using diagnostic criteria, and other potential outcome assessments.  Sponsors may 
244  consider demonstrating an effect in one or more of these options.  
245   
246   
247  1.  Change in Pattern of Stimulant Use 
248   
249  The term pattern of stimulant use refers to the frequency (days of use per week or month), 
250  timing, and intensity (uses per day or amount per use) of stimulant use by an individual subject.  
251  As discussed above, from a practical standpoint, intensity parameters are difficult to reliably 
252  measure, and frequency measures are more feasible to measure. 
253   
254  FDA prefers the phrase change in pattern of stimulant use (as opposed to the more ambiguous 
255  phrase reduction in stimulant use) and recommends its use to emphasize that within-subject 
256  responses are of interest.  In practice, the proportion of subjects achieving a target pattern of use 
257  days per period of time could be an acceptable endpoint, with a prespecified target pattern of use 
258  that defines a relevant within-subject response.  In contrast, evaluation of the difference between 
259  treatment groups in the mean number of days free of use is not recommended.   
260   
261  Sponsors should prespecify in the protocol a target pattern that reflects a satisfactory response to 
262  treatment for individual subjects, to be used to define a responder for the purposes of analysis.  A 
263  trial to evaluate a treatment aimed at modifying the number of days per period of time should 
264  include a minimum frequency of use as an entry criterion, such that the target pattern represents 
265  improvement.  Note that some individuals have a baseline pattern of infrequent binge use of a 
266  stimulant (e.g., cocaine use every several weeks); a study of such subjects would need to define a 
267  target pattern that reflects meaningful change for that pattern.  
268   
269  Although stimulant use patterns are not direct measures of how subjects feel or function, such 
270  assessments may be considered as candidate surrogate endpoints.  Given the unmet medical need 
 
13 See footnote 9.  
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271  for stimulant use disorder medication treatments, a candidate surrogate or intermediate clinical 
272  endpoint may be appropriate based on the scientific support for that endpoint.  Sponsors should 
273  explain their choice of a responder definition, ideally using data supporting the relationship of 
274  the target pattern to clinical benefit.  This recommendation may not apply to sponsors proposing 
275  a prolonged period of nonuse as a target pattern because the benefit of this pattern can be 
276  assumed.  It may be appropriate for the responder definition to incorporate allowances for a 
277  certain number of missing visits.  It may also be appropriate to focus on the last several months 
278  of the treatment period, recognizing that treatment response may not occur right away.  
279   
280  To aid in interpretation of results, sponsors should provide a graph that shows the proportions of 
281  responders by treatment arm over the entire range of possible response definitions.  Sponsors 
282  should also display results over time by presenting a summary measure (e.g., proportion of 
283  subjects by treatment group that meets response criteria) over the duration of the trial and by 
284  using methods that permit visualization of the progress of individual subjects over time.  
285   
286  Sponsors should consider the following caveat to using pattern of stimulant use as an outcome 
287  measure.  Some types of treatment might prolong or potentiate stimulant effects such that 
288  subjects reduce use of the stimulant without reducing the subjective and rewarding effects, or 
289  reducing health harms of the stimulant use.  In this scenario, reliance on pattern of stimulant use 
290  as an assessment of response to treatment may lack validity, and direct measures of clinical 
291  benefit would be more suitable. 
292   
293  2.  Change in Disease Status Using Diagnostic Criteria 
294   
295  Sponsors should enroll trial subjects who meet DSM-5 criteria for moderate to severe stimulant 
296  use disorder at baseline, based on clinical interview.  These criteria include a variety of 
297  symptoms and reflect how subjects feel and function.  DSM-5 also provides a definition of 
298  remission to be used as a specifier.  After criteria for stimulant use disorder were previously met, 
299  early remission is defined as meeting none of the criteria for stimulant use disorder for between 3 
300  and 12 months, and sustained remission is defined as meeting none of the criteria for at least 12 
301  months.  Both definitions for remission contain an exception that the criterion for craving may 
302  continue to be met.14  
303   
304  A suitable primary endpoint could be the proportion of subjects meeting criteria for early 
305  remission from stimulant use disorder at the end of the trial.  
306   
307  We do not recommend using change in the number of DSM-5 diagnostic criteria endorsed.  
308  Although this may seem to be an appropriate way to detect changes in the severity of stimulant 
309  use disorder, this approach has several concerns.  The DSM-5 is intended as a diagnostic 
310  instrument, not a method of monitoring response to treatment.  The presence or absence of many 
311  criteria is determined based on an interviewers judgment of whether the problem occurs often, 
312  frequently, persistently, or recurrently.  The frequency or intensity of symptoms may increase or 
313  decrease without the number of criteria changing; one symptom may resolve while another 
314  appears; or, potentially, several symptoms may resolve but a more concerning one may arise, 
 
14 American Psychiatric Association, 2013, Diagnostic and Statistical Manual of Mental Disorders, 5th edition, 
Arlington, VA: American Psychiatric Association, 562. 
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315  yielding a misleading appearance of improvement.  For these reasons, FDA strongly encourages 
316  sponsors interested in using endpoints reflecting disease severity to select, modify, or develop 
317  suitable instruments (see section III.C.3., Use of Other Clinical Outcome Assessments). 
318   
319  3.  Use of Other Clinical Outcome Assessments 
320   
321  Using input from patients, family members, and/or clinicians to determine the most concerning 
322  symptoms or experiences associated with stimulant use disorder, sponsors could develop a 
323  clinical outcome assessment (e.g., a patient-, observer-, or clinician-reported outcome measure to 
324  evaluate a direct effect on how patients feel or function).  A suitably developed, fit-for-purpose 
325  measure that assesses relevant aspects of a subjects health status, functioning, and/or symptoms 
326  may be appropriate as a primary endpoint for a clinical trial and may be the most suitable 
327  approach for some investigational drugs.  
328   
329  FDA is also aware of interest in stimulant craving (usually defined as a strong desire or wish to 
330  use stimulants) as a potential target for treatment.  Craving has not been consistently defined or 
331  understood, but it is viewed as a significant source of distress for patients and could be a suitable 
332  target for treatment.  FDA encourages the development of a suitably developed, fit-for-purpose 
333  measure of craving and envisions incorporating claims about effects on craving as secondary 
334  endpoints for drugs that are effective treatments for stimulant use disorder.  We are also open to 
335  data demonstrating the ability of craving modification to predict clinical benefit to consider 
336  craving as a potential primary endpoint. 
337   
338  We encourage sponsors to evaluate the effect of drugs in development for stimulant use disorder 
339  on various adverse clinical outcomes.  Examples of meaningful outcomes may include reduced 
340  overall or overdose mortality or fewer hospitalizations.  Similarly, FDA is interested in outcome 
341  measures that sponsors might use to demonstrate clinical benefit of investigational drugs for 
342  treating stimulant use disorder such as improvements in the ability to resume work, school, or 
343  other productive activity or fewer encounters with the criminal justice system.  We are open to a 
344  well-designed, appropriately justified composite endpoint, as described in the guidance for 
345  industry Multiple Endpoints in Clinical Trials (October 2022).15 
346   
347  FDA recognizes that evaluating these outcomes could require larger trials than those usually 
348  conducted for marketing approval.  However, collecting data on clinically meaningful outcomes 
349  even if not intended as primary support for a regulatory decision would be highly valuable, and 
350  FDA encourages sponsors to consider collecting such data.  Furthermore, using these outcomes 
351  as clinical trial endpoints may help to validate endpoints that may be considered for use in 
352  clinical trials in the future.  It is of note that retention in treatment is not recommended as a 
353  stand-alone endpoint.  Many features of trial design can produce incentives to remain in 
354  treatment without accruing clinical benefit.  If a sponsor plans to include novel endpoints in a 
355  drug development program for treating stimulant use disorder, FDA strongly encourages the 
356  sponsor to discuss such plans with the division early in the drug development process.  
357   
 
15 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. 
 
9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
358   
359  IV.  BENEFIT-RISK CONSIDERATIONS 
360   
361  When selecting an endpoint to demonstrate efficacy for a specific drug, sponsors should consider 
362  that, ultimately, the demonstrated benefit of a drug will be weighed against the risk under FDAs 
363  drug approval standard (section 505(d) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
364  355(d))).16  Uncertainties regarding benefits and risks are considered when making an approval 
365  determination; a drug with greater risks may require a greater magnitude and certainty of benefit 
366  to support approval.17  If the drug itself has abuse potential,18 FDA may consider the public 
367  health effects of the drug as part of the overall benefit-risk assessment, including the drugs 
368  potential effect on risks to both patients and nonpatients, such as members of the patients 
369  household (e.g., children, visitors).  The risks considered may include those related to misuse,19 
370  abuse, stimulant use disorder, overdose, and accidental exposures, particularly in children.20 
371   
372   
373  V.  LABELING 
374   
375  Regardless of the outcome measure chosen, a drug that has been determined to be safe and 
376  effective could be indicated for the treatment of [specific drug] use disorder and modified by 
377  the level of severity studied (e.g., moderate to severe methamphetamine use disorder). 
378   
379  FDA envisions that the indication would generally mirror the studied population (potentially 
380  including the stimulant route(s) of administration for the studied population);21 however, the 
381  labeled population is determined based upon the results of the clinical program that may support 
382  use in a broader or narrower population than was studied.22  It is possible that a drug with 
 
16 See also the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products.  
 
17 See footnote 16. 
 
18 As used in this guidance, the term abuse refers to the intentional, nontherapeutic use of a drug for its desirable 
psychological or physiological effects.  The term abuse is used in this document to describe a specific behavior that 
confers a risk of adverse health outcomes.  FDA is committed to reducing stigma, expanding therapeutic options, 
and ensuring access to evidence-based treatment for individuals with substance use disorders. 
 
19 As used in this guidance, the term misuse refers to the intentional use, for therapeutic purposes, of a drug in a 
manner other than as prescribed or by an individual for whom it was not prescribed. 
 
20 See the draft guidance for industry Benefit-Risk Assessment for New Drug and Biological Products (September 
2021).  When final, this guidance will represent the FDAs current thinking on this topic. 
 
21 See the draft guidance for industry Diversity Plans to Improve Enrollment of Participants From Underrepresented 
Racial and Ethnic Populations in Clinical Trials (April 2022). When final, this guidance will represent the FDAs 
current thinking on this topic. 
 
22 See the draft guidance for industry Indications and Usage Section of Labeling for Human Prescription Drug and 
Biological Products  Content and Format (July 2018). When final, this guidance will represent the FDAs current 
thinking on this topic. 
 
10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
383  clinical trials finding efficacy and safety in multiple populations using different stimulants, in 
384  different contexts, by different routes, could be approved for a broad indication for the treatment 
385  of stimulant use disorder.  An all-comers trial could theoretically support such a broad indication 
386  if it were convincingly positive in all subgroups, but the size of a trial needed to support such a 
387  conclusion could likely make it less practical than studying groups separately.  
388   
389   
390  VI.  EXPEDITED PROGRAMS 
391   
392  FDA encourages the development of treatments for stimulant use disorder and novel trial 
393  designs.  Stimulant use disorder development programs may be eligible for one or more of 
394  FDAs expedited programs, as applicable.  FDA encourages early discussion of drugs that could 
395  treat stimulant use disorder and may be eligible for expedited programs.  
396   
397  These expedited programs and their relevant criteria are described in the guidance for industry 
398  Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014).  Potentially 
399  applicable expedited programs include fast track designation, breakthrough therapy designation, 
400  priority review designation, and accelerated approval.  Although each program differs, they all 
401  offer some form of expedited review and guidance for sponsors of drug development programs 
402  for serious or life-threatening conditions to address unmet medical need. 
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