Opioid Use Disorder: 
Endpoints for Demonstrating 
Effectiveness of Drugs for 
Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
October 2020 
Clinical/Medical 
   
Opioid Use Disorder: 
Endpoints for Demonstrating 
Effectiveness of 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 2020 
Clinical/Medical 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  CLINICAL ENDPOINTS ................................................................................................ 3 
A.  Adverse Outcomes of OUD ........................................................................................................... 3 
B.  Change in Disease Status Using Diagnostic Criteria for OUD .................................................. 3 
C.  Change in Drug Use Pattern ......................................................................................................... 4 
D.  Patient-Reported Outcomes .......................................................................................................... 4 
IV.  OTHER OUTCOME MEASURES ................................................................................. 5 
V.  BENEFIT-RISK CONSIDERATIONS .......................................................................... 5 
 
  Contains Nonbinding Recommendations 
Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of 
Drugs for Treatment 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page. 
 
 
 
I.  INTRODUCTION 
 
This guidance is intended to help sponsors develop drugs for treatment of opioid use disorder 
(OUD).  This guidance addresses clinical endpoints acceptable for demonstrating effectiveness 
of such drugs.  This guidance does not address the development of drugs intended only to 
provide symptomatic relief of opioid withdrawal. 
 
For assistance on specific drug development programs to treat OUD, sponsors should contact the 
Division of Anesthesiology, Addiction Medicine, and Pain Medicine (the division) in the Center 
for Drug Evaluation and Research. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
II.  BACKGROUND 
 
Treatments for OUD can be initiated in patients who are actively ill and not currently receiving 
other drug treatments for OUD or in patients who have already discontinued problematic opioid 
use.2  Drugs that have opioid agonist activity can be initiated in patients with current problematic 
use of opioids.  However, because of the risk of causing severe withdrawal symptoms, drugs 
                                                 
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 As used in this guidance, the term problematic use refers to drug use in an inappropriate, unsanctioned manner in 
the context of opioid use disorder.  Although the concept is well-understood by patients and treatment providers, 
some more commonly used terms (typically, illicit use) are considered stigmatizing and others (e.g., abuse) are 
ambiguous. 
1  Contains Nonbinding Recommendations 
with opioid antagonist activity cannot be initiated until patients discontinue opioid use.  Drugs 
that are neither agonists nor antagonists can be used in either population. 
 
Patients with OUD may discontinue problematic opioid use through inpatient programs, 
medically supervised withdrawal, self-initiated discontinuation, or as a result of incarceration.  
Each of these pathways may or may not include drugs to manage the symptoms of opioid 
withdrawal.  Drugs intended to provide symptomatic relief of opioid withdrawal may support 
patients completing opioid detoxification but are usually not sufficient to reduce the risk of 
returning to problematic opioid use.  Therefore, these drugs are not covered by this guidance. 
 
Efficacy trials of drugs for treating OUD have typically employed a randomized, blinded, 
controlled trial design.  For drugs intended for use as initial therapy, patients should be new 
entrants to treatment3.  Different trial design choices can be employed, including superiority or 
noninferiority studies (with a prespecified noninferiority margin) using appropriate comparators.  
Trial designs should generally incorporate standard-of-care nonpharmacologic treatments.  
Patients experiencing clinical deterioration during the trial should be transferred out of the 
protocol to receive another OUD treatment appropriate to their clinical condition.  The 
recommended primary efficacy endpoint is the proportion of responders (discussed in section III. 
D).  The effects of the study drug on other (nonopioid) problematic drug use should also be 
evaluated as a secondary endpoint.  The responder definition should be prespecified, taking into 
account the schedule of assessments, and may incorporate a grace period.  Efficacy analyses 
should include comparison of responder rates, cumulative responder curves,4 and graphic 
displays of individual patient responses. 
 
For drugs intended to reduce the risk of relapse, patients already stable5 on other treatments for 
OUD should be studied, and the comparator should be an approved therapy.  Patients should be 
seen at frequent intervals and assessed for adverse events and clinical status (including drug-
taking behavior measured by urine toxicology screen and self-report of opioid or other 
problematic drug use, and measures of clinical benefit or function).  These trials can employ 
different designs, including superiority or noninferiority (with a prespecified noninferiority 
margin). 
 
                                                 
3 For purposes of this guidance, new entrants to treatment are individuals with OUD who regularly use opioids in an 
unsanctioned manner and whose drug use is having substantial impact on their function.  Such patients may or may 
not have had previous episodes of treatment but are currently not engaged in treatment for OUD. 
 
4 A cumulative responder curve or cumulative distribution function refers to an approach in which various possible 
definitions of responder are considered and compared graphically.  The graph shows, for example, the percentage of 
patients who provided a given percentage of negative samples or better.  The curves, therefore, fall from 100% at the 
left to 0% at the right. 
 
5 For purposes of this guidance, stable patients are those who have been engaged in treatment for OUD for a 
sustained period of time and have demonstrated a good response.  They have ceased problematic drug use or use 
only very sporadically while receiving treatment.  Such patients may or may not meet criteria for full remission 
under DSM-5.  Patients who have been recently started on medication and are titrated to a particular dose are 
sometimes referred to as stabilized because their dose is no longer being titrated, but this is to be distinguished from 
patients who are clinically stable. 
2  Contains Nonbinding Recommendations 
Since patients with OUD who are new entrants to treatment are considered a more difficult 
population to treat than patients who are clinically stable, substantial evidence to support 
effectiveness for the treatment of OUD in new entrants to treatment would typically also support 
approval for the treatment of OUD in patients who are clinically stable on other approved 
therapies.  However, with respect to OUD, substantial evidence to support effectiveness in stable 
patients would generally not support approval in new entrants to treatment. 
 
In general, clinical trials evaluating effectiveness of drugs for treating OUD have used reduction 
in drug-taking behavior (drug use patterns) as an endpoint.  There is great interest in expanding 
the primary and secondary endpoints used in clinical trials of drugs for treating OUD, including 
other outcome measures important to patients and their families, clinicians, and the public.  The 
following discussion enumerates various outcome measures that could potentially be used as 
primary and/or secondary endpoints in clinical trials and included in FDA-approved labeling. 
 
 
III.  CLINICAL ENDPOINTS 
 
A.  Adverse Outcomes of OUD 
 
Reductions in adverse outcomes related to OUD are desirable endpoints for study.  FDA 
encourages sponsors to evaluate the effect of drugs in development for OUD on various adverse 
outcomes. 
 
Examples of these adverse outcomes include: 
 
  Mortality (overall mortality or overdose mortality) 
  Need for emergency medical interventions 
  Hepatitis C virus infection or reinfection 
 
Sponsors can propose other adverse outcomes and can study several of these endpoints in the 
same trial, selecting one as the primary endpoint, selecting one or more as secondary endpoints, 
or combining outcomes in a composite endpoint.  Data on background rates of the adverse 
outcomes in specific target populations would be useful in determining needed sample size and 
trial duration. 
 
B.  Change in Disease Status Using Diagnostic Criteria for OUD 
 
Diagnostic criteria for OUD encompass drug use and its effect on patient well-being.  We 
recommend  that,  if  all  trial  patients  meet  the  Diagnostic  and  Statistical  Manual  of  Mental 
Disorders, Fifth Edition, (DSM-5) criteria for moderate-severe OUD at baseline,6 sponsors could 
use the proportion of patients meeting DSM-5 criteria for remission of OUD at the end of the trial 
as a primary or secondary efficacy endpoint. 
 
                                                 
6 American Psychiatric Association, 2013, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 
Arlington, Virginia:  American Psychiatric Publishing. 
3  Contains Nonbinding Recommendations 
C.  Change in Drug Use Pattern7 
 
FDA generally accepts change in drug use patterns as a surrogate for the benefits of abstaining 
from drug taking or for the presumed benefits of reducing drug taking.  Change in drug use 
pattern is the most commonly used endpoint in registration trials for drugs in development to 
treat OUD.  Sponsors have used it successfully to provide support of efficacy for all approved 
products for treating OUD.  Sponsors have used a variety of approaches to evaluate drug use 
patterns.  FDA recommends that sponsors compare percentage of responders rather than group 
means.  One method is to define a responder as a patient who reduces the use of opioids to or 
below a threshold known to be associated with clinical benefit.  A successful trial would show 
either a higher percentage of responders in the treatment arm (for superiority trials) or 
noninferiority in the percentage of responders (for active-controlled noninferiority trials). 
 
A commonly used definition for a responder is abstinence, defined as no detected or self-
reported use during the specific assessment window.  It is not possible to have absolute 
confidence that a responder achieved complete abstinence.  Very frequent measurements provide 
more assurance of a substantial reduction in drug use, whereas infrequent drug use measurements 
result in greater uncertainty about the true magnitude of reduction in drug use.  For this reason, 
absence of positive urine drug tests, absence of self-reported drug use, and attendance at frequent 
scheduled observations for these measures are components of a complete abstinence response 
definition.   
 
Sponsors can employ drug use patterns other than abstinence to define response to OUD 
treatment.  In proposing other drug use patterns to define clinical response, sponsors should 
specify how the change in drug use pattern will be measured.  Certain changes in drug use 
patterns, such as fewer occasions of use per day or reduced amount of use per occasion, may 
prove impractical to measure.  In addition, to support a drug use pattern to define clinical 
response, sponsors should evaluate and submit evidence from clinical trials, longitudinal 
prospective observational studies, or other sources of information to show that such reduction in 
drug use predicts clinical benefit (i.e., better health outcomes or psychosocial function).  
Sponsors should discuss with the division approaches to measure change in drug use patterns and 
how evidence of clinical benefit could be generated. 
 
D.  Patient-Reported Outcomes 
 
Using input from patients and family members to determine the most concerning 
symptoms/experiences associated with OUD, sponsors could develop a patient-reported outcome 
(PRO) instrument to evaluate a direct effect on how patients feel or function (e.g., improvement 
in sleep or mood). 
                                                 
7 Drug use pattern refers to the frequency, timing, quantity, and intensity (uses per day or amount per use) of 
problematic drug use by an individual patient.  From a practical standpoint, several of these parameters are 
infeasible to measure, and the most commonly used parameter is days of use.  Abstinence refers to zero days of use 
within an assessment window.  The more general phrase reduction in drug use is subject to many interpretations, 
including reduction of group means on quantity or frequency of problematic drug use with no single individual 
having an improvement in their OUD.  The phrase change in drug use pattern is used to emphasize that individual 
patient responses are of interest. 
4  Contains Nonbinding Recommendations 
 
Sponsors could also use this approach to develop a measure for the intensity of the urge to use 
opioids.  Outcomes on this measure could be used as a secondary endpoint in trials that use 
behavioral change, such as change in drug use patterns, as a primary endpoint.  If sponsors plan 
to use such a PRO instrument as a secondary endpoint, sponsors should first determine the 
magnitude of the change in the PRO measure that represents a clinical benefit and how long such 
change should be maintained in a clinical trial to predict a sustained clinical benefit.  Sponsors 
interested in using a reduction in craving endpoint should contact the division about developing a 
fit-for-purpose instrument to measure craving or the urge to use opioids to complement other 
endpoints and to determine how the endpoint correlates with sustained clinical benefit. 
 
In developing any of the PRO instruments mentioned above, sponsors should follow the 
principles outlined in the guidance for industry Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims (December 2009).8 
 
 
IV.  OTHER OUTCOME MEASURES 
 
FDA is interested in other outcome measures that sponsors might use to demonstrate clinical 
benefit of drugs for treating OUD, such as reduction in hospitalizations or improvements in the 
ability to resume work, school, or other productive activity.  FDA recognizes that evaluating 
these outcomes could require larger trials than those usually conducted for marketing approval.  
However, collecting data on clinically meaningful outcomes would be highly valuable, and FDA 
encourages sponsors to consider collecting such data even if not intended to support a regulatory 
decision.  Furthermore, using these outcomes as clinical trial endpoints could provide the basis 
for inclusion in the FDA-approved labeling.  It is of note that retention in treatment is not 
recommended as a stand-alone endpoint.  Many features of trial design can produce incentives to 
remain in treatment without accruing clinical benefit.  If a sponsor plans to include novel 
endpoints in a drug development program for treating OUD, FDA strongly encourages the 
sponsor to discuss such plans with the division early in the drug development process. 
 
 
V.  BENEFIT-RISK CONSIDERATIONS 
 
When selecting an endpoint to demonstrate efficacy for a specific product, sponsors should bear 
in mind that, ultimately, the demonstrated benefit of a product will be weighed against the risk 
under FDAs drug approval standard (section 505(c) and (d) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 355(c) and (d))).  If a product is associated with a risk of serious 
adverse events, more compelling demonstrations of clinical benefit may be needed to outweigh 
this risk.  If the product itself has abuse9 potential, FDA will consider the positive and negative 
                                                 
8 We update guidances periodically.  To make sure you have 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 As used in this guidance, the term abuse refers to any intentional, nontherapeutic use of a drug product or 
substance, even once, for the purpose of achieving a desired psychological or physiological effect. 
 
5  Contains Nonbinding Recommendations 
public health effects of the drug, including risk of diversion, the drugs potential effect on risks 
to both patients and nonpatients, such as members of the patients household (e.g., children, 
teenagers, visitors, and others).  The risks considered include those related to misuse,10 abuse, 
OUD, overdose, and accidental exposures, particularly in children. 
 
                                                 
10 As used in this guidance, the term misuse refers to any intentional therapeutic use of a drug product in an 
inappropriate way.  Misuse specifically excludes those events that meet the definition of abuse. 
6