Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Treatment Guidance for Industry

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

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
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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, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s 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.

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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.

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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.

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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.

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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 FDA’s 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.

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public health effects of the drug, including risk of diversion, the drug’s potential effect on risks
to both patients and nonpatients, such as members of the patient’s 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.