Opioid Use Disorder:  
Developing Depot 
Buprenorphine 
Products for Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2019 
Clinical/Medical 
   
Opioid Use Disorder:  
Developing Depot 
Buprenorphine 
Products 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) 
 
February 2019 
Clinical/Medical
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  DEVELOPMENT PROGRAMS ..........................................................................2 
A.  Types of Studies to Support Approval............................................................................. 2 
1. Depot Buprenorphine Products That Are Similar to an Approved Depot Product ............. 2 
2. Depot Buprenorphine Products With Novel Features Relative to Approved Depot 
Products ............................................................................................................................... 4 
B.  Efficacy Trials .................................................................................................................... 5 
1. Trial Design ......................................................................................................................... 5 
2. Recommended Efficacy Endpoints ...................................................................................... 6 
3. Novel Efficacy Endpoints .................................................................................................... 7 
 
 
  Contains Nonbinding Recommendations 
 
Opioid Use Disorder: Developing  
Depot Buprenorphine Products 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 reflects the Agencys current thinking regarding drug product development and 
trial design issues relevant to the study of depot buprenorphine products (i.e., modified-release 
products for injection or implantation) for the treatment of opioid use disorder (OUD). This 
guidance focuses on the development of depot buprenorphine products for which submission of a 
new drug application (NDA) through the pathway described in section 505(b)(2) of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) may be appropriate.2 
 
For recommendations on specific depot buprenorphine product development programs, sponsors 
should contact the Division of Anesthesia, Analgesia, and Addiction Products (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. 
 
 
                                                 
1 This guidance has been prepared by the Division of Anesthesia, Analgesia, and Addiction Products in the Center 
for Drug Evaluation and Research at the Food and Drug Administration.  
 
2 The 505(b)(2) pathway is appropriate for applications that contain full reports of investigations of safety and 
effectiveness, where at least some of the information required for approval is derived from studies that are not 
conducted by or for the applicant and for which the applicant has not obtained a right of reference. Such 
investigations or information can include, for example, FDAs finding of safety and/or efficacy for a listed drug or 
published literature. NDAs submitted through the 505(b)(2) pathway may be subject to patent certification 
requirements and periods of exclusivity that could affect approval. See generally 505(b)(2) of the FD&C Act; see 
also the draft guidance for industry Applications Covered by Section 505(b)(2) (October 1999). 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/RegulatoryInformation/Guidances/default.htm.  
1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
Buprenorphine, at sufficient plasma exposures, can block the effects of exogenous opioids and, 
at lower plasma exposures, may be sufficient for maintaining patients who have achieved 
sustained clinical stability on other buprenorphine therapies. Passive-compliance formulations 
such as sustained-release injectable depots and implants can provide effective treatment of OUD 
in a treatment paradigm that may be less subject to misuse, abuse, or accidental exposure 
compared to self-administered formulations such as transmucosal tablets and films.  
 
 
III.  DEVELOPMENT PROGRAMS 
 
In general, an application for a depot buprenorphine product can be submitted through an 
abbreviated new drug application (ANDA) under section 505(j) or an NDA under section 
505(b)(2) of the FD&C Act.3 The regulatory pathway and the need for additional studies depend 
on the characteristics of the investigational depot buprenorphine product (e.g., delivery system, 
formulation) relative to an approved buprenorphine product.4 For example, an investigational 
monthly subcutaneous depot buprenorphine product that does not meet criteria for submission 
under an ANDA may be submitted under a 505(b)(2) NDA with relative bioavailability 
pharmacokinetic studies and may not require additional efficacy and/or safety studies in certain 
instances.5 Applications for other investigational depot buprenorphine products with novel 
features could also be eligible for submission through the 505(b)(2) pathway, but may require 
efficacy and/or safety trials.  
 
A.  Types of Studies to Support Approval 
 
1.  Depot Buprenorphine Products That Are Similar to an Approved Depot Product 
 
For new depot buprenorphine products that could be submitted under a 505(b)(2) NDA, new 
efficacy trials may not be necessary, and a sponsor may be able to rely on the Agencys previous 
findings of safety and/or efficacy for an approved depot buprenorphine formulation using 
relative bioavailability pharmacokinetic studies. 
 
The final to-be-marketed drug product (including drug delivery component and formulation) and 
the dosing regimen proposed for inclusion in the drug product labeling should be used in the 
pharmacokinetic studies and clinical trials to support approval. If a drug product other than the 
                                                 
3 Although it is not the focus of this guidance, applicants can also submit an NDA for a depot buprenorphine product 
through the 505(b)(1) pathway for which the application contains full reports of investigations of safety and 
effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference. See 
section 505(b)(1) of the FD&C Act.  
 
4 Under these abbreviated approval pathways, in general, an applicant can rely on FDAs finding of safety and 
effectiveness for a drug product approved under section 505(c) of the FD&C Act. For brevity, the remainder of this 
guidance refers to an approved drug product generally without reference to the legal pathway for approval.    
 
5 See the draft guidance for industry Determining Whether to Submit an ANDA or a 505(b)(2) Application (October 
2017). When final, this guidance will represent the FDAs current thinking on this topic. 
2  Contains Nonbinding Recommendations 
 
final to-be-marketed drug product is used, the sponsor should provide additional bridging 
information or justification to address the difference. 
 
In determining whether a sponsor needs to conduct efficacy trial(s) of an investigational depot 
buprenorphine product, key comparative parameters between the investigational depot 
buprenorphine product and an approved depot buprenorphine product include the degree of 
similarity in the following:  
 
  The shape of the pharmacokinetic profile 
 
  The time to reach a plasma level associated with blockade of exogenous opioids6 
 
  The maximum plasma concentration 
 
  The minimum (trough) plasma concentration  
 
  The plateau buprenorphine concentration following the initial peak after the first depot 
injection  
 
  Accumulation after multiple doses 
 
  Estimated time for complete clearance of the drug product after steady state has been 
reached 
 
If these parameters are sufficiently similar to the approved depot buprenorphine product, efficacy 
trials would not need to be conducted because the sponsor of the investigational depot 
buprenorphine product could typically rely for approval on the Agencys findings of safety and 
efficacy for the approved depot buprenorphine product. Sponsors should include the following 
elements in the development program for such depot buprenorphine products: 
 
  Human-factors engineering processes should be utilized throughout development of the 
depot buprenorphine product. For example, the sponsor should develop and test training 
materials for insertion and removal of the depot buprenorphine product, if applicable.  
 
  Comparative bioavailability pharmacokinetic studies should demonstrate that exposure to 
the investigational depot buprenorphine product is similar to that of an approved depot 
buprenorphine product both after single dose and at steady state following multiple doses. 
 
  The safety of any new excipients or materials should be demonstrated. 
 
                                                 
6 Comparison of partial areas under the curve may be a useful method of assessment. 
3  Contains Nonbinding Recommendations 
 
2.  Depot Buprenorphine Products With Novel Features Relative to Approved Depot 
Products 
 
A sponsor could likely submit an investigational depot buprenorphine product with novel 
features relative to approved buprenorphine products (e.g., dosing interval, dose range, route of 
administration) under a 505(b)(2) NDA, but an efficacy trial and/or safety study may be needed. 
To ensure that any necessary efficacy trials and/or safety studies are designed based on relevant 
information specific to the investigational depot buprenorphine product, the development 
program for such depot buprenorphine product should proceed in a sequential fashion, as 
follows:  
 
  The sponsor should determine the target plasma concentration. The sponsor can use 
receptor occupancy studies, literature, or other sources of information for this 
determination. 
 
  The sponsor should perform initial pharmacokinetic studies to identify doses or regimens 
that deliver the target plasma concentration during the desired treatment period, including 
any appropriate comparisons to an approved depot buprenorphine product as described in 
section III. A. 1., Depot Buprenorphine Products That Are Similar to an Approved Depot 
Product. 
 
  The sponsor should provide human behavioral pharmacology data to identify doses in 
nontreatment seeking trial subjects (a blockade trial). This trial should establish that the 
investigational depot buprenorphine product blocks completely (i.e., not merely 
attenuates) the subjective responses to a clinically relevant dose of an exogenous opioid. 
 
  The sponsor should consider human-factor issues related to the procedures necessary to 
administer the investigational depot buprenorphine product during the entire development 
program. If a surgical procedure is required, the sponsor should develop and test 
appropriate training materials for methods of insertion and, if applicable, removal. 
 
  If the investigational buprenorphine product dosing, including interdose interval and 
timing of treatment initiation (e.g., with respect to the last time of abused drug use, need 
for initial treatment with a transmucosal buprenorphine product), is significantly different 
from that of an approved buprenorphine product, the efficacy of the investigational depot 
buprenorphine product should be demonstrated in at least one adequate and well-
controlled clinical trial. 
 
  Studies may be needed to show the safety of the investigational depot buprenorphine 
product (e.g., if using a novel drug product delivery component or route). If an 
independent efficacy trial is needed, the safety data from this trial may satisfy part or all 
the safety study requirement, after preliminary human safety testing is done. Otherwise, 
the sponsor can study human safety independently, along with a strategy for mitigating 
any risks identified. 
 
4  Contains Nonbinding Recommendations 
 
B.  Efficacy Trials 
 
1.  Trial Design 
 
When a sponsor needs to conduct efficacy trial(s), it should include the following elements:  
 
  The trial should be a blinded, controlled trial studying the doses or regimens established 
as blocking in the blockade trial.  
 
  Controls should include placebo or an approved formulation of buprenorphine product. 
Active-controlled trials can employ either superiority or noninferiority designs. Sponsors 
should consult the Division regarding different aspects of trial design, including the 
noninferiority margin. 
 
  All trials, particularly those with placebo, should include in the protocol careful 
monitoring for clinical worsening or relapse and provisions for rescue treatment or 
removal of the patient from the trial with transfer to standard of care.  
 
  The characteristics of patients enrolled in the trial should reflect the intended use of the 
investigational depot buprenorphine product including the following: 
 
  Patients should meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth 

Edition, (DSM-5) criteria for moderate-severe OUD.  
 
  For use as initial therapy, patients should be new entrants to treatment (i.e., actively 

ill and not currently receiving other drug product treatments for OUD). A history of 
previous drug product treatments for OUD is acceptable. 
 
  Sponsors can conduct trials in patients already stable on other treatments. Such trials, 

if appropriately designed, would support a claim of reduction in risk of relapse but 
would not support a claim of efficacy in new entrants to treatment. 
 
  Patients should be either new entrants to treatment or stable on other treatments. 

Trials in a heterogeneous population of new and stable patients present significant 
barriers to interpretation and, therefore, are much less likely to demonstrate efficacy. 
 
  The sponsor can employ an initial titration period using an approved transmucosal 
buprenorphine product formulation if this is the intended regimen for transitioning to the 
investigational depot buprenorphine product. Similarly, the sponsor can employ a period 
of stabilization with a transmucosal formulation if this is anticipated to be part of the 
intended regimen for the investigational depot buprenorphine product. 
 
  Patients should be seen at least weekly and assessed for the following:  
 
  Safety, including injection or implantation site reactions 

 
5  Contains Nonbinding Recommendations 
 
  Clinical response, including urine toxicology screen for opioid and other abused drug 

use, self-report of drug use, and measures of clinical benefit or function  
 
  Attempts to remove the investigational drug product  

 
2.  Recommended Efficacy Endpoints 
 
FDAs recommended primary efficacy endpoint is a decrease (for superiority trials) or 
noninferiority (for active-controlled trials) in use of opioids.  
 
  A sponsor should consider the following when developing a responder definition: 
 
  The responder definition should be appropriate to the schedule of assessments. The 

sponsor should consider the pharmacokinetic and pharmacodynamic profiles of the 
investigational depot buprenorphine product in determining the frequency of 
sampling to evaluate clinical response. The definition of a responder depends, in part, 
on the frequency of sampling. 
 
  If the sampling for toxicology screen is frequent enough to capture every opioid use, 

a negative assessment at all sampling visits (complete abstinence) is not necessary to 
define a clinical responder. However, as the interval between sampling is increased, 
the ability to detect opioid use decreases, and the absence of positive assessments 
becomes more critical to the responder definition.  
 
  The following are other principles sponsors should follow when developing a 

responder definition:  
 
  Noncompleters should be adjudicated as nonresponders 
 
  For superiority comparisons, missing values for illicit or unauthorized drug use 
should be imputed as positive. Note that this approach could bias the results 
toward no treatment difference achieving noninferiority even when the 
investigational drug product is inferior.7  
 
  A grace period can be included. A grace period is a predefined period of time 
during which the abused drug use information is not incorporated into the efficacy 
assessment. It may be appropriate to allow patients time for engagement in 
treatment because patients entering treatment may not respond immediately.  
 
                                                 
7 For approaches to address this bias in noninferiority comparisons, refer to the guidance for industry Non-Inferiority 
Clinical Trials to Establish Effectiveness (November 2016). 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/RegulatoryInformation/Guidances/default.htm. 
 
6  Contains Nonbinding Recommendations 
 
  Efficacy analyses should include the following: 
 
  Comparison of responder rates 

  Cumulative responder curves8 

  Graphic displays of individual patient responses 

 
For recommendations on the adequacy of the responder definition and additional analyses for 
specific depot buprenorphine product development programs, sponsors should contact the 
Division.   
 
3.  Novel Efficacy Endpoints 
 
Sponsors can also propose novel efficacy endpoints (e.g., reduction in craving, improvement in 
sleep or mood, other patient-reported outcomes) that are not focused on opioid and other abused 
drug use assessed by toxicological testing. To assess efficacy the sponsor should appropriately 
support these novel endpoints with data demonstrating the ability of the endpoints to identify a 
clinically meaningful benefit. Currently, such endpoints are not well supported by publicly 
available data. Additional research is needed to explore and better define instruments to measure 
these patient-reported outcomes9 in trials. If a sponsor plans to include novel endpoints in a 
depot buprenorphine product development program, FDA strongly encourages the sponsor to 
discuss such plans with the Division early in the drug product development process.  
 
There is great public heath interest in assessing additional, clinically meaningful endpoints such 
as reduction in hospitalizations, emergency department visits, overdose, and death, as well as 
improvements in the ability to resume work, school, or other productive activity. Though 
understanding these outcomes would be highly valuable, the Agency recognizes that evaluating 
these outcomes could require larger trials than those usually conducted for marketing approval. 
However, use of such endpoints could provide the basis for additional claims for approved 
buprenorphine products. 
                                                 
8 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. Therefore, the curves fall from 100 percent 
at the left to zero percent at the right. 
 
9 See the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims (December 2009).  
7