Abuse-Deterrent Opioids  
Evaluation and Labeling 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
Clinical Medical  
April 2015 
 
   
Abuse-Deterrent Opioids  
Evaluation and Labeling 
 
Guidance for Industry 
 
 
Additional copies are available from: 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
10903 New Hampshire Ave. 
Silver Spring, MD 20993-0002  
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov  
http://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) 
 
Clinical Medical 
April 2015 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  ABUSE-DETERRENT PRODUCTS .............................................................................. 3 
IV.  PREMARKET STUDIES ................................................................................................ 4 
A.  Laboratory Manipulation and Extraction Studies (Category 1) ............................................... 6 
B.  Pharmacokinetic Studies (Category 2) ......................................................................................... 8 
C.  Clinical Abuse Potential Studies (Category 3) ............................................................................ 9 
1. Blinding .......................................................................................................................................... 10 
2. Pre-qualification Phase ................................................................................................................. 10 
3. Assessment Phase .......................................................................................................................... 11 
4. Subjects .......................................................................................................................................... 11 
5. Route of Administration, Dose Selection, Manipulation Mode, and Sample Preparation ............ 12 
6. Outcome Measures and Data Interpretation ................................................................................. 12 
7. Data Interpretation ........................................................................................................................ 13 
8. Statistical Analysis ......................................................................................................................... 14 
a.  Background ............................................................................................................................. 14 
b.  Primary analyses ..................................................................................................................... 15 
c.  Secondary analyses ................................................................................................................. 15 
d.    Multiplicity .............................................................................................................................. 17 
V.  POSTMARKET STUDIES (CATEGORY 4) .............................................................. 17 
A.  Formal Studies ............................................................................................................................. 18 
1. General Characteristics ................................................................................................................. 18 
2. Study Design Features.................................................................................................................... 19 
B.  Supportive Information ............................................................................................................... 21 
VI.  LABELING ..................................................................................................................... 22 
VII.  ADDITIONAL RESEARCH NEEDS ........................................................................... 25 
  Contains Nonbinding Recommendations 
Abuse-Deterrent Opioids  Evaluation and Labeling 
1
Guidance for Industry  
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not create 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 staff responsible for this guidance as listed on the title 
page.   
 
 
 
I.  INTRODUCTION  
 
This guidance explains FDAs current thinking about the studies that should be conducted to 
demonstrate that a given formulation has abuse-deterrent properties.  The guidance makes 
recommendations about how those studies should be performed and evaluated and discusses how 
to describe those studies and their implications in product labeling.   
 
This guidance is intended to assist sponsors who wish to develop opioid drug products with 
potentially abuse-deterrent properties and is not intended to apply to products that are not opioids 
or opioid products that do not have the potential for abuse.  
 
This guidance also does not address issues associated with the development or testing of generic 
formulations of abuse-deterrent opioid products.  FDA intends to address that topic in one or 
more future guidance documents. 
 
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 
 
Prescription opioid products are an important component of modern pain management.  
However, abuse and misuse of these products have created a serious and growing public health 
problem.  One potentially important step towards the goal of creating safer opioid analgesics has 
                                                 
1 This guidance has been prepared by the Division of Anesthesia, Analgesia, and Addiction Products, the Office of 
Regulatory Policy, the Office of Surveillance and Epidemiology, the Office of Biostatistics, and the Controlled 
Substance Staff in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.   
  1  Contains Nonbinding Recommendations 
been the development of opioids that are formulated to deter abuse.  FDA considers the 
development of these products a high public health priority.   
 
Because opioid products are often manipulated for purposes of abuse by different routes of 
administration or to defeat extended-release (ER) properties, most abuse-deterrent technologies 
developed to date are intended to make manipulation more difficult or to make abuse of the 
manipulated product less attractive or less rewarding.  It should be noted that these technologies 
have not yet proven successful at deterring the most common form of abuseswallowing a 
number of intact capsules or tablets to achieve a feeling of euphoria.  Moreover, the fact that a 
product has abuse-deterrent properties does not mean that there is no risk of abuse. It means, 
rather, that the risk of abuse is lower than it would be without such properties.  Because opioid 
products must in the end be able to deliver the opioid to the patient, there may always be some 
abuse of these products.  
 
For purposes of this guidance, abuse-deterrent properties are defined as those properties shown 
to meaningfully deter abuse, even if they do not fully prevent abuse. The term abuse is defined 
as the intentional, non-therapeutic use of a drug product or substance, even once, to achieve a 
desirable psychological or physiological effect.2 Abuse is not the same as misuse, which refers to 
the intentional therapeutic use of a drug product in an inappropriate way and specifically 
excludes the definition of abuse.3 This guidance uses the term abuse-deterrent rather than 
tamper-resistant because the latter term refers to, or is used in connection with, packaging 
requirements applicable to certain classes of drugs, devices, and cosmetics.4  
 
The science of abuse deterrence is relatively new, and both the formulation technologies and the 
analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving.  
Based on the evolving nature of the field, FDA intends to take a flexible, adaptive approach to 
the evaluation and labeling of potentially abuse-deterrent products.  Methods for evaluating the 
abuse-deterrent properties of new molecular entities may have to be adapted based on the 
characteristics of those products and the anticipated routes of abuse.  The development of an 
abuse-deterrent opioid product should be guided by the need to reduce the abuse known or 
expected to occur with similar products.   
 
Because FDA expects that the market will foster iterative improvements in products with abuse-
deterrent properties, no absolute magnitude of effect can be set for establishing abuse-deterrent 
characteristics.  As a result, FDA intends to consider the totality of the evidence when reviewing 
the results of studies evaluating the abuse-deterrent properties of a product. 
 
                                                 
2 Smith S M, Dart R C, Katz N P, et al. 2013. Classification and definition of misuse, abuse, and related events in 
clinical trials: ACTTION systematic review and recommendations.  Pain, 154:2287-2296. 
3 Ibid. 
4 FDAs current Good Manufacturing Practice regulations include tamper-evident packaging requirements.  See 21 
CFR 211.132.  There are also requirements for child resistant special packaging under the Poison Prevention 
Packaging Act and regulations adopted by the Consumer Protect Safety Commissioner (CPSC) in 16 CFR 1700.  
  2  Contains Nonbinding Recommendations 
As with all NDA products, FDA intends to consider opioids with abuse-deterrent properties 
within the context of available therapy.  The standard against which each products abuse-
deterrent properties are evaluated will depend on the range of abuse-deterrent and non-abuse-
deterrent products on the market at the time of that application.5   
 
Abuse-deterrent properties can generally be established only through comparison to another 
product.     
 
FDA encourages additional scientific and clinical research that will advance the development 
and assessment of abuse-deterrent technologies.  
 
FDA believes it is critical to address the problem of opioid abuse while seeking to ensure that 
patients in pain have appropriate access to opioid products.  Moreover, it is important that 
opioids without abuse-deterrent properties remain available for use in some clinical settings.  For 
example, patients in hospice care and with difficulty swallowing may need access to opioid 
products that are in solution or that can be crushed.  
 
The following section describes the categories of abuse-deterrent products.  The premarket and 
postmarket studies that should be performed to assess the impact of a potentially abuse-deterrent 
product are discussed in subsequent sections.  Finally, information is provided about labeling for 
abuse-deterrent products. 
 
III.  ABUSE-DETERRENT PRODUCTS 
 
Opioid products can be abused in a number of ways.  For example, they can be swallowed 
whole, crushed and swallowed, crushed and snorted, crushed and smoked, or crushed, dissolved 
and injected.  Abuse-deterrent technologies should target known or expected routes of abuse 
relevant to the proposed product.  As a general framework, abuse-deterrent formulations can 
currently be categorized as follows: 
 
1.  Physical/chemical barriers  Physical barriers can prevent chewing, crushing, cutting, 
grating, or grinding of the dosage form.  Chemical barriers, such as gelling agents, can 
resist extraction of the opioid using common solvents like water, simulated biological 
media, alcohol, or other organic solvents.  Physical and chemical barriers can limit drug 
release following mechanical manipulation, or change the physical form of a drug, 
rendering it less amenable to abuse. 
2.  Agonist/antagonist combinations  An opioid antagonist can be added to interfere with, 
reduce, or defeat the euphoria associated with abuse.  The antagonist can be sequestered 
and released only upon manipulation of the product.  For example, a drug product can be 
                                                 
5 For guidance on the evaluation of abuse potential for purposes of the Controlled Substances Act (CSA), we refer 
sponsors to FDAs draft guidance for industry Assessment of Abuse Potential of Drugs. This guidance is available 
at:  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf. 
FDA guidances are available at http://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
  3  Contains Nonbinding Recommendations 
formulated such that the substance that acts as an antagonist is not clinically active when 
the product is swallowed, but becomes active if the product is crushed and injected or 
snorted.   
3.  Aversion  Substances can be added to the product to produce an unpleasant effect if the 
dosage form is manipulated or is used at a higher dosage than directed.  For example, the 
formulation can include a substance irritating to the nasal mucosa if ground and snorted.  
4.  Delivery System (including use of depot injectable formulations and implants)  Certain 
drug release designs or the method of drug delivery can offer resistance to abuse.  For 
example, sustained-release depot injectable formulation or a subcutaneous implant may 
be difficult to manipulate.   
5.  New molecular entities and prodrugs The properties of a new molecular entity (NME) 
or prodrug could include the need for enzymatic activation, different receptor binding 
profiles, slower penetration into the central nervous system, or other novel effects.  
Prodrugs with abuse-deterrent properties could provide a chemical barrier to the in vitro 
conversion to the parent opioid, which may deter the abuse of the parent opioid.  New 
molecular entities and prodrugs are subject to evaluation of abuse potential for purposes 
of the Controlled Substances Act (CSA).   
6.  Combination  Two or more of the above methods could be combined to deter abuse.  
7.  Novel approaches  This category encompasses novel approaches or technologies that 
are not captured in the previous categories.  
 
IV.  PREMARKET STUDIES 
 
First and foremost, any studies designed to evaluate the abuse-deterrent characteristics of an 
opioid formulation should be scientifically rigorous.  Important general considerations for the 
design of these studies include the appropriateness of positive controls6 and comparator drugs, 
outcome measures, data analyses to permit a meaningful statistical analysis, and selection of 
subjects for the study.   
 
The evaluation of an abuse-deterrent formulation should take into consideration the known 
routes of abuse for the non-abuse-deterrent predecessor or similar products, as well as anticipate 
the effect that deterring abuse by one route may have on shifting abuse to other, possibly riskier 
route.  For example, if a product is known to be abused using nasal and intravenous routes, 
developing deterrent properties for the nasal route in the absence of deterrent properties for the 
intravenous route risks shifting abusers from the nasal to the intravenous route, which is 
associated with a greater risk for the spread of infectious diseases.   
 
Another concept that should be considered is whether the deterrent effects can be expected to 
have a meaningful impact on the overall abuse of the product.  For example, immediate-release 
(IR) opioid and acetaminophen combination products are predominantly abused using the oral 
                                                 
6 For purposes of this guidance, a positive control is an opioid drug product or drug substance expected to result in a 
predictable opioid drug liking effect and has a known potential for, or history of, abuse.   
  4  Contains Nonbinding Recommendations 
route.  Demonstrating a deterrent effect by the nasal route may not meaningfully reduce overall 
abuse of the product.  
 
FDA is committed to retaining a flexible, adaptive approach to evaluating potentially abuse-
deterrent opioid drug products.  This flexibility is intended to permit a sponsor to tailor the 
development program to suit the abuse-deterrent characteristics of their product and the routes of 
abuse for that product.  The adaptive aspect is intended to permit a sponsor to take into 
consideration the relevant products on the market at the time they are developing their product, 
so that appropriate non-abuse-deterrent and abuse-deterrent comparators can be used. For 
example, for some proposed products the appropriate comparator may be a conventional 
formulation.  However, if there are similar approved products with abuse-deterrent properties 
described in labeling, the appropriate comparator should be one of those abuse-deterrent 
products.  
 
The following sections describe three categories of premarket studies. Although, in general, any 
development program for studying abuse-deterrent technologies should include data from all 
three categories of studies, there may be exceptions.  For example, a formulation with a 
sequestered antagonist may intentionally be formulated not to resist crushing, so testing the 
syringeability of the product may not be relevant.  In most cases, however, to obtain a full and 
scientifically rigorous understanding of the impact of a technology or technologies on a 
products abuse potential, data from each of the following three categories of premarket studies 
are appropriate: 
 
1.  Laboratory-based in vitro manipulation and extraction studies (Category 1) 
2.  Pharmacokinetic studies (Category 2)  
3.  Clinical abuse potential studies (Category 3)  
 
The results of Category 1 studies may influence the design of Category 2 pharmacokinetic 
studies and Category 3 clinical abuse potential studies by suggesting the methods of 
manipulation that would yield the greatest release of opioid.  The results of Category 2 studies 
may influence the need for Category 3 studies of clinical abuse potential and the designs and 
goals of these studies. For example, if the extended-release characteristics of an abuse-deterrent 
opioid formulation cannot be defeated and the pharmacokinetic profile remains unchanged 
following oral or nasal administration of the manipulated product, oral and nasal studies of abuse 
potential may not be necessary. 
 
Additional studies (i.e., Category 4 studies) analyze postmarket data to assess the impact of an 
abuse-deterrent formulation on actual abuse.  Nonclinical drug discrimination studies are useful 
in the evaluation of the abuse potential of a drug, but their utility in predicting the impact of 
abuse-deterrent properties on human behavior has not been established.7 
 
                                                 
7 See FDA draft guidance for industry, Assessment of Abuse Potential of Drugs see 
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm198650.pdf.  
  5  Contains Nonbinding Recommendations 
A.  Laboratory Manipulation and Extraction Studies (Category 1)  
 
The goal of laboratory-based Category 1 studies should be to evaluate the ease with which the 
potentially abuse-deterrent properties of a formulation can be defeated or compromised.  This 
information should be used when designing Category 2 and Category 3 studies.  These studies 
are critical to the understanding of product characteristics and performance.8   
 
Methodologically, these studies should be designed with knowledge of the physicochemical 
properties of the product and the methods available to abusers to manipulate the product and 
should be conducted on the to-be-marketed formulation.  Sponsors should consider both the 
mechanisms by which abusers can be expected to attempt to deliberately overcome the abuse-
deterrent properties of the product as well as the ways that patients may alter the formulation 
(unintentionally or intentionally) that change the rate or amount of drug released (e.g., dose 
dumping may occur when taking the product with alcohol or when the product is cut, chewed, or 
crushed).  Testing should provide information sufficient to fully characterize the products 
abuse-deterrent properties, including the degree of effort required to bypass or defeat those 
properties.  In some cases, when designing in vitro studies, it may be useful to obtain information 
from prescription opioid abusers about how they would manipulate and abuse an abuse-deterrent 
product.   
 
In vitro studies should assess various simple and sophisticated mechanical and chemical ways a 
drug could be manipulated, such as by (1) defeating or compromising the controlled release of an 
opioid from ER formulations for purposes of abuse by different routes of administration; (2) 
preparing an IR formulation for alternative routes of administration; or (3) separating the opioid 
antagonist, if present, from the opioid agonist, thus compromising the products abuse-deterrent 
properties.  The goal of these studies is to manipulate the product to the point of defeating its 
abuse-deterrent properties.  Once this goal is achieved, it is no longer necessary to continue 
experiments using more sophisticated methods.  For example, if 90% of the opioid can be 
extracted under a set of conditions in 10 minutes, there is no need to test the same condition for 
30 minutes. 
 
The test product should be compared to appropriate comparator products for ease of mechanical 
manipulation.  The ability to crush, cut, grate, or grind the product formulation using readily 
available items such as spoons, cutters, and coffee grinders should be assessed.  Particular 
attention should be given to particle size distribution following each mode of physical 
manipulation because particle size may influence the rate of opioid extraction from manipulated 
product.  The effect of heat and cold on mechanical manipulation should also be studied. 
 
Extractability and solubility studies should be designed to determine whether any of the 
formulation components might be differentially solubilized and extracted, allowing an abuser to 
                                                 
8 This topic has been discussed at meetings of the Anesthetic & Life Support Drugs Advisory Committee and the 
Drug Safety & Risk Management Advisory Committee (NDA 022272, OxyContin, May 5, 2008, and September 24, 
2009).  Additional information on these meetings is available on FDAs web site at the following location: 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesic
DrugProductsAdvisoryCommittee/UCM187082.pdf. 
  6  Contains Nonbinding Recommendations 
bypass the drugs abuse-deterrent properties.  In addition to extraction and solubility studies, an 
assessment should be made to determine if free-base opioid can be precipitated from solution by 
pH adjustment.  After establishing how a product could be manipulated, chemical extraction of 
the opioid from the intact and the manipulated product should be assessed and compared to 
opioid extraction from the selected intact and similarly manipulated comparator products.   
 
The ease of extracting the opioid from the intact and manipulated product should be determined 
using a variety of solvents that are commonly available (e.g., water, vinegar, ethanol, 
isopropanol, acetone, mineral spirits) and those that have potentially relevant solvent 
characteristics (e.g., pH, polarity, protic vs. aprotic).  The effects of time, temperature, pH, and 
agitation on solvent extraction should also be determined.  For products containing more than 
one drug substance, extractability and solubility studies should be designed to determine whether 
any of the active ingredients might be differentially solubilized and extracted.  Sampling times 
should start early (e.g., 30 seconds) and continue until at least 80% of the opioid has been 
released, or 12 hours has been reached. The in vitro drug-release characteristics of the intact and 
manipulated product should also be compared using a discriminatory and robust dissolution 
method. 
 
In addition to the general evaluation of the effects of physical and chemical manipulation on the 
product, there are important route-specific data that should be generated, as follows:   
 
  For a product with potential for abuse by the nasal route, the particle size distribution 
following attempted manipulation by various methods should be established, and the 
method that provides the smallest particle size should be used in subsequent studies.   
 
  For a product with potential for abuse by smoking, the amount of drug produced by 
vaporization at temperatures encompassing the range from the melting point of the active 
ingredient to its degradation point should be determined.  Appropriate controls, such as 
pure active ingredient, both in salt and free-base form should be included in these 
assessments.   
 
  For a product with potential for abuse by injection, the amount of opioid that can be 
obtained in a syringe should be based on studies of intact and manipulated test product 
and comparator(s) using small volumes of water (5-10 mL) at room temperature and at 
90 C  95 C with and without agitation.  Extraction times should range from 30 seconds 
to 30 minutes.  The amount of opioid extracted, the volume of solution collected and the 
viscosity of the samples should be recorded.  The ability to get the sample into a syringe 
and expel the sample using needles of various gauges should also be explored.   
 
The following examples illustrate the kinds of outcomes that in vitro studies should evaluate. 
 
1.  Characteristics of the product by crushing, grinding or melting, or by changing the intact 
formulation using other methods that would limit nasal administration of the manipulated 
product, and/or that would limit dissolution of the manipulated product and incorporation 
into a solvent that could then be injected by intravenous or subcutaneous routes. 
 
  7  Contains Nonbinding Recommendations 
2.  Quantity of the opioid extracted from the product following the various methods attempted 
that could be used for injection by intravenous or subcutaneous routes and a description of 
any barriers resulting from attempts at dissolution for drawing the drug into a syringe. 
 
3.  Quantity of opioid antagonist released from an agonist/antagonist combination when it is 
manipulated for administration by ingestion, nasal administration, or injection. 
 
4.  Quantity of opioid product following in vitro manipulation of the prodrug. 
 
B.  Pharmacokinetic Studies (Category 2)  
 
The goal of the clinical pharmacokinetic studies, Category 2, should be to understand the in vivo 
properties of the formulation by comparing the pharmacokinetic profiles of the manipulated 
formulation with the intact formulation and with manipulated and intact formulations of the 
comparator drugs through one or more routes of administration.  Even though the same routes of 
administration should be studied for the new product and comparators, if specific circumstances 
prevent this approach, the study design should be discussed with FDA.  The method of 
manipulation used for the pharmacokinetic studies should be based on the methods explored 
during in vitro testing that can be expected to result in the greatest drug release.  The routes of 
administration chosen should be relevant to the proposed product, and likely will be based on 
what is known about the abuse of similar products.  Note that, for some development programs, 
it may be preferable to combine measures of pharmacokinetic parameters for Category 3 studies, 
in which case separate Category 2 studies may not be necessary. 
 
In general, the pharmacokinetic profile for the oral route of administration should be studied.  
Appropriate study subjects for Category 2 studies include healthy volunteers as long as 
naltrexone is used to block the pharmacodynamic effects of the opioids. 
 
Depending on the product, it may be important to evaluate the pharmacokinetic profile for the 
nasal route of administration as well.  For nasal pharmacokinetic studies, it is important to weigh 
the risk to the subject based on the excipients in the formulation.  Only subjects with a history of 
nasal abuse of opioids should be recruited for these studies. As with the oral route of 
administration, it may be possible to combine the pharmacokinetic assessment and the 
pharmacodynamic assessment in one clinical abuse potential study with sampling for the 
pharmacokinetic analysis. 
 
Relevant pharmacokinetic parameters for the opioid drug and any psychoactive metabolites that 
should be measured in these studies include the following. 
  Maximum concentration (C )  
max
  Time to maximum concentration (T )  
max
  Area under the curve (AUC  and AUC )  
0-t 0-
  Relevant partial AUC, including early time points such as AUC  minutes or AUC  
0-30 0-2
hours, the period of time when Cmax is expected 
  Terminal elimination half-life (T ) 
1/2
  8  Contains Nonbinding Recommendations 
 
Traditional pharmacokinetic study designs should be employed (e.g., crossover designs), and the 
results should be analyzed using bioequivalence methods.  The rate of rise of drug concentration 
should be assessed when possible because it is thought to contribute to differential abuse 
potential among drugs, formulations, and routes of administration.9  To support these analyses, it 
is important to have specimen collection and analysis time points sufficient to cover the onset, 
peak, and offset of the effects of both IR and ER formulations, in both the intact and manipulated 
conditions.  In addition, these data are necessary to calculate the relevant partial area under the 
curve, which should capture the time to maximum concentration of the opioid.   
 
If food and alcohol alter the pharmacokinetic parameters of the formulation, data should be 
provided to characterize those effects.10  If food significantly increases systemic exposure of the 
intact formulation, the underlying mechanism for the food effect should be established by 
assessing whether the effect is based on the drug substance or the formulation and whether the 
effect is present with intact product as well as with manipulated product.  When food is expected 
to increase exposure, subsequent abuse potential studies of the oral route should be conducted in 
the fed state to maximize the potential systemic exposure.   
 
In addition to the pharmacokinetic profile of the opioid, for agonist/antagonist combinations , the 
pharmacokinetic characteristics of the antagonist should be defined for the intact product as well 
as for the manipulated formulation. 
 
As with all clinical studies, adverse events should be collected, and those that can provide 
additional insight about the abuse-deterrent effects are especially important.  For example, if the 
manipulated formulation is abused by snorting, it would be important to assess adverse events 
related to intranasal tolerability.   
 
C.  Clinical Abuse Potential Studies (Category 3)  
 
In addition to their use by FDA to formulate its scheduling recommendation under the CSA for 
drug products containing a controlled substance, clinical studies of abuse potential, Category 3, 
are important for assessing the impact of potentially abuse-deterrent properties.  As discussed in 
                                                 
9 References suggesting that drugs associated with a rapid onset of action are associated with greater abuse potential 
include:  
Abreu M E, Bigelow G E, Fleisher L, and Walsh S L. 2001. Effect of intravenous injection speed on responses 
to cocaine and hydromorphone in humans. Psychopharmacology, 154:76-84. 
de Wit H, Bodker B, and Ambre J.1992. Rate of increase of plasma drug level influences subjective responses 
in humans. Psychopharmacology, 107:352-358. 
de Wit H, Didish S, and Ambre J. 1993. Subjective and behavioral effects of diazepam depend on its rate of 
onset. Psychopharmacology, 112: 324-330.   
10 FDA has issued a draft guidance on this topic (Assessment of Abuse Potential of Drugs). Once finalized, it will 
represent FDAs current thinking on this topic.  
 
  9  Contains Nonbinding Recommendations 
FDAs guidance on that topic,11 the preferred design is a randomized, double-blind, placebo-
controlled and positive controlled crossover study.  These studies generally are conducted in a 
drug-experienced, recreational user population.  The use of a pre-qualification phase (see section 
2 below) to identify subjects who can reproducibly distinguish active drug from placebo is a 
common enrichment strategy used to improve the power of the study to establish a difference 
between treatments.  
 
Additional considerations applicable to clinical abuse potential studies used to assess potentially 
abuse-deterrent properties are discussed below.  For products that are not susceptible to 
manipulation based on Category 1 and 2 testing, study designs for Category 3 testing should be 
discussed with FDA. 
 
1.  Blinding 
 
Clinical studies of abuse potential should use a randomized, double-blind, placebo-controlled 
and positive controlled crossover design.  Because study subjects are recreational drug users and 
familiar with the effects of the drug substances being studied, the double-dummy technique or 
other techniques should be used to ensure the blinding of all tests when possible.  However, 
alternative designs may be suitable when the blinding of the study drug and the positive control 
cannot be maintained and treatment by period interactions may lead to sequence effects in a 
crossover design.  For example, a parallel design may be useful when studying the intranasal 
route of administration, where subjects may be able to see the differences in volume or color 
between test drug and placebo or positive control, or when it is not possible to create similar 
results from manipulation, such as particle size from crushing.  In these circumstances, early 
discussion with FDA is recommended. 
 
For clinical abuse potential studies in which the subjects will snort test samples, administration 
of the samples in a narrow neck, opaque container with a pre-inserted straw may help facilitate 
blinding.  However, even though subjects might not be able to see the sample, un-blinding may 
still occur due to the physical properties of samples with similar particle size distribution.  In 
some formulations, higher crushed tablet/capsule volume or larger particle size may inhibit 
complete intranasal administration thereby contributing to the deterrence effects.  To be able to 
evaluate these effects, it may be necessary to maintain differences in tablet/capsule volume 
between the potentially abuse-deterrent formulation and the comparator.  To facilitate blinding 
and maintain the crossover design, placebos matched to each of the differing weights or particle 
sizes may be useful. The details of the preparation of the samples should be provided in the study 
protocol. 
 
2.  Pre-qualification Phase 
 
The purpose of the pre-qualification phase is to increase the power of a study to detect 
differences in the abuse potential of the various formulations of drug and placebo.12  In general, 
                                                 
11 Ibid. 
12 An additional advantage of a pre-qualification phase is that it helps familiarize subjects with and train them in the 
use of various scales and questionnaires that measure subjective effects. 
  10  Contains Nonbinding Recommendations 
the pre-qualification phase should ensure that subjects can distinguish between placebo and a 
conventional IR formulation of the same opioid being developed in an abuse-deterrent 
formulation, using the same route of administration as planned for the assessment phase.  There 
is little value in having subjects unable to distinguish placebo from active drug continue in the 
study.  The positive control should include a strength that is at least equal to the lowest strength 
selected for the assessment during the clinical phase.  An important aspect of the pre-
qualification phase is assessing the ability of subjects to tolerate the study dose. If the dose used 
in the pre-qualification phase is lower than the lowest strength planned for the assessment phase, 
some subjects may not be able to tolerate the higher dose that will be administered in the 
assessment phase.  Thus, when tolerability may be an issue, particularly if more than one dose is 
planned for the assessment phase, a pre-qualification dose that is no lower than the lowest dose 
planned may be the most efficient choice to establish that the subject can distinguish active drug 
from placebo and can tolerate the study drug in the range to be tested. For example, a 30 mg or 
45 mg dose of opioid could be used in the pre-qualification phase when a 30 mg and 60 mg 
doses will be assessed in the clinical phase.   
 
Qualifying criteria that help identify subjects with an acceptable placebo response and an 
acceptable response for the positive control should be pre-specified in the study protocol.  After a 
range for an acceptable placebo response is set, a minimum value for the maximum effect (E  
max)
for the positive control should be defined.  The minimum E  for the positive control may vary 
max
from measure to measure, and from study to study.  However, an acceptable response for the 
positive control should not overlap with the acceptable range for placebo response.  
 
3.  Assessment Phase 
 
The potentially abuse-deterrent product should be compared to a positive control, and the 
positive control should be compared to placebo to validate the study.  For an IR product with 
potentially abuse-deterrent properties, the positive control should be an IR formulation of the 
same opioid.  For an ER formulation with potentially abuse-deterrent properties, the positive 
control could be an IR formulation of the same opioid or an ER formulation of the same opioid. 
In general, these studies should include one strength of the positive control which is associated 
with high levels of drug liking.  However, when assessing drug liking through the intranasal 
route, the use of two strengths of the positive control may be helpful to both identify a strength 
of the positive control associated with high drug liking scores and to validate the study.   
 
If there are no approved products with the same drug substance, the positive control should be a 
drug that, based on pharmacological profile or nonclinical data, can be expected to have similar 
pharmacodynamic effects.  Selection of the positive control in this setting should be discussed 
with FDA. 
 
4.  Subjects 
 
Studies should be conducted in opioid-experienced, recreational drug users who have experience 
with the particular route of abuse being studied.  Subjects should generally not be physically 
dependent and should not be currently seeking or participating in treatment for drug abuse such 
that participating in the study could make them vulnerable to relapse.  Depending on the 
  11  Contains Nonbinding Recommendations 
formulation being studied, however, clinical abuse potential studies can be conducted in 
physically dependent subjects.  For example, if the deterrent product contains an opioid 
antagonist, clinical abuse potential studies in a physically dependent population may provide 
information not only on the drug liking of the product, but on the ability of the antagonist to 
precipitate withdrawal in this population.  
 
Detailed characteristics of the study population with respect to past and current drug use and 
abuse should be captured (e.g., drugs abused, drug of choice, duration of abuse or abstinence).   
 
5.  Route of Administration, Dose Selection, Manipulation Mode, and Sample 
Preparation 
 
The selection of the route(s) of administration should be based on epidemiological data showing 
that a selected route is a relevant route of abuse.  For NMEs, the sponsor should review the 
relevant routes of abuse for products similar to the test product and discuss the selected routes 
with FDA.  For each relevant route of administration, the potentially abuse-deterrent product and 
comparator should be manipulated based on the results of Category 1 studies to cause the highest 
release of the opioid and the highest plasma levels.  The dose of the opioid selected for the study 
should be known to produce high levels of liking in non-tolerant opioid-experienced recreational 
users. 
 
For studies using the intranasal route of administration, the preparation of the samples is 
extremely important.  The potentially abuse-deterrent product and comparator study drug should 
be produced with similar particle size distribution based on a detailed protocol for the 
preparation of the samples, even if different methods are necessary to do so.13  With some 
formulations, a high volume of the crushed tablet/capsule or larger particle size may inhibit 
complete intranasal administration and, thereby, contribute to deterrence effects.  To evaluate 
these effects, it may be necessary to maintain differences in tablet/capsule volume between the 
potentially abuse-deterrent product and the comparator.  
 
For studies using the intravenous route of administration, the oral formulations may not be safe 
for intravenous use depending on the excipients used in the formulation.  In place of the 
manipulated oral formulation, a solution for injection should be prepared using approved, 
commercially available parenteral products when available, or products suitably formulated for 
the study.  The amount of the opioid and that of the antagonist, when relevant, should be based 
on extrapolation from in vitro extraction studies of manipulated solid formulations.   
 
6.  Outcome Measures and Data Interpretation 
 
In abuse potential studies, the primary method for evaluating the subjective effects of drugs 
should be through the use of standardized instruments.   
 
                                                 
13 Available safety-related information on the use of the various excipients through the intranasal route should be 
provided.  Additionally, some sponsors have conducted intranasal tolerability studies before the abuse potential 
studies to evaluate irritation of the nasal cavity, nasal congestion, and discharge, among other measures. 
  12  Contains Nonbinding Recommendations 
In typical abuse potential studies, several instruments have been used to measure subjective 
responses predictive of the likelihood of abuse.  These instruments include:  
 
  Visual Analogue Scales (VAS)  used for drug liking, good effects, bad effects, and other 
drug abuse-related effects  
  Profile of Mood States 
 
The VAS should be the primary measure for drug liking because it appears to correlate most 
directly with potential for abuse.  Other measures of particular interest include assessment of 
likelihood to take the drug again and assessment of overall drug liking.14  
These measures can be assessed using either a unipolar or bipolar scale, and a rationale should be 
provided for the choice for a particular scale.  In general, FDA recommends using a bipolar scale 
for the primary measure of drug liking.  Unipolar scales have been used to measure other drug 
effects, such as good and bad effects.  Regardless of whether a unipolar or bipolar scale is 
selected, FDA recommends that for purposes of training subjects, the same scale be used in the 
pre-qualification and assessment phases.   
 
7.  Data Interpretation 
 
For clinical studies of abuse potential conducted on potentially abuse-deterrent opioid drug 
products, the primary analysis should be the difference in means of the E 15 for the primary 
max
measure(s) based on the population of study completers.  A statistical analysis plan (SAP) should 
be included in the study protocol or submitted as a separate document before un-blinding the 
study.  The sponsor should provide data and dropout information for non-completers.  To ensure 
adequate power, the sponsor should take into account that there will be subjects who drop out of 
the study early and plan the sample size calculation accordingly.  Proper planning should avoid 
any need to replace subjects who discontinue without completing the study. 
 
Additional pharmacodynamic measures, including positive subjective effects other than drug 
liking (e.g., take drug again, high, overall drug liking) and other subject-rated assessments, are 
generally considered secondary endpoints.  Other subject-rated assessments of interest include: 
alertness; drowsiness; nausea; and, when the intranasal route is used, intranasal irritation, 
burning, need to blow nose, runny nose/nasal discharge, facial pain/pressure, and nasal 
congestion.   
 
Some sponsors provide descriptive statistics including mean, standard error, median, and 
interquartile range, calculated for all pharmacodynamic endpoints by time and treatment.16 What 
                                                 
14 Overall drug liking measures the users retrospective assessment of a drug, whereas VAS for drug liking measures 
the users immediate assessment. 
15 In general, the primary endpoint of interest is drug liking, and the E  is captured within 8 hours after dosing.  
max
However, the timeframe of measuring the maximum response will be determined by the pharmacokinetic and 
pharmacodynamic parameters of the formulations studied. 
16 See Statistical Analysis Section for further guidance. 
  13  Contains Nonbinding Recommendations 
constitutes a clinically significant difference in drug liking, between the manipulated and intact 
versions of the potentially abuse-deterrent product and positive control, is an area requiring 
further research and will be evaluated on a case-by-case basis.  Analysis of postmarket data on 
abuse levels associated with the potentially abuse-deterrent product being studied may help to 
support the findings from abuse potential studies.   
 
In addition, when interpreting results from clinical abuse potential studies, attention should be 
given to the profile of subjective effects produced by the manipulated and intact formulation in 
terms of onset, peak duration of activity, and offset.  The rate of rise of drug onset for the intact 
and manipulated potentially abuse-deterrent product should be given appropriate weight in the 
overall analysis of the abuse-deterrent properties.  A more rapid onset of action or a shorter time-
to-reach peak effect is generally associated with greater abuse potential.  Regarding the duration 
of effect, it may be difficult to interpret the abuse potential of a formulation that produces a 
sustained liking effect when taken intact or after manipulation, though lower than that produced 
by the positive control formulation.   
 
The overall assessment of abuse potential should be based on the pattern of findings across all of 
the measures.  In addition, qualitative aspects of the findings, such as the steepness of the drug 
liking response and duration of the liking effects associated with manipulated formulations, 
should be taken into consideration, along with other positive effects and negative effects.   
 
8.  Statistical Analysis  
 
a.  Background 
 
The overall goal of a clinical study of abuse potential is to assess a number of abuse 
potential outcome measures (e.g., drug liking VAS) in the potentially abuse-deterrent 
product (T) relative to a formulation of the drug without abuse-deterrent properties (C), or 
a newly formulated opioid product (positive control).  Substantial decreases in the 
responses for the potentially abuse-deterrent formulation compared to the positive control 
are evidence of deterrence. 
 
A clinical study of abuse potential should be validated by comparing the responses to C 
with those of placebo (P).  Thereafter, the assessment of the abuse-deterrence properties 
of T is of primary interest.  This can be achieved by comparing the difference in means 
between C and T with a margin for abuse potential measures and comparing the 
difference between C and T relative to C in drug liking on a bipolar VAS. 
 
The statistical analysis of the data in a clinical study should begin with descriptive 
statistics making up tabulations and graphs that include tables of the mean, standard 
error, and other summary statistics: minimum, Q1, median, Q3, and maximum of the 
responses of interest for each treatment and for each paired difference among treatments.   
  14  Contains Nonbinding Recommendations 
Useful graphs include mean time course profiles, heat-maps,17 and continuous responder 
profiles.   
 
The next subsection describes the statistical test that sponsors should use for the primary 
analysis of E  on the VAS for drug liking.  An analysis of the percent reduction in drug 
max
liking for T relative to C on the individual level in subsection c is recommended as a 
secondary analysis. 
 
b.  Primary analyses 
 
The primary analysis of abuse-deterrent effects should be based on the comparison of 
means18 between crushed, chewed, or otherwise modified T and C with an abuse 
deterrence margin on drug liking VAS.  That is, test 
 
H :   versus H :  > 
0 C T 1 a C T 1
 
where  =*( 50), and 0<* <1.  Because C is an opioid drug, the validation 
1 C
test also needs a margin, say .  That is,  
2
H :    versus H :  >  
0 C P 2 a C P 2
where  15. 
2
 
The significant level for both tests is 2.5%. 
 
The actual value of  is related to , hence, it may vary according to abuse potential 
1 C
measures and the route of drug administration.  The * should be pre-specified in the 
protocol.  We also suggest the use of 95% confidence intervals to assess both the 
differences    and  . 
C T C P
 
c.  Secondary analyses 
 
In addition to the primary analysis, an analysis should be performed of the percent 
reduction for the potentially abuse-deterrent product T relative to C from each individual 
study subject for drug liking VAS on a bipolar scale from 0 to 100. One definition for 
percent reduction for individual subjects is as follows:   
c t
%reduction = i i 100%, i =1,2,...,n, 
c  p
i i
where c , t and  p  are the E  values for C, T, and P from the ith subject, respectively; 
i i i max
n is the sample size. 
                                                 
17 Chen L and Wang Y. 2012. Heat map displays for data from human abuse potential crossover studies. Drug 
Information Journal, 46:701:707. 
18 If a nonparametric method is necessary, analysis of the median difference in E  may be appropriate. 
max
  15  Contains Nonbinding Recommendations 
 
However, this definition is problematic because for two subjects having the same E  
max
values for T and C (t =t  and c =c ), the larger the placebo response, the greater the 
1 2 1 2
percent reduction.  A more appropriate definition of percent reduction can be derived by 
replacing  p  by the neutral score 50 on a bipolar scale; that is, 
i
c t
% reduction= i i 100%, i =1,2,...,n 
c 50
i
where we assume that c >50.  In case some subjects havec 50, define % reduction = 0. 
i i
 
Note that even though most abuse potential studies have a pre-qualification phase, 
approximately 10% of subjects still have placebo responses p  over 65, with 5% over 75 
i
in the assessment phase.  Consequently, it may be necessary to penalize subjects with 
large values of p in computing percent reduction.  For example, the percent reduction 
i
could be multiplied by an adjustment factor that equals 1 when p  is around 50 or less 
i
and decreases from 1 when  p  is large.  Sponsors should discuss with FDA the need for 
i
an adjustment factor in computing percent reduction and an appropriate formula for 
defining the penalty to be applied before finalizing the study protocol. 
 
Two approaches for assessing the deterrent effects using percent reduction for crossover 
design studies are provided below.  Note that when a parallel design is used, the percent 
reduction for individual subjects is not applicable, and the primary analysis may also 
serve the purpose for assessing the percent reduction based on    related 
C T
to 50. 
C
 
  Responder Analysis 
 
A responder is defined as a subject who had at least *100% of reduction, in E  for T 
max
relative to C.  To ensure that a majority of subjects are responders, a proportion test can 
be used to test the null hypothesis that 50% or fewer subjects are responders.  That is, test 
 
H :p*50% versus H :p*>50% 
0 a
 
at the 2.5% significance level where p* denotes the percentage of responders.  The 95% 
confidence interval of p* can also be calculated. 
 
  Analysis of the Median Percent Reduction 
 
The median of the percent reduction (ptr) is a descriptive measure of central tendency of 
ptr.  At most 50% of subjects have ptr less than the median, and at most 50% of subjects 
have ptr greater than the median.  If the median of ptr is equal to 30%, for example, it 
means that approximately 50% of subjects have greater than or equal to a 30% reduction. 
 
  16  Contains Nonbinding Recommendations 
For assessing deterrent effects, we can test 
 
H :median(ptr)DR% versus H :median(ptr)>DR% 
0 a
 
at the 2.5% significance level, where DR denotes deterrent reduction.  To be consistent 
with the responder analysis, we recommend DR % = *100%.  If the distribution of ptr is 
symmetric, the Wilcoxon-signed rank test can be used to test the null hypothesis that 
themedian(ptr)DR%, and a 95% confidence interval for the median based on this test 
can be readily calculated using standard methods.  Otherwise, the sign test should be used 
or an alternate method of this test can be pre-specified in the SAP. 
 
Sponsors should pre-specify one of the two analysis methods for the percent reduction in 
their SAP in addition to the primary analysis in their clinical studies and discuss with 
FDA the definition of a responder in the responder analysis or the value of DR% used in 
the analysis of the median percent reduction before finalizing the study protocol. 
 
d.   Multiplicity 
 
Whether or not an adjustment for multiplicity is needed for claiming significant results on 
the primary or key secondary endpoints varies from study to study.  Sponsors should 
refer to the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) guidance E9 Statistical Principles 
for Clinical Trials19 for statistical principles regarding the multiplicity adjustment. 
 
V.  POSTMARKET STUDIES (CATEGORY 4)  
 
Premarket studies focus on assessing the potentially abuse-deterrent properties of a product 
under controlled conditions.  The goal of postmarket20 studies, Category 4, is to determine 
whether the marketing of a product with abuse-deterrent properties results in meaningful 
reductions in abuse, misuse, and related adverse clinical outcomes, including addiction, 
overdose, and death in the post-approval setting.  As more abuse-deterrent products are 
approved, it is possible that the amount of reduction observed in an epidemiologic study may 
also change.  Consequently, a reduction that is deemed meaningful at one time may not be 
meaningful at another.  Given the changing landscape, a numerical threshold cannot define what 
would be considered a meaningful reduction. 
 
Currently, data on the impact of an abuse-deterrent product on drug abuse in the U.S. population 
are limited, and thus the optimal data sources, study variables, design features, analytical 
                                                 
19 ICH guidelines are available on FDAs guidance webpage at 
http://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
20 FDA requires postmarket studies for all opioids with abuse-deterrent labeling claims.  For more information on 
postmarket requirements, see http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-
marketingPhaseIVCommitments/ucm070766.htm. 
 
  17  Contains Nonbinding Recommendations 
techniques, and outcomes of interest of postmarket epidemiologic studies are not fully 
established.   
 
Postmarket evaluations of abuse deterrence fall into two categoriesformal studies and 
supportive information.  Sponsors should submit protocols to FDA for all formal studies of abuse 
deterrence.  Supportive information can also be submitted to FDA, but cannot substitute for 
formal studies. 
 
A wide range of interrelated behavioral, clinical, and societal factors contribute to drug abuse; 
therefore, the effects of an abuse-deterrent formulation can manifest in a variety of ways.  
Understanding the actual impact of a particular abuse-deterrent formulation may require using a 
variety of study designs to examine different abuse-related outcomes in given populations of 
interest.  Generally, multiple formal studies using a variety of data sources should be conducted 
to provide insights into product-specific abuse and the effect of an abuse-deterrent product on the 
outcomes of interest for other opioid drug products.  The use of multiple study designs will also 
generally help with assessment of the impact of abuse-deterrent products on the full spectrum of 
abuse-related outcomes (i.e., addiction, overdose, and death) and to characterize and quantify the 
relevant clinical events that are associated with these outcomes.  
 
Recognizing that the current thinking in this area may change, the following subsections provide 
recommendations for designing postmarket epidemiologic studies that are capable of detecting a 
change in the occurrence of abuse as a result of a drug products abuse-deterrent properties. 
 
A.  Formal Studies 
 
1.  General Characteristics 
 
Formal studies have the following characteristics:   
 
1.  They are hypothesis-driven, population-based, observational evaluations that follow good 
epidemiological practices21,22 and use outcomes that provide meaningful measures of 
abuse deterrence. 
2.  They capture one or more outcomes that can be used to assess meaningful reductions in 
misuse, abuse, addiction, overdose, and death. 
3.  They produce estimates of abuse and related clinical outcomes that are nationally 
representative, or are based on data from multiple large geographic regions that can 
reasonably be generalized to the national level.  In the absence of nationally generalizable 
                                                 
21 See FDA guidance Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using 
Electronic Healthcare Data, available at 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm243537.pdf.  
22 International Society for Pharmacoepidemiology and Risk Management, Guidelines for Good Practices and 
Pharmacoepidemiologic Studies, available at http://www.pharmacoepi.org/resources/guidelines_08027.cfm, 
accessed January 25, 2015.  
  18  Contains Nonbinding Recommendations 
data, smaller or regional studies may be informative, but must be accompanied by a clear 
explanation of their representativeness and generalizability for appropriate interpretation. 
4.  They assess overall and route-specific (i.e., injected, snorted, smoked) changes in abuse 
levels that are associated with an abuse-deterrent product. 
5.  They are sufficiently powered statistically to assess meaningful changes in drug abuse 
and are of sufficient duration to examine trends in abuse following the marketing of the 
abuse-deterrent product.  The necessary duration of the studies will depend on a variety 
of factors, including drug utilization and market share, early postmarket abuse deterrence 
data, and changes in the prescription opioid or illicit drug market. 
 
2. Study Design Features 
 
The epidemiologic methods and data sources that underlie formal postmarket studies to evaluate 
the effect of abuse-deterrent formulations are evolving, and best practices have not been 
established.  In addition, characterizing the relevant clinical events that are most useful for 
understanding the actual impact of a product on abuse-related adverse events is also an evolving 
science.  Based on the current state of this field, we provide below some basic guidelines on 
recommended study design features that will enable FDA to evaluate the results of formal 
studies.  
 
1.  The study hypothesis and its relationship to assessing abuse deterrence should be clearly 
stated.  The study hypothesis should also include the route(s) of abuse that will be 
studied. 
2.  An understanding of each data source is important to the design and interpretation of the 
study.  A description of each data source should be provided in the protocol and should 
include if and how the data source captures drugs, study outcomes, drug formulation, and 
route of abuse.  The sampling methods, study population, or catchment area for the data 
source should be clearly described.23 
3.  The choice of population(s) in each study should be carefully considered.  The 
populations included in the study should be described in the protocol.  At least one study 
should include a high-risk population, such as a population of known drug abusers, but 
formal studies should not be limited to only high-risk populations. 
4.  The protocol and study reports should thoroughly define the study outcomes. The choice 
of the outcome measure(s) should be justified.  Formal studies should, as a group, capture 
all relevant outcomes: misuse, abuse, addiction, overdose, and death, as well as misuse 
and abuse clinical outcomes. Overall and route-specific misuse and abuse estimates 
should include prevalence and frequency of abuse.  Clinical outcomes should include, 
when possible, an assessment of severity of abuse outcomes (e.g., addiction or overdose). 
                                                 
23 See FDA guidance Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using 
Electronic Healthcare Data. 
  19  Contains Nonbinding Recommendations 
5.  Both population- and drug utilization-based estimates should be included in the study 
protocol.24 Drug utilization-based estimates should use multiple denominators.  The 
denominators are generally the number of prescriptions and the number of extended units 
(e.g., tablets or capsules).  The catchment area for drug utilization data should be 
specified, particularly for sub-national or regional populations. 
6.  Sponsors should list all proposed opioid comparators and describe the rationale behind 
their inclusion.  When branded and generic versions of a comparator are marketed, all 
should be included in the study when possible because many data sources used in abuse 
studies can identify only active ingredients and do not distinguish between branded and 
generic products or among multiple generic products.  Information should be provided on 
the ability of data sources and study participants to accurately discriminate among 
different opioid products and formulations.  The choice of comparator is critical for 
determining if a reduction in drug abuse is the result of a products abuse-deterrent 
properties or the result of other factors (e.g., educational programs, prescription drug 
monitoring programs, changes in law enforcement policies, and the availability of other 
drugs) or secular trends.  The choice of comparators will depend on the particular abuse-
deterrent product studied and the opioid market environment at the time the study is 
initiated.  Multiple comparators should be used to achieve the most complete picture of 
the impact of a products abuse-deterrent properties.  For the purposes of hypotheses, 
some comparators should be selected and justified as primary comparators in the study 
protocol before data collection, with additional comparators providing context.  The 
following are examples of several potential abuse-deterrent study comparator scenarios. 
 
If an abuse-deterrent formulation of a previously marketed product is introduced 
to the market, the primary comparators should include historical and currently 
available non-abuse-deterrent formulations of the products (including branded and 
generic whenever possible).  Additional individual opioid products should be 
included as well and should be agreed upon with FDA and identified before the 
start of the study. 
If a new abuse-deterrent product does not have an historical or currently available 
non-abuse-deterrent version of the same opioid, an appropriate group of 
comparators should be identified before the start of the study through mutual 
agreement with FDA.  Examples of appropriate primary comparators include 
immediate release non-abuse-deterrent products with the same active moiety 
and/or a non-abuse-deterrent product with a relatively stable market share and 
abuse estimates captured at baseline during the postmarket period.  Larger 
groupings of products can also serve as comparators and can help determine 
secular trends. 
 
When available, a product that has the same active moiety, but has a different 
abuse-deterrent property, can serve as a comparator. 
                                                 
24 Secora A, Dormitzer C, Staffa J, and Dal Pan G.  2014.  Measures to quantify the abuse of prescription opioids: a 
review of data sources and metrics.  Pharmacoepidemiology and Drug Safety, 23(12):1227-37. 
  20  Contains Nonbinding Recommendations 
 
7.  Understanding the background rates of drug abuse is important for protocol design and 
interpretation of study results.  A baseline assessment of the prevalence of drug abuse for 
formulations of the same opioid that lack abuse-deterrent properties should be conducted 
and the baseline time period should be justified. 
8.  Submissions should include the SAP.  The plan should include parameter definitions, unit 
of analysis, model specification, power and sample size calculations, and any additional 
variables or predictors.  Assessment of the abuse outcome measures should consider both 
average levels of abuse comparing pre- and post-periods to currently available product 
(means analysis) and trend analysis. 
9.  Statistical models should include variables that may affect how the product is used and 
also other related confounders (e.g., geographic variability and demographic 
characteristics).  
10. Exposure and outcome measures that include self-reported assessments should be 
validated before the start of the study.  
11. The precision of outcome measures will also influence the observational period.  
Outcome measures with large uncertainty (due to bias or variability) in the exposure or 
study variable measures, for example, may warrant longer observational periods.   
12. Interim analyses are encouraged, but results should be considered tentative in light of 
their preliminary nature. 
 
B.  Supportive Information 
 
Information is considered supportive if it can be used to provide additional context on societal, 
behavioral, and clinical aspects of abuse and abuse-deterrence.  Supportive information may be 
qualitative or descriptive, and it may rely on sources that capture drug utilization or prescribing 
patterns, diversion events, attitudes and practices (e.g., tampering) of abusers and other 
information that may not directly be considered abuse (e.g., data concerning the street value of 
prescription drugs, information about drug use and misuse from social websites).  Investigations 
that provide supportive information may also include investigations that are conducted in smaller 
populations or subgroups, and that while perhaps not broadly generalizable, may contribute to 
the totality of the evidence relating to abuse deterrence.   
 
As is the case for formal studies, best practices for collecting and submitting supportive 
information are still evolving.  However, below are some basic recommendations relating to 
supportive information. 
 
1.  Supportive information should be clearly stated, and the rationale for how the supportive 
information contributes to a sponsors portfolio of abuse-related studies should be clearly 
identified. 
2.  How supportive information is representative of the population from which it is derived 
or sampled should be clearly described. 
  21  Contains Nonbinding Recommendations 
3.  How the exposure and outcome are measured should be clearly described along with the 
relationship between the outcomes measured and the primary outcomes of interest: 
misuse, abuse, addiction, overdose, and death.   
4.  Collections of supportive information that include populations of particular interest or 
geographically diverse settings is strongly encouraged.  Overlapping geographic areas 
between formal and supportive information should be considered. 
 
VI.  LABELING  
 
Including information about a products abuse-deterrent properties in labeling is important to 
inform health care professionals, the patient community, and the public about a products abuse 
potential.  Accordingly, FDA encourages sponsors to propose labeling that sets forth the results 
of in vitro, pharmacokinetic, clinical abuse potential and formal postmarket studies and 
appropriately characterizes the abuse-deterrent properties of a product.   
 
There are several important concepts about the state of the science of pre- and postmarket studies 
of abuse deterrence that should be considered as these are reflected in labeling.  First, as stated 
earlier in the guidance, abuse-deterrent does not mean abuse-proof.  Therefore, labeling should 
reflect a products abuse-deterrent properties, as supported by the data, but should include a 
caveat that abuse is still possible.  Next, premarket studies are intended to demonstrate properties 
that are predictive of a meaningful abuse-deterrent effect for a particular route of administration.  
FDA has limited data correlating the abuse-deterrent properties of certain opioid drug products, 
as demonstrated by premarket studies, with the impact of those properties on abuse or adverse 
events associated with abuse in the post-approval setting.  Even though postmarket studies have 
the potential to demonstrate such effects, the findings of postmarket studies are not available at 
the time of initial product approval.  Labeling should reflect the predictive quality of premarket 
studies and include results of relevant completed postmarket studies. 
 
When premarket data show that a products abuse-deterrent properties can be expected to result 
in a meaningful reduction in that products abuse, these data, together with an accurate 
characterization of what the data mean, should be included in product labeling.25  When 
postmarket data become available that demonstrate a meaningful reduction in abuse by one or 
more routes of administration, these data should be added to the product labeling.  However, if 
these postmarket data fail to confirm that the abuse-deterrent properties result in a reduction in 
abuse, or demonstrate a shift in routes of abuse that represent a greater risk (e.g., a shift from oral 
and nasal abuse to intravenous abuse), FDA may determine that labeling revisions are needed. 
 
Labeling language regarding abuse deterrence should describe the products specific abuse-
deterrent properties as well as the specific routes of abuse that the product has been developed to 
deter.  For example, a formulation that limits an abusers ability to crush a tablet and to extract 
the opioid can be described as limiting manipulation for the purpose of snorting or injection if 
                                                 
25  Abuse-deterrence information in labeling should be presented in the DRUG ABUSE AND DEPENDENCE 
section under 9.2 Abuse. 
  22  Contains Nonbinding Recommendations 
the data support such a statement.  For this characterization to be accurate and not misleading, 
however, appropriate caveats are likely to be necessary as described above.  For example, a 
products labeling should explain that the products abuse-deterrent properties only make abuse 
more difficult, not impossible, and that these properties provide no deterrence against other 
potential forms of abuse.   
 
As noted at the outset of this guidance, FDA will take a flexible, adaptive approach to the 
evaluation and labeling of abuse-deterrent opioid products.  FDA expects sponsors to update 
their formulations to take advantage of technological improvements and further expects to allow 
labeling statements related to abuse deterrence commensurate with those advances.   
 
Furthermore, FDA expects sponsors to compare their formulations against approved abuse-
deterrent versions of the same opioid.  The comparisons should be based on the relevant 
categories of testing.  For instance, if a proposed product is less resistant to manipulation than an 
approved product, the proposed product may not be eligible for labeling regarding abuse-
deterrent properties. 
 
FDA is concerned that, with time, abusers may adapt to abuse-deterrent technologies and 
discover methods to defeat them.  If and when abusers can overcome a technology such that it no 
longer has a meaningful effect in deterring abuse, FDA may require labeling revisions. 
 
As discussed below, the nature of information in labeling on abuse deterrence for a particular 
product will depend on the types of studies performed and the result of those studies.  Because it 
cannot provide specific guidance on the magnitude of effect that would be sufficient to support 
each type of claim, FDA will assess the appropriateness of all proposed labeling statements 
about abuse deterrence based on the data provided. 
 
Information describing the results of the evaluation of abuse-deterrent properties can be used to 
support labeling statements based on the three premarket categories (i.e., in vitro data, 
pharmacokinetic data, and clinical abuse potential studies) and the fourth category (postmarket 
data) once it is available. 
 
The data necessary to support abuse-deterrent labeling will depend on the characteristics of the 
product that impart the abuse deterrence and the route of abuse.  In general, most abuse-deterrent 
information included in product labeling will be based on data from more than one category. 
 
Key elements of the study design and conduct should be summarized in the product labeling.  
Category 1 studies can be described in general terms to avoid creating a road map for defeating 
the products abuse-deterrent properties.  However, the design, conduct, and results of Category 
2 and 3 studies should be described in sufficient detail, including the primary outcome measure 
data from Category 3 studies, to support clear labeling regarding a products abuse-deterrent 
properties. 
 
The following are examples of information for inclusion in labeling for different types of abuse-
deterrent effects based on various types of premarket studies performed. 
 
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  Category 1  
 
For this product, in vitro data demonstrated that an abuse-deterrent product cannot be 
crushed and dissolved or extracted in a small volume of solution suitable for injection.   
In this case, Category 1 in vitro data may be sufficient to support a statement in labeling 
about abuse deterrence for the intravenous route of abuse (See Section IV Premarket 
Studies).  Possible labeling text: 
 
In vitro physical and chemical tablet manipulation studies were performed 
to evaluate the ability of different extraction methods to defeat the 
formulation.  Results support that Tradename resists crushing, breaking, 
and dissolution using a variety of tools and solvents and retains some 
extended-release properties despite manipulation. 
 
These in vitro data demonstrate that Tradename has physical and 
chemical properties that are expected to deter intravenous abuse.  
However, abuse of this product is still possible by the oral and nasal 
routes. 
 
  Category 1 and Category 2 
 
For this product, in vitro and pharmacokinetic data from study of the oral and nasal routes 
of administration demonstrated that no changes occurred in the extended-release 
properties of the opioid after crushing or dissolution in a variety of solvents.  These data 
may be sufficient to support statements in labeling about abuse deterrence for the nasal 
and intravenous routes of abuse.  Possible labeling text: 
 
In vitro physical and chemical tablet manipulation studies were performed 
to evaluate the ability of different extraction methods to defeat the 
formulation, and pharmacokinetic studies of the oral and intranasal routes 
were performed to determine the effect of manipulation on drug release.  
Results support that Tradename resists crushing, breaking, and 
dissolution using a variety of tools and solvents and retains its extended-
release properties despite manipulation. 
 
The in vitro data demonstrate that Tradename has physical and chemical 
properties that are expected to deter oral, nasal and intravenous abuse.  
However, abuse of intact product is still possible by the oral route. 
 
 
  Category 2 and Category 3 
 
For this product, pharmacokinetic and clinical abuse potential studies demonstrated the 
release of an antagonist from an opioid and antagonist combination product following 
crushing and that the presence of the antagonist resulted in less drug liking compared to a 
similar amount of opioid alone when administered by the oral and intranasal routes.  In 
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addition, an additional clinical abuse potential study simulating intravenous abuse using 
the amounts of opioid and antagonist found to be released from the crushed product also 
demonstrated reduced drug liking. 
 
The pharmacokinetic data demonstrate that crushing Tradename results in 
the simultaneous release and rapid absorption of opioid and antagonist.  
These data along with the results from oral and intranasal clinical abuse 
potential studies and a clinical abuse potential study of intravenous opioid 
and antagonist to simulate crushed Tradename indicate that Tradename 
has properties that are expected to deter abuse via the oral, intranasal, 
and intravenous routes.  However, abuse of Tradename by these routes is 
still possible.  
 
All of these statements based on Categories 1, 2, or 3 testing should be followed by a statement 
that data from laboratory and clinical studies may not fully predict abuse potential in the post-
approval setting. 
 
As discussed in Section V, postmarket data from a variety of sources can demonstrate that a 
products abuse-deterrent properties result in persistent and relevant abuse deterrence.  These 
data can result from appropriately designed, conducted, and analyzed formal postmarket studies 
and from supportive information on the abuse of the product. 
 
FDA is currently considering formal studies plus a variety of supportive information (e.g., data 
concerning the street value of prescription drugs) as sources that may be acceptable to provide 
evidence that a products formulation has had an actual impact on reducing its abuse.  FDA 
anticipates that data from some or all three of the premarket categories along with data from 
postmarket studies (including both formal studies and supportive information) would be needed 
to support a statement in labeling that the product has been shown to reduce abuse.  The 
combined results from all of these studies would be described in the product labeling, including 
specific study designs, conduct, analyses, and study data. 
 
An example of labeling for a product with evidence of a reduction in abuse is: 
 
These data demonstrated a reduction in the abuse of Tradename in the community 
setting compared to the levels of abuse, overdose, and death that occurred when 
only formulations of the same opioid without abuse-deterrent properties were 
available.  This reduction in abuse appears to be attributable to the products 
formulation, which deters abuse by injection or snorting of the manipulated 
product.  However, such abuse of this product is still possible, and the products 
abuse deterrence properties do not deter abuse associated with swallowing the 
intact formulation. 
 
VII.  ADDITIONAL RESEARCH NEEDS 
 
As discussed above, the science of abuse deterrence is relatively new.  Both the technologies 
involved and the analytical, clinical, and statistical methods for evaluating those technologies are 
  25  Contains Nonbinding Recommendations 
rapidly evolving.  For these reasons, FDA will take a flexible, adaptive approach to the 
evaluation and labeling of potentially abuse-deterrent opioid products.  Additionally, there is 
considerable room for additional scientific work that could advance the development and 
assessment of abuse-deterrent products.  In particular, FDA encourages additional research on 
the following topics:   
  The quantitative link between changes in the pharmacokinetics of opioids in different 
formulations and results of a clinical abuse potential study with those same formulations. 
  The best assessment methods to employ when analyzing a clinical study of abuse 
potential. 
  The quantitative link between the outcomes from a clinical study of abuse potential 
comparing formulations and the effect on those same formulations on abuse in the 
community. 
  Further understanding of the best study methods to employ to assess the effect of a 
product with abuse-deterrent properties on the rates of abuse in the community.   
  Development of a communication tool (e.g., a simple graph or chart) to inform 
prescribers of the relative impact the product has on the different routes of abuse. 
 
Progress on these topics could facilitate the ability of sponsors to propose and FDA to approve 
labeling that would give a more complete picture of the anticipated effect of products with 
abuse-deterrent properties.  Ultimately, progress in these areas could facilitate product 
development by reducing the amount of information that is needed to accurately assess a product 
with abuse-deterrent properties and predict its impact on abuse in the community.   
 
 
 
 
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