Opioid Analgesic 
Drugs: Considerations 
for Benefit-Risk 
Assessment Framework 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Sharon Hertz at 301-796-1225.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2019 
Clinical/Medical 
24217694dft.docx 
06/05/19   
Opioid Analgesic 
Drugs: Considerations 
for Benefit-Risk 
Assessment Framework 
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) 
 
June 2019 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................1 
III.  BENEFIT-RISK ASSESSMENT .........................................................................3 
A.  Benefits to the Patient Using the Drug as Labeled ......................................................... 3 
B.  Risks to the Patient Using the Drug as Labeled .............................................................. 3 
C.  Effectiveness and Safety Relative to Approved Analgesic Drugs .................................. 4 
D.  Broader Public Health Effects: Risks and Mitigation of Risks Related to Misuse,  
  Abuse, Opioid Use Disorder, Accidental Exposures, and Overdose ............................. 5 
E.  Risk Management .............................................................................................................. 6 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Opioid Analgesic Drugs: Considerations  
2  for Benefit-Risk Assessment Framework 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  The purpose of this guidance is to describe the benefit-risk assessment framework that the 
18  Agency uses in evaluating whether applications for opioid analgesic drugs meet the standard for 
19  approval under section 505 of the Federal Food, Drug, and Cosmetic Act.  This guidance 
20  summarizes the information that should be included in a new drug application for an opioid 
21  analgesic drug to facilitate the Agencys benefit-risk assessment.  
22   
23  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
24  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
25  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
26  the word should in Agency guidances means that something is suggested or recommended, but 
27  not required. 
28   
29   
30  II.  BACKGROUND 
31   
32  Benefit-risk assessment is the foundation for FDAs regulatory review of human drugs and 
33  biologics.  These assessments capture the evidence, uncertainties, and reasoning used by FDA to 
34  arrive at its regulatory decisions.  Additionally, these assessments serve as tools for 
35  communicating that information to those interested in a better understanding of FDAs thinking.  
36   
                                                 
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.  
 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
37  FDA has developed a benefit-risk assessment framework  a structured, qualitative approach to 
38  FDAs benefit-risk assessment2 formatted as a table (see Figure 1 below).3  In Figure 1, the 
39  factors affecting the benefit-risk assessment are listed on the left side.  As reflected in the shaded 
40  boxes, the top two factors (Analysis of Condition and Current Treatment Options) relate to the 
41  specific therapeutic area  the current state of knowledge regarding the condition to be treated 
42  and the available therapies.  The bottom two factors (Benefit and Risk and Risk Management) are 
43  specific to the drug at issue.   
44   
45  FDA assesses risks and benefits of all drugs in the context of the use indicated in the labeling.  
46  However, because of the widespread misuse and abuse of prescription opioid analgesic drugs, for 
47  this class of drugs, FDA also considers the broader public health effect of opioid analgesic drugs; 
48  this involves consideration of the risks related to misuse, abuse, opioid use disorder, accidental 
49  exposure, and overdose, for both patients and others.  Likewise, FDA considers any properties of 
50  a drug expected to mitigate these risks.  This guidance describes the various factors that FDA 
51  will consider in evaluating the benefits and risks of an opioid analgesic drug.  FDA encourages 
52  applicants to provide information relevant to these factors.     
53   
54  Figure 1: FDAs Benefit-Risk Assessment Framework 
55   
* 
56   
57  * For purposes of this figure, Risk and Risk Management includes not only risks to the patient when used as 
58  indicated but also risks related to the broader public health sometimes described as second-order effects.  And, in 
59  assessing risks to the broader public health, the Agency is making an assessment relative to other currently available 
60  analgesic drugs.   
61   
62   
                                                 
2 See the Enhancing Benefit-Risk Assessment in Regulatory Decision-Making web page available at 
https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm326192.htm.  
 
3 See the Benefit-Risk Assessment in Drug Regulatory Decision-Making implementation plan available at 
https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM602885.pdf.  
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
63  III.  BENEFIT-RISK ASSESSMENT 
64   
65  The following sections describe the information that FDA will consider in assessing the benefits 
66  and risks of an opioid analgesic drug.  Consistent with the benefit-risk assessment framework, 
67  FDA considers the benefits and risks to the patient when the drug is used as labeled, as well as 
68  the benefits and risks relative to other available therapies for pain.  Additionally, FDA considers 
69  the public health risks of the drug related to misuse, abuse, opioid use disorder, accidental 
70  exposure, and overdose in both patients and nonpatients, as well as any properties of the drug 
71  that may mitigate such risks.  Note that the risk of opioid use disorder can arise even when a 
72  patient is taking an opioid analgesic drug as labeled.   
73   
74  The sections below provide recommendations for information the applicant should provide to 
75  assist FDA in its assessment.   
76   
77  A.  Benefits to the Patient Using the Drug as Labeled 
78   
79  The Agency will consider questions including the following about benefits to patients who are 
80  prescribed the drug and take it as labeled and directed by their prescribers: 
81   
82    Analgesic efficacy of the drug when used for its proposed indication 
83   
84    What is the body of evidence supporting a finding of analgesic drug efficacy? 
85   
86    In what patient population(s) was efficacy demonstrated?  Why was the patient 
87  population chosen for the efficacy study?  How does the population studied reflect the 
88  proposed indication (i.e., is the proposed indication broader than the population 
89  studied)? 
90   
91    What is the body of evidence supporting the proposed duration of use for each 
92  proposed indication? 
93   
94    Safety of the drug when used for its proposed indication 
95   
96    Does the drug have characteristics that mitigate adverse events associated with opioid 
97  analgesic drugs, including respiratory depression, sedation, and constipation?  What 
98  data support the conclusion that these risks are mitigated? 
99   
100    Does the drug have characteristics that mitigate the risk of opioid use disorder when 
101  used as labeled?  How do the safety data support this? 
102   
103  B.  Risks to the Patient Using the Drug as Labeled 
104   
105  In addition to the already known risks associated with opioid analgesic drugs, the Agency will 
106  also consider questions including the following about risks to patients who are prescribed this 
107  drug and take it as labeled and directed by their prescribers: 
108   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
109    Does this particular drug have any novel risks not typically associated with opioid 
110  analgesic drugs?  How serious are they?  Can they be mitigated through monitoring, 
111  patient selection characteristics, or limiting duration of use?  Are the novel risks 
112  reversible? 
113   
114    Do the formulation and/or excipients pose risks to patients (e.g., tablets that swell in the 
115  gastrointestinal tract, tablets that may adhere to moist mucosal surfaces)?  For drugs 
116  formulated to have abuse-deterrent properties, are there any adverse events associated 
117  with the drug product when used as labeled that are attributable to aversive excipients or 
118  excipients intended to impart resistance to manipulation? 
119   
120    Are there characteristics of the drug that increase or decrease the risk for respiratory 
121  depression, sedation, or development of opioid use disorder in patients (e.g., large 
122  residual opioid in transdermal systems, high dosage strengths)?  Can the risks be 
123  mitigated by particular packaging configurations or storage and disposal conditions?    
124   
125    Is there evidence that adverse events typically associated with opioid analgesic drugs 
126  occur at a higher rate or with greater severity with the new drug than expected for similar 
127  drugs based on clinical trials or theoretical risks? 
128   
129  C.  Effectiveness and Safety Relative to Approved Analgesic Drugs 
130   
131  As part of the benefit-risk assessment for a particular drug and proposed indication, FDA 
132  considers the benefits and risks relative to other available therapies for the condition.  FDA will 
133  consider the questions including the following in assessing effectiveness and safety of an opioid 
134  analgesic drug: 
135   
136    Do any comparative efficacy data exist for the drug relative to approved opioid or 
137  nonopioid analgesic drugs?  Does this analgesic drug offer any advantages relative to 
138  available approved analgesic drugs for each indication, with regard to effectiveness or 
139  duration of response? 
140   
141    Do any comparative safety data exist for the drug relative to approved opioid or 
142  nonopioid analgesic drugs?  Does this analgesic drug offer any other safety 
143  advantages or disadvantages relative to available approved analgesic drugs for each 
144  indication (e.g., abuse-deterrent properties, less risk of drug-drug interactions)? 
145   
146    What is the anticipated benefit-risk balance relative to available approved analgesic 
147  drugs for each indication?  Do any comparative safety data exist for the drug relative 
148  to approved opioid or nonopioid analgesic drugs?  Does this analgesic drug offer any 
149  other safety advantages or disadvantages relative to available approved analgesic 
150  drugs for each indication (e.g., less risk of drug-drug interactions)? 
151   
152    Does the drug have any other advantages over other available approved analgesic 
153  drugs (e.g., can be mixed with food)? 
154   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
155  FDA notes that, while the comparative data described above is helpful in applying the benefit-
156  risk framework, superiority to other available treatments is not a requirement for approval under 
157  FDAs drug approval authorities.   
158   
159  D.  Broader Public Health Effects: Risks and Mitigation of Risks Related to 
160  Misuse, Abuse, Opioid Use Disorder, Accidental Exposures, and Overdose 
161   
162  In the overall benefit-risk assessment of opioid analgesic drugs, FDA will consider the positive 
163  and negative public health effects of the drug, which includes the drugs potential effect on risks 
164  to both patients and nonpatients, such as members of the patients household (e.g., children, 
165  teenagers, visitors, and others).  The risks considered include those related to misuse, abuse, 
166  opioid use disorder, accidental exposure, and overdose.  FDAs evaluation of the broader public 
167  health effect of a new opioid analgesic drug is made relative to other currently available 
168  analgesic drugs. 
169   
170    In evaluating ways in which an opioid analgesic drug positively or negatively affects 
171  public health FDA will consider the following:  
172   
173    Are there characteristics of the drug that increase or decrease the risk of accidental 
174  exposure in children (e.g., tablet size, color, flavor, packaging configuration, 
175  appearance of topical systems)?   
176   
177    Are there characteristics of the drug that increase or decrease the risk of misuse, 
178  abuse, opioid use disorder, and related adverse outcomes such as overdose and 
179  infectious complications of injection (e.g., abuse-deterrent properties, large residual 
180  opioid in transdermal systems, high dosage strengths)?  Can the risks be mitigated by 
181  particular packaging configurations or storage and disposal conditions? 
182   
183    Are there increased or decreased risks associated with the indicated method of 
184  delivery (i.e., delivery device)?  For example, does the delivery method affect an 
185  existing risk or introduce a novel risk? 
186   
187    To support the opioid-specific public health benefit-risk evaluation, the applicant 
188  should use traditional epidemiologic data sources (e.g., surveys, emergency 
189  department visits, poison control center calls) and nontraditional sources (e.g., 
190  internet discussion forums and blogs, social media, qualitative/ethnographic studies, 
191  law enforcement data) to provide information about how this moiety or similar opioid 
192  analgesic drugs are misused and abused in postmarketing settings.  These data should 
193  address demographic patterns of abuse, the routes by which these drugs are abused, 
194  concomitant abuse of other substances, as well as risks of related adverse outcomes 
195  (e.g., addiction, fatal and nonfatal overdose, infectious complications of abuse). 
196   
197    For abuse-deterrent formulations, in addition to considering any potential benefits of such 
198  drug products, FDA also will consider the following in terms of opioid-specific public 
199  health considerations: 
200   
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
201    Potential unintended adverse consequences with introduction of the abuse-deterrent 
202  formulation, such as the following: 
203   
204    A shift to more dangerous routes of abuse (e.g., nasal to the more dangerous 
205  intravenous) based on properties of the formulation. 
206   
207    Potential tampering methods that could result in harmful effects, including 
208  injection-related harms (e.g., large volume extraction of drug that leads to 
209  increased sharing of drug paraphernalia increasing the risk of human 
210  immunodeficiency virus and hepatitis transmission). 
211   
212    Any other potential safety concerns related to the abuse-deterrent formulation. 
213   
214    For safety of excipients by unintended routes of administration, FDA will consider the 
215  following in terms of opioid-specific public health considerations: 
216   
217    Based on a risk assessment of the excipients in the drug, the potential safety concerns 
218  for the drug when administered by unintended routes of administration, including 
219  intravenous, intranasal, and inhalation. 
220   
221    For specific populations that may present distinct benefit-risk profiles, FDA will consider 
222  the following in terms of opioid-specific public health considerations: 
223   
224    The potential for subpopulations where the benefit-risk balance may be unfavorable 
225  (e.g., adolescents, patients with mental health and/or substance use disorders, patients 
226  with certain other comorbidities).  The applicant should include a discussion of 
227  anticipated use-specific subpopulations and proposed approaches to mitigate such 
228  risks, if present.   
229   
230  E.  Risk Management 
231   
232  FDA has determined that a class-wide risk evaluation and mitigation strategy (REMS) is 
233  necessary for all opioid analgesic drugs intended for outpatient use to ensure that the benefits of 
234  these drugs continue to outweigh the risks.4  The Opioid Analgesic REMS program requires that 
235  training be made available to all health care providers (HCPs) who are involved in the 
236  management of patients with pain, including nurses and pharmacists.5  To meet this requirement, 
237  drug companies with approved opioid analgesic drugs provide unrestricted grants to accredited 
238  continuing education providers for the development of education courses for HCPs based on 
                                                 
4 See the Opioid Analgesic Risk Evaluation and Mitigation Strategy web page at 
https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm.  Note that certain opioid 
analgesic drugs are subject to other REMS.  Information on the specific REMS associated with each approved 
opioid analgesic drug can be found on the FDAs Approved Risk Evaluation and Mitigation Strategies (REMS) web 
page at https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm.  
 
5 Ibid. 
 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
239  FDAs Opioid Analgesic REMS Education Blueprint for Health Care Providers Involved in the 
240  Treatment and Monitoring of Patients with Pain.6 
241   
242  To the extent that the safety profile of a drug product may differ from those drug products 
243  covered by the class-wide REMS, a product-specific REMS or REMS element may be required.  
244  For example, an opioid analgesic drug that must be restricted to use in a monitored inpatient 
245  setting may need additional risk mitigation strategies to ensure the drug product does not leave 
246  the hospital.  In short, the applicant for an opioid analgesic drug should include any proposed 
247  REMS that the applicant considers necessary to ensure a drugs benefits outweigh its risks.  All 
248  sponsors of opioid analgesic drugs should begin discussions with FDA early during drug 
249  development regarding product-specific risks and the potential need for additional risk 
250  mitigation. 
                                                 
6 Available at 
https://www.accessdata.fda.gov/drugsatfda_docs/rems/Opioid_analgesic_2018_09_18_FDA_Blueprint.pdf.  
7