Development of Non-
Opioid Analgesics for 
Acute Pain 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (CDER) Theresa Wells at 703-380-3900. 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2022 
Clinical/Medical 
 
34355740dft.docx 
02/07/22   
Development of Non-
Opioid Analgesics for 
Acute Pain 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD 20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2022 
Clinical/Medical 
 
  TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DEVELOPMENT OF NON-OPIOID ANALGESICS .................................................. 2 
A.  Non-Opioid Analgesic Product Development for Acute Pain .................................................... 2 
1. General Considerations ................................................................................................................... 2 
2. Trial Design ..................................................................................................................................... 3 
3. Outcome Measures to Obtain an Acute Pain Analgesic Indication ................................................. 4 
4. Safety ConsiderationsClinical Trial Elements ............................................................................... 6 
B. Potential Claims in Labeling for Non-Opioid Analgesic Products for Acute Pain That 
Eliminate or Reduce Opioid Use and Data Needed to Support Those Claims ............................. 7 
1. FDA Thinking Regarding Concept of Opioid-Sparing ................................................................ 7 
2. Reductions in the Use of Opioid Analgesics That May Merit Description in Labeling ................... 7 
a.  Product eliminates patient use of opioid analgesics .................................................................. 7 
b.  Product enables patient discharge without opioid analgesics ................................................... 8 
c.  Product reduces patient exposure to opioid analgesics with direct clinical benefit to the 
patient ............................................................................................................................................... 8 
3. Data to Support Language in Labeling Describing Clinically Meaningful Reductions in Opioid 
Analgesic Use ................................................................................................................................... 8 
C.  Expedited Programs ...................................................................................................................... 9 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Development of Non-Opioid Analgesics for Acute Pain 
2  Guidance for Industry1 
3   
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page. 
11   
12   
13   
14  I.  INTRODUCTION 
15   
16  This guidance is written in response to the statutory requirements of section 3001(b) of the 
17  Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) 
18  for Patients and Communities Act, which directs the Food and Drug Administration (FDA) to 
19  issue or update existing guidance to help address challenges to developing nonaddictive medical 
20  products to manage pain.  In keeping with the mandate of section 3001(b), and considering the 
21  severity of the ongoing opioid crisis, this guidance is also intended to assist sponsors in the 
22  development of alternatives to opioids for the management of acute pain.  Accordingly, this 
23  guidance addresses FDAs current thinking about three specific topics:  development of non-
24  opioid analgesic products for acute pain, labeling claims, and expedited programs as they pertain 
25  to this purpose. 
26   
27  This guidance does not address the management of chronic pain, which will be the focus of a 
28  future guidance.  This guidance also does not address the development of opioid products. 
29   
30  The contents of this document do not have the force and effect of law and are not meant to bind 
31  the public in any way, unless specifically incorporated into a contract.  This document is 
32  intended only to provide clarity to the public regarding existing requirements under the law.  
33  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
34  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
35  Agency guidances means that something is suggested or recommended, but not required. 
36   
37   
38  II.  BACKGROUND 
39   
40  FDA is committed to using its authorities to take measures targeted to combat the opioid crisis.  
41  In 2017, FDA announced its intention to focus on four priorities, two of which directly relate to 
42  this guidance:  (1) fostering the development of novel analgesic drugs and (2) decreasing opioid 
 
1 This guidance has been prepared by the Division of Anesthesiology, Addiction Medicine, and Pain Medicine in the 
Center for Drug Evaluation and Research at the Food and Drug Administration. 
 
1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
43  analgesic exposure and preventing new addiction.2  To address these two priorities, and 
44  consistent with our mandate under SUPPORT Act section 3001(b) to issue guidance in this area, 
45  FDA is publishing this guidance. 
46   
47  For context, it is important to set forth FDAs general understanding of pain and specific 
48  definition of acute pain.  For the purposes of this guidance, acute pain is defined as pain, lasting 
49  up to 30 days, typically in response to some form of tissue injury, such as trauma or surgery.3 
50   
51  This understanding informs the development of this guidance, which describes FDAs current 
52  thinking about three aspects of non-opioid analgesic drug development: 
53   
54    The drug development program appropriate for a non-opioid analgesic to support an 
55  indication for the management of acute pain (acute pain indication)  
56   
57    The availability of claims in labeling of non-opioid analgesic products for acute pain 
58  regarding elimination or reduction of opioid use and the data needed to support those 
59  claims 
60   
61    The use of expedited programs to support the development program for non-opioid 
62  analgesics to manage acute pain 
63   
64   
65  III.  DEVELOPMENT OF NON-OPIOID ANALGESICS 
66   
67  A.  Non-Opioid Analgesic Product Development for Acute Pain 
68   
69  1.  General Considerations 
70   
71  Indications for analgesics intended to manage acute pain can be general or specific.  A general 
72  acute pain indication would reflect the expectation that the product will be effective for most 
73  types of acute pain.4  The number of adequate and well-controlled clinical trials needed to 
74  support a general acute pain indication depends on the mechanism of action of the drug, the 
75  populations studied, and the degree to which the available information would support the 
76  efficacy across the acute pain settings in which the product would be used.  Products with well-
77  established analgesic mechanisms of action may be able to obtain a general acute pain indication 
78  when supported by at least two clinical trials, each in a different pain population.  For example, a 
79  novel nonsteroidal anti-inflammatory drug with two successful clinical trials in postoperative 
 
2 See the Opioid Policy Steering Committee web page, available at https://www.fda.gov/about-fda/office-medical-
products-and-tobacco/opioid-policy-steering-committee. 
 
3 This definition of acute pain is consistent with the International Association for the Study of Pains definition, 
which is as follows: Acute Pain is generally accepted as being of recent onset and limited short duration.  It usually 
has a temporal (follows immediately after surgery/trauma) and causal (has a known cause) relationship to injury or 
disease.  The intensity of acute pain is greatest at the onset of injury, but with healing pain intensity reduces. 
 
4 Because of interindividual differences, a product indicated for general acute pain, and expected to be appropriate to 
manage many kinds of acute pain, does not mean the product is expected to be effective for every patient. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
80  pain, one following bunionectomy and one following herniorrhaphy, may be suitable for a 
81  general acute pain indication.  In contrast, products with novel mechanisms of action are likely to 
82  require clinical trials in more than two different pain populations to support a general acute pain 
83  indication.  As it is generally not feasible to study all possible populations that fall within a 
84  general acute pain indication, it may be necessary to include language in labeling describing the 
85  limitations of the indication. 
86   
87  A specific acute pain indication reflects results from studies in a specific pain population (e.g., 
88  postsurgical analgesia following hernia repair).  Some products may be suitable only for specific 
89  populations (e.g., topical analgesic for underlying soft tissue injury).  A specific pain-type 
90  indication generally requires evidence from at least two adequate and well-controlled clinical 
91  trials.  
92   
93  Some sponsors may initially choose to demonstrate effectiveness of a particular drug in a 
94  specific pain-type population and then subsequently pursue additional specific indications, or a 
95  general indication, with additional trials in other acute pain settings to support broader use.  In 
96  both of these scenarios, additional patient populations and types of pain can be studied and study 
97  results submitted as efficacy supplements to broaden the indication.  In many cases, for both 
98  additional specific indications or to expand the indication from a specific pain indication to a 
99  general indication, one additional adequate and well-controlled efficacy trial may be sufficient. 
100   
101  2.  Trial Design 
102   
103  Clinical trials to support a finding of efficacy for a non-opioid analgesic should be randomized, 
104  double-blind, superiority trials.  The trials should include repeat-dose design as appropriate.  
105  Treatment duration should be based on the pain model used to support the proposed indication 
106  sought but should be no fewer than 24 hours for products that are not limited to a single dose.  
107  The primary endpoint should be based on the change in pain intensity over a suitable time period 
108  based on the pain model used in the trial and the products expected duration of pain relief; 
109  however, the time period assessed does not have to be for the full duration of the pain.  After 
110  evaluation of the primary endpoint, we recommend continued evaluation of both safety and 
111  efficacy, for evidence of sustained effect, which may be relevant to acute pain lasting up to 30 
112  days.   
113   
114  For acute pain, it is common to use an analysis such as the Sum of Pain Intensity Difference 
115  (SPID) over a prespecified time period that reflects the expected duration of treatment effect of 
116  the product.  Demonstrating superiority to a comparator is important in non-opioid analgesic 
117  trials because the primary endpoint, pain intensity, can be influenced by study design factors 
118  such as the use of rescue medication and placebo effect.  As a result, a noninferiority trial 
119  showing no difference between analgesic treatments could mean that neither product worked in 
120  that study.5  Suitable comparators for the superiority study could include placebo or another 
 
5 See 21 CFR 314.126(b)(2)(iv) (providing Similarity of test drug and active control can mean either that both 
drugs were effective or that neither was effective.)  For more information about noninferiority trials, see the 
guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016).  We update 
guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
121  analgesic if the new product is expected to be more effective than the comparator analgesic.  In 
122  some cases, the test treatment and control (placebo or a different analgesic drug) may also be 
123  added to background therapy (an add-on study).  The background therapy could be specified or 
124  caregiver selected. 
125   
126  Protocols should prespecify allowed rescue medications.  Depending on the pain condition being 
127  studied, rescue medications might include nonsteroidal anti-inflammatory drugs or, in clinical 
128  settings in which opioids are typically required for adequate pain relief, opioids may be 
129  considered.  Protocols should also prespecify the frequency, amount, and threshold of pain at 
130  which allowable rescue medication(s) can be administered.  This is particularly important in 
131  placebo-controlled trials where increased use of rescue medication in the control group may 
132  diminish the study drugs treatment effect, leading to a conclusion of ineffectiveness.  The 
133  statistical analysis plan should describe how discontinuations caused by inadequate pain control 
134  will be handled.  The concept of rescue use, including the prospective plan in the effectiveness 
135  analysis to assess its use, as well as how the data support the overall indication, is important and 
136  is discussed further in section III. A. 3. below, under Secondary Efficacy Endpoints. 
137   
138  3.  Outcome Measures to Obtain an Acute Pain Analgesic Indication 
139   
140  Primary Efficacy Endpoint 
141   
142  In general, an assessment of pain intensity is the primary outcome measure to establish the 
143  efficacy of an analgesic intended to manage acute pain.  Efficacy endpoints (e.g., change in pain 
144  intensity) in a non-opioid analgesic trial should reflect a direct rating of pain intensity by the 
145  subject for all settings in which the subject can communicate in a reliable manner.  We 
146  recommend using a well-defined and reliable patient-reported outcome measure of the subjects 
147  pain intensity.6  The selected instrument should have the subject assess their pain at the time of 
148  the assessment (i.e., without using a recall period).  Generally, a numerical rating scale is the 
149  appropriate measure. 
150   
151  We recommend that sponsors take frequent pain intensity measurements at preselected time 
152  points during the trial to accurately measure the effect of a non-opioid analgesic and that effect 
153  over time (e.g., every hour for X number of hours, then every 4 hours for X number of hours).  
154  All pain intensity measurements, including at baseline, should be obtained before rescue drug 
155  administration.  In general, the frequency of pain intensity assessment is greater with initial drug 
156  administration, early post-event (e.g., post-injury or surgery), when pain may be more intense.  
157  The primary efficacy analysis should compare the SPID between treatments at a prespecified 
158  time point that, at a minimum, includes the duration of drug effect, and may extend beyond this 
159  duration.  For example, a non-opioid analgesic with an expected 4- to 6-hour duration of action 
160  might have the primary efficacy analysis performed at 24 hours post-dose (SPID ), but 
24
161  secondary efficacy analyses may also be performed at 6 and 12 hours post dose (SPID  and 
6
162  SPID , respectively) to evaluate pain control during the recommended dosing interval. 
12
163   
 
 
6 For a thorough discussion of patient-reported outcome measures, see the guidance for industry Patient-Reported 
Outcome Measures: Use in Medical Product Development to Support Labeling Claims (December 2009). 
4  Contains Nonbinding Recommendations 
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164  We discourage using a primary endpoint that is based on pain relief (i.e., decrease in pain) rather 
165  than pain intensity (i.e., how bad the pain is), as pain relief scales require subjects to report 
166  current pain relative to their prior pain experience and may be influenced by other factors such as 
167  concurrent adverse reactions, and may be limited by patients ability to recall their prior 
168  experience of pain.  Additionally, sponsors should generally avoid using composite scales that 
169  are composed of multiple domains (e.g., pain, function, sleep) as the primary outcome measure 
170  in a non-opioid analgesic trial.  Such multiple domain scales may be difficult to interpret across a 
171  population, as the same change in overall score can be based on differing patterns of response to 
172  the individual domain scores.  For example, an overall score may be higher at baseline, reflecting 
173  poor sleep (with functional consequences), with improvement in the score reflecting 
174  improvement in sleep, such as might be seen with a sedating drug that does not provide 
175  substantive pain control.  Multi-item scales, where the items all relate to pain (e.g., pain at rest or 
176  with movement), may be useful depending on the type of pain being studied. 
177   
178  Secondary Efficacy Endpoints 
179   
180  Secondary outcome measures are important to fully characterize the efficacy of a non-opioid 
181  analgesic and should support the primary efficacy endpoint.  These secondary outcome measures 
182  include measurement of time to onset of pain relief and time to rescue or request for next dose of 
183  the study drug.  Other informative secondary outcome measures include assessment of use of 
184  rescue medications, physical function, and patient global impression of change of pain. 
185   
186  To measure time to onset of pain relief, FDA has accepted the two stopwatch method.  In this 
187  method, patients are instructed to stop the first stopwatch when they first perceive any analgesic 
188  effect and instructed to stop the second stopwatch when they perceive a meaningful amount of 
189  analgesia, which may be translated into a description in labeling of median time to meaningful 
190  pain relief.  FDA remains open to discussion and consideration of approaches beyond the two 
191  stopwatch method to assess the time to onset of pain relief, which is particularly important to 
192  establish if there is an expectation of rapid onset of action (e.g., intravenous formulation). 
193   
194  For all acute pain non-opioid analgesic studies, it is particularly important that sponsors record 
195  the following information:   
196   
197    The type and amount of rescue medication used, including dose, frequency, and duration 
198   
199    The time that the study drug or rescue medication was administered 
200   
201    The pain intensity measurements before the rescue medication was used and throughout 
202  the dosing interval (e.g., evaluating SPID over the course of expected duration of action) 
203   
204  Use of rescue medication can inform important properties of the drug and should be carefully 
205  considered in the design of the study so as not to jeopardize the validity of the study.  A sooner-
206  than-expected first use of rescue medication may suggest that the investigational drug has a 
207  delayed onset of pain relief.  Time to second use of rescue medication may be informative when 
208  considering dosing interval for the investigational drug and supplement knowledge of the drugs 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
209  pharmacokinetic properties.  If the time to second use of rescue medication is earlier than 
210  expected based upon drug exposure, waning efficacy can be considered a potential issue.   
211   
212  Endpoints Associated with Reducing or Eliminating Opioid Use 
213   
214  As discussed further below, total elimination of opioid or a numerical reduction in the number of 
215  doses, dose per day, or duration of opioid use may support the efficacy of the investigational 
216  drug in alleviating pain.  In order to support a clinical benefit of a reduction in opioid use that 
217  would be described in labeling, sponsors should demonstrate a direct patient benefit, such as 
218  clinically meaningful reduction in the incidence and/or severity of opioid-induced adverse 
219  reactions.  See section III. B. below. 
220   
221  Biomarkers 
222   
223  FDA is not aware of any biomarkers that are useful in developing pain management products, 
224  but we welcome feedback on this issue.  If sponsors identify a way to use biomarkers in any 
225  aspect of a clinical trial associated with non-opioid analgesics for acute pain, we are interested in 
226  engaging on this topic. 
227   
228  4.  Safety ConsiderationsClinical Trial Elements 
229   
230  When monitoring safety during clinical trials, sponsors should consider the nature of the drug 
231  and the trial population.  Sponsors may also need to include subject discontinuation and/or study 
232  stopping criteria in protocols, depending on the expected safety profile of a non-opioid analgesic. 
233   
234  Appropriate assessment of both effectiveness and safety relies on accurate and complete capture 
235  of the reason for subject discontinuation.  Sponsors should assure that when a subject 
236  discontinues study drug or withdraws from the trial that the specific reason is obtained.  
237  Investigators should be prompted to provide detailed information, with specific causes rather 
238  than report terms such as other, subject request, investigator decision, or other such 
239  nonspecific categories.  Sponsors also should ensure that case report forms are designed to 
240  accurately capture the reason for patient discontinuation. 
241   
242  The size of the safety database needed to support approval for an acute pain indication depends 
243  on a number of factors, including whether the drug is a new molecular entity or a reformulation 
244  of an approved drug substance.  In addition, a nonclinical safety finding or safety data from early 
245  clinical studies suggesting a potential serious adverse reaction may necessitate enlargement of 
246  the safety database to better define the safety profile of the proposed product.  Safety 
247  assessments should continue as appropriate after dosing is completed, with consideration of 
248  patient population and setting (i.e., inpatient versus outpatient). 
249   
250  Early in development, sponsors should discuss safety considerations, including the safety 
251  database requirements, with FDA. 
252   
6  Contains Nonbinding Recommendations 
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253  B.  Potential Claims in Labeling for Non-Opioid Analgesic Products for Acute 
254  Pain That Eliminate or Reduce Opioid Use and Data Needed to Support 
255  Those Claims 
256   
257  1.  FDA Thinking Regarding Concept of Opioid-Sparing 
258   
259  Consistent with the feedback of the Anesthetic and Analgesic Drug Products Advisory 
260  Committee on November 15, 2018, FDA believes the term opioid-sparing as a statement in 
261  labeling is unlikely to be sufficiently descriptive to be meaningful.  Instead, FDA recommends 
262  labeling that more clearly and specifically explains the benefits provided by eliminating or 
263  reducing the need for opioid analgesics as discussed in section III. B. 2. below.7  For drugs that 
264  are already approved and for those that are seeking initial approval, considerations in describing 
265  elimination or reduction in the need for opioid analgesics are similar. 
266   
267  2.  Reductions in the Use of Opioid Analgesics That May Merit Description in 
268  Labeling 
269   
270  There are several ways in which a non-opioid analgesic may show benefit in reducing opioid use 
271  that would merit description in labeling: 
272   
273    Eliminating patient use of opioid analgesics in some or all patients in a pain setting in 
274  which use of opioids would typically be required to alleviate pain  
275   
276    Providing adequate analgesia such that the patient can be discharged from the health care 
277  facility without opioid analgesics when patients would be expected to be discharged with 
278  opioid analgesics 
279   
280    Showing a direct patient benefit related to reduced opioid analgesic use, such as a 
281  clinically meaningful reduction in opioid-associated adverse reactions or earlier 
282  functional recovery (e.g., earlier ability to participate in physical therapy with earlier 
283  regain of ambulation) 
284   
285  In each of these scenarios, data should support a finding that the non-opioid and opioid have 
286  comparable effects on pain. 
287   
288  a.  Product eliminates patient use of opioid analgesics 
289   
290  Exposure to an opioid analgesic presents a risk of addiction, misuse, or abuse.  In addition to the 
291  risk of addiction, opioid use also may cause serious adverse reactions, including overdose, and 
292  death.  Therefore, a non-opioid analgesic for acute pain that completely eliminates the need for 
293  an opioid in a setting in which opioid-level analgesic would be otherwise necessary would have 
294  the greatest impact on reducing the risk of opioid addiction.  In addition to reducing the risk for 
 
7 This view is consistent with feedback provided at the November 15, 2018, Meeting of the Anesthetic and 
Analgesic Drug Products Advisory Committee. See https://www.fda.gov/advisory-committees/advisory-committee-
calendar/november-15-2018-meeting-anesthetic-and-analgesic-drug-products-advisory-committee-meeting. 
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
295  the patient, the absence of opioid analgesics in the home lessens access to others in the same 
296  residence who may seek opioid analgesics for misuse or abuse. 
297   
298  If a sponsor can show that a product eliminates the need for an opioid analgesic in a statistically 
299  significant number of patients in a setting in which opioids are routinely required for adequate 
300  acute pain control, this finding could be sufficient to support description in labeling.  In such 
301  circumstances, labeling that describes analgesia comparable to or better than the comparator 
302  opioid may be appropriate. 
303   
304  b.  Product enables patient discharge without opioid analgesics 
305   
306  As with products that eliminate opioid use, if a sponsor demonstrates that a non-opioid analgesic 
307  product eliminates the need for an opioid to manage acute pain at discharge from a health care 
308  facility or other outpatient settings, when opioid use post-discharge is routinely needed, this also 
309  could be considered adequate to support description in labeling.  Additional assessments after 
310  discharge would be required to confirm patients pain can be managed without opioids.  
311  Reducing the supply of prescription opioid analgesics in the home reduces the risks of misuse 
312  and abuse by both the patient and others within the home.  Labeling that describes these findings 
313  may be appropriate. 
314   
315  c.  Product reduces patient exposure to opioid analgesics with direct clinical 
316  benefit to the patient 
317   
318  Apart from discharge by a health care facility without opioids, reduction in dosage and/or 
319  duration of opioid use alone is not likely to be adequate to support description in labeling.  To 
320  include a reduction in opioid use in labeling, the reduction claim should be associated with a 
321  direct patient benefit such as (1) reduced time to recovery of function, such as more rapid 
322  mobility and/or earlier ability to participate in rehabilitation or other clinically meaningful 
323  functional outcomes, or (2) a relevant decrease in opioid-related adverse reactions such as less 
324  sedation, fewer gastrointestinal side effects (such as constipation), or other adverse reactions.  If 
325  these types of clinical benefits are adequately demonstrated in clinical trials, language in the 
326  labeling delineating these benefits could be included. 
327   
328  3.  Data to Support Language in Labeling Describing Clinically Meaningful 
329  Reductions in Opioid Analgesic Use 
330   
331  To support language describing clinically meaningful reductions in opioid analgesic use in 
332  product labeling for any of the categories described above, sponsors should provide data from at 
333  least two adequate and well-controlled trials.  As described in section III. B. 2. above, examples 
334  of clinically meaningful outcomes include not requiring opioids for a pain model where opioid 
335  use is usually required, or, where use of opioids is still needed, showing reduced opioid dose 
336  requirements in concert with either a shortening of time to mobility (e.g., following orthopedic 
337  surgery) or a reduction in the frequency of major complications of opioid treatment, such as 
338  delirium in an elderly population or a reduction in opioid-related adverse reactions. 
339   
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340  FDA also encourages sponsors to include open-label extensions with follow-up assessment of 
341  opioid analgesic utilization (e.g., 30 days after discharge following a surgical procedure) to 
342  assess whether patients have been taking opioid analgesics during the period of extension. 
343   
344  FDA does not recommend observational study designs or exclusive use of electronic health care 
345  data (e.g., electronic health record or administrative claims data) to support labeling language 
346  describing clinically meaningful reductions in opioid analgesic use.  Electronic health care data 
347  are not sufficiently able to measure factors that may drive selection of patients for the 
348  investigational versus the control treatment.  Likewise, routinely collected health care data (e.g., 
349  administrative claims data) are insufficient to ascertain primary endpoints, such as pain control, 
350  level of function, actual opioid use, and adverse effects. 
351   
352  However, incorporating electronic health care data may be useful in other respects.  For instance, 
353  such data may be valuable (1) in assessing opioid analgesics dispensed at discharge and 
354  persistent prescribed opioid analgesic dispensing, (2) in understanding current practices and 
355  standards of pain management in specific clinical settings, and (3) in identifying patients who 
356  may be eligible for study participation.  We remain interested in feedback on ways in which 
357  these data could be useful to support the development of non-opioid analgesic products. 
358   
359  We recognize that we are not addressing all aspects of clinical trial design for products that may 
360  reduce the use of opioid analgesics in a way that may merit description in product labeling, and 
361  we invite comment on this area of clinical trial design in response to this guidance.  We also 
362  encourage sponsors of any non-opioid analgesic for acute pain seeking a claim of opioid 
363  replacement or reduction in labeling to have early and regular discussions with FDA to help 
364  ensure the use of adequate and interpretable assessments of treatment benefits that are consistent 
365  with a drugs mechanism of action. 
366   
367  C.  Expedited Programs 
368   
369  FDA encourages the development of non-opioid analgesic products and novel study designs.  
370  Non-opioid analgesic development programs designed to replace or reduce the use of opioid 
371  analgesics may be eligible for one or more of FDAs expedited review programs, as applicable.  
372  FDA encourages early discussion of products that could eliminate or reduce opioid analgesic use 
373  and may be suitable for expedited reviews. 
374   
375  These expedited programs and their relevant criteria are described in the guidance for industry 
376  Expedited Programs for Serious ConditionsDrugs and Biologics (May 2014).  The applicable 
377  expedited programs include fast track, breakthrough therapy, priority review, and accelerated 
378  approval.  Although each program differs, they all offer some form of expedited review and 
379  guidance for sponsors for drug development programs.8 
 
8 In addition to the programs outlined above, the Breakthrough Devices Program may be available for certain 
nonaddictive medical products to manage pain. (Federal Food, Drug, and Cosmetic Act  515B (21 U.S.C. 360e-3)).  
The Breakthrough Devices Program is a voluntary program for certain medical devices and device-led combination 
products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating 
diseases or conditions.  The guidance for industry and Food and Drug Administration staff Breakthrough Devices 
Program (December 2018) outlines the criteria for designation as a breakthrough device as well as the policies FDA 
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380  FDA has not had experience with an analgesic approval based on a surrogate or intermediate 
381  endpoint that is reasonably likely to predict clinical benefit, as would be consistent with 
382  accelerated approval.9  Given that pain intensity is a subjective experience that can only be 
383  directly reported by the patient, it is difficult to envision how surrogate or intermediate endpoints 
384  could be used to predict analgesic effect.  However, consistent with applicable statutory criteria, 
385  FDA will consider a non-opioid analgesics abuse or misuse potential and its risk profile relative 
386  to available opioid analgesics to determine if the application qualifies for fast track or 
387  breakthrough designation during development, or for priority review upon receipt of the 
388  marketing application. 
 
intends to use to implement the program.  The considerations set forth in that guidance document apply to FDAs 
review of devices as nonaddictive methods to manage pain. 
 
9 See FD&C Act 506(c) and 21 CFR 314.500 et seq.  For drugs granted accelerated approval, postmarketing trials 
have been required to verify and describe clinical benefit.   
10