Development of Local 
Anesthetic Drug Products 
With Prolonged Duration  
of Effect 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Swati Patwardhan at 301-796-4085. 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2023 
Clinical/Medical 
25979032dft.docx 
03/09/23     
Development of Local 
Anesthetic Drug Products 
With Prolonged Duration 
of Effect 
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) 
 
March 2023 
Clinical/Medical
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  DEVELOPMENT PROGRAMS ..........................................................................2 
A.  General Clinical Pharmacology Considerations ............................................................. 4 
B.  Human Factors Engineering Evaluation ......................................................................... 6 
C.  Trial Design ........................................................................................................................ 7 
D.  Clinical Evaluation  Efficacy ........................................................................................ 8 
1. Pharmacodynamic Profile ................................................................................................... 8 
2. Indications ........................................................................................................................... 9 
a.  Incisional infiltration/instillation .................................................................................. 9 
b.  Peripheral nerve block (e.g., interscalene nerve block) ................................................ 9 
c.  Fascial plane block (e.g., transverse abdominis plane block) ....................................... 9 
d.  Neuraxial block (e.g., spinal or epidural block) ......................................................... 10 
3. Fixed-Combination Drug Product .................................................................................... 10 
4. Combination Product ........................................................................................................ 10 
5. Efficacy Endpoints and Analyses....................................................................................... 11 
E.  Clinical Evaluation  Safety ......................................................................................... 12 
IV.  CONSIDERATIONS FOR LABELING CLAIMS...........................................13 
A.  Superiority Claims .......................................................................................................... 13 
B.  Novel Endpoints ............................................................................................................... 13 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Development of Local Anesthetic Drug Products 
2  With Prolonged Duration of Effect 
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 assist sponsors that are developing local anesthetic drug 
18  products to produce postoperative analgesia for a prolonged duration, for which submission of a 
19  new drug application (NDA) through the pathway described in section 505(b) of the Federal 
20  Food, Drug, and Cosmetic Act (FD&C Act) is appropriate.  This guidance is not applicable to 
21  applications that meet criteria for submission under section 505(j) of the FD&C Act, petitioned 
22  abbreviated new drug applications under section 505(j)(2)(C) of the FD&C Act, or applications 
23  submitted under section 351 of the Public Health Service Act.2  
24   
25  For assistance with specific local anesthetic drug product development programs, sponsors 
26  should contact the Division of Anesthesiology, Addiction Medicine, and Pain Medicine (the 
27  Division) in the Office of New Drugs in the Center for Drug Evaluation and Research.3  
28   
29  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
30  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
31  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
32  the word should in Agency guidances means that something is suggested or recommended, but 
33  not required. 
34   
35   
 
1 This guidance has been prepared by the Division of Anesthesiology, Addiction Medicine, and Pain Medicine in the 
Office of New Drugs in the Center for Drug Evaluation and Research at the Food and Drug Administration.  
 
2 See the guidance for industry Determining Whether to Submit an ANDA or a 505(b)(2) Application (May 2019).  
We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
3 For the purposes of this guidance, the term sponsor will be used to refer to both sponsors of investigational new 
drug applications and applicants of NDAs. 
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36  II.  BACKGROUND 
37   
38  Local anesthetic drug products may be used to either reduce painful sensations (i.e., provide 
39  analgesia) or to completely eliminate sensation (i.e., provide anesthesia).  The administration of 
40  these drug products has been used to reduce or eliminate the pain associated with many surgical 
41  procedures, such as inguinal hernia repair or total knee arthroplasty.   
42   
43  Local anesthetic drug products are administered in a number of ways, including subcutaneous 
44  injection, wound instillation or smear, perineural infiltration (e.g., peripheral nerve block), 
45  fascial plane blocks (i.e., transverse abdominis plane block), or via the neuraxial administration 
46  (i.e., epidural, intrathecal).  Although there may be other modes of administration (e.g., deep 
47  sympathetic block) utilized for chronic pain etiologies, this guidance only focuses on methods of 
48  administration targeted to provide postoperative analgesia.   
49   
50  Local anesthetic drug products include those that have a single active ingredient or multiple 
51  active ingredients, such as a local anesthetic in combination with a vasoconstrictor (e.g., 
52  epinephrine).  Additionally, local anesthetic drug products may be immediate-release products or 
53  modified-release products (e.g., extended-release injectable suspension).  In addition, local 
54  anesthetic drug products can be administered using various types of devices.  Although different 
55  local anesthetic drug products have different pharmacokinetic (PK) profiles, in general their 
56  effects last a few hours.  However, the increasing interest in reducing or eliminating the use of 
57  opioid analgesic drug products is leading to development of dosage forms of local anesthetic 
58  drug products that prolong the duration of action of the drug product to a period of days rather 
59  than hours.  
60   
61  In addition, some local anesthetic drug product dosage forms may be drug-device combination 
62  products as defined under 21 CFR 3.2(e).4  For example, the local anesthetic may be embedded 
63  or otherwise contained in an implant that controls the rate of drug release/delivery to the 
64  surrounding tissues.  In this context the anesthetic drug would be the drug constituent part and 
65  the implant would be the device constituent part of the combination product.5, 6  Other 
66  combination product examples include a local anesthetic drug-prefilled syringe or a copackage of 
67  a local anesthetic drug in a vial and a software-controlled delivery device. 
68   
69   
70  III.  DEVELOPMENT PROGRAMS 
71   
72  The development program of a local anesthetic drug product with prolonged duration of effect 
73  will depend, in part, on the intended use, such as anesthesia, analgesia, or both, and whether the 
74  drug substance has already been approved in a drug product or if it is a new drug substance.  This 
 
4 For general information on combination products, see the Combination Products: Guidance and Regulatory 
Information web page at http://www.fda.gov/combination-products/guidance-regulatory-information.   
 
5 See 21 CFR 4.2 for the definition of constituent part.  For purposes of this guidance, the terms device and device 
constituent part are used interchangeably. 
 
6 For purposes of this guidance, the terms drug, drug product, and drug constituent part are interchangeable.  Also, 
the term product applies to the to-be-marketed drug product or combination product. 
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75  guidance focuses on development programs for local anesthetic drug products for the indication 
76  of postoperative analgesia.  
77   
78  For a new dosage form or a new formulation of a previously approved dosage form of an 
79  approved local anesthetic drug product, the NDA can be submitted as a stand-alone application 
80  (i.e., 505(b)(1)) or pursuant to section 505(b)(2) of the FD&C Act.7  For drug products submitted 
81  as stand-alone applications, sponsors should plan to provide data and/or conduct studies that 
82  establish the efficacy and safety of the drug product as a local anesthetic drug product, in 
83  addition to supporting the safety and efficacy of the formulation.  For drug products submitted 
84  under section 505(b)(2), the number and type of studies necessary to support approval of the 
85  drug product will depend on the proposed indication, proposed dosage and administration, the 
86  known safety and efficacy profile of the previously approved local anesthetic drug product (i.e., 
87  listed drug), drug product composition, and other characteristics of the proposed drug product 
88  (e.g., in vitro drug release profile, delivery device, formulation) relative to the listed drug.8   
89   
90  Sponsors should discuss their development plans with the Division early in development, 
91  including, but not limited to, planned comparative bioavailability studies and efficacy and safety 
92  studies.  Efficacy and safety studies will be necessary to support drug products that are the first 
93  modified-release formulation for any existing immediate-release local anesthetic drug product or 
94  that have significant differences (e.g., in PK profile) from approved drug products.   
95   
96  To ensure that the necessary efficacy and/or safety studies are adequately designed and include 
97  the relevant information specific to the proposed local anesthetic drug product, the development 
98  program for the local anesthetic drug product should proceed in a sequential fashion, as follows:  
99   
100    Sponsors should conduct in vitro studies to characterize drug release profile.  Based on 
101  the proposed formulation, the type and design of these studies should be discussed with 
102  the Division early on in the development program. 
103   
104    Sponsors should conduct initial PK studies to identify doses and dosing regimens that 
105  deliver target PK and pharmacodynamic (PD) profiles during the desired treatment 
 
7 Although applications submitted as stand-alone applications are not the focus of this guidance, a sponsor can 
submit an NDA for an extended-release local anesthetic drug product as a stand-alone application when the 
application contains full reports of investigations of safety and effectiveness that were conducted by or for the 
applicant or for which the applicant has a right of reference.  See section 505(b)(1) of the FD&C Act.  The 505(b)(2) 
pathway is appropriate for applications that contain full reports of investigations of safety and effectiveness, where 
at least some of the information required for approval is derived from studies that were not conducted by or for the 
applicant and for which the applicant has not obtained a right of reference.  Such investigations or information can 
include, for example, FDAs finding of safety and/or efficacy for a listed drug or published literature.  NDAs 
submitted through the 505(b)(2) pathway may be subject to patent certification requirements and periods of 
exclusivity that could affect approval.  See generally section 505(b)(2) of the FD&C Act; see also the draft guidance 
for industry Applications Covered by Section 505(b)(2) (October 1999).  When final, this guidance will represent the 
FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
8 Under these abbreviated approval pathways, generally an applicant can rely on FDAs finding of safety and 
effectiveness for a drug product approved under section 505(c) of the FD&C Act.  For brevity, the remainder of this 
guidance refers to an approved drug product generally without reference to the legal pathway for approval.    
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
106  period, including PK parameters described in section III.A., General Clinical 
107  Pharmacology Considerations.  
108   
109    Sponsors should conduct safety and efficacy studies designed to support the proposed 
110  indication.  The number, type, and design of these studies should be discussed with the 
111  Division and will be based on multiple considerations, including if the proposed local 
112  anesthetic drug product:  
113   
114   Is the first modified-release formulation for an existing immediate-release local 
115  anesthetic drug product (i.e., has no previously approved modified-release 
116  formulation) and is being compared to the immediate-release formulation of the 
117  proposed local anesthetic drug product. 
118   
119   Has significant differences compared to the listed drug, namely the following:  
120   
121    The in vitro data, such as drug release profile, for the proposed local anesthetic 
122  drug product differs significantly from the listed drug. 
123   
124    The proposed local anesthetic drug product has novel features, such as the 
125  following: 
126   
127  i.  Dosing, including timing interval of repeated doses, dose range, route of 
128  administration, etc., relative to the listed drug. 
129   
130  ii.  A novel device constituent part or excipient that facilitates drug delivery.  In 
131  this case, if an independent efficacy trial is conducted, the safety data from 
132  this trial may satisfy part or all of the safety evaluation requirements.  
133   
134  A.  General Clinical Pharmacology Considerations 
135   
136  For the purposes of this guidance, the term pharmacokinetics refers to systemic drug exposure, 
137  unless noted otherwise.  When characterizing the PK profile of a local anesthetic drug product, 
138  sponsors should consider and/or address the following concepts: 
139   
140    Due to the method(s) of administration of these products, it may be challenging to 
141  measure local drug concentrations and characterize PK profile for local drug exposure.  If 
142  the sponsor plans to collect PK samples for local drug exposure and characterize the PK 
143  profile, the sponsor should propose a reliable methodology or approach to accurately 
144  measure local drug concentrations and discuss the proposal with the Division early in 
145  development. 
146   
147    The PK profile may differ at various sites of administration and may depend on total 
148  dose, method of administration, and the vascularity of the anatomical site.  
149   
150    The sponsor should characterize the PK profile for every anatomic site/route(s) of 
151  administration that the sponsor proposes to include in drug product labeling.  If the 
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152  sponsor is seeking a broad postsurgical indication for administration of the proposed drug 
153  product at any anatomical surgical site, the sponsor should demonstrate the predictability 
154  of the PK profile for different anatomic sites and routes of administration or provide 
155  justification on how data can be extrapolated to additional, nonstudied, sites.  
156   
157    The sponsor should use maximum systemic exposure at the highest dose, via the 
158  proposed route of administration to assess safety; however, systemic exposure does not 
159  typically correlate with efficacy for local anesthetic drug products. 
160   
161    The sponsor should consider the time for complete clearance of the drug product after last 
162  administration to delineate the duration of systemic safety monitoring and determine the 
163  appropriate timing for additional dose(s) of local anesthetic drug products.   
164   
165  For any proposed local anesthetic drug product, the sponsor should obtain the following key PK 
166  parameters:  
167   
168    The shape of the PK profile   
169    The time to reach maximum plasma concentration (T ) 
max
170    The maximum plasma concentration (C ) 
max
171    The extent of systemic exposure (AUC) 
172    The minimum (trough) plasma concentration (C ) 
trough
173    Accumulation after multiple doses, if applicable 
174    Estimated time for complete clearance of the drug product after last administration  
175   
176  Although demonstrating there are no clinically significant differences in the pharmacokinetics of 
177  systemic drug exposure, including AUC and C , compared to another approved drug product 
max
178  with prolonged duration of effect could potentially support approval, additional efficacy and 
179  safety studies may be necessary for the following reasons: 
180   
181    Product composition will likely vary between different local anesthetic drug products, 
182  which may affect local safety as well as local efficacy of the drug product.  
183   
184    In vitro release characteristics may vary based on drug product formulation, which may 
185  affect local drug exposure, even if there are no clinically significant differences in 
186  systemic drug absorption.  
187   
188    The rate of systemic absorption of local anesthetic drug products may also vary based on 
189  the total dose of drug product administered, the route of administration, and the 
190  vascularity of the administration site.  Therefore, comparable AUC and C  does not 
max
191  necessarily mean that the shape of the PK profiles of the two drug products are 
192  comparable.  
193   
194    Comparable levels of systemic exposure (i.e., systemic pharmacokinetics) between two 
195  different drug products may not reflect comparable local drug concentration at the same 
196  site of administration. 
197   
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198    Because local drug concentrations do not necessarily correlate with systemic exposure, it 
199  is unlikely that comparable local efficacy can be demonstrated.  
200   
201  If a sponsor decides to conduct only relative bioavailability PK studies with the proposed local 
202  anesthetic drug product and to rely on the Agencys findings of safety and/or efficacy for the 
203  listed drug, the following data may be necessary: 
204   
205    Comparative in vitro data, such as drug product composition, formulation characteristics 
206  (e.g., liposome characteristics), in vitro release characteristics, etc.  The sponsor may use 
207  available in vitro data to inform in vivo PK characteristics of the drug product. 
208   
209    Comparative bioavailability PK studies that demonstrate that local and systemic exposure 
210  to the proposed local anesthetic drug product is similar to that of the listed drug after 
211  single dose administration and following multiple doses of the same drug product. 
212   
213    Data to assess the impact of the differences in the proposed formulation, in vitro 
214  characteristics, dosing and administration, etc., on local drug exposure, and 
215  consequentially local safety and local efficacy. 
216   
217  If clinical studies are not needed to support efficacy and safety (local and systemic safety) of the 
218  proposed local anesthetic drug product, it will be necessary for the sponsor to submit data to 
219  characterize local drug exposure in addition to systemic drug exposure.9  Because of the unique 
220  product-specific characteristics of local anesthetic drug products with prolonged duration of 
221  effect, if a sponsor decides to conduct only relative bioavailability PK studies to support its local 
222  anesthetic drug product, or is considering exploring a modeling approach with available in vitro 
223  and in vivo data, the sponsor should discuss the plans with the Division early in the drug product 
224  development program.  
225   
226  B.  Human Factors Engineering Evaluation 
227   
228  Sponsors should use human-factors engineering (HFE) processes throughout the development of 
229  a local anesthetic drug product.  The application of HFE processes during drug product 
230  development maximizes the likelihood that the product user interface, which includes all points 
231  of interaction between the drug product and the users (e.g., delivery device, packaging labeling, 
232  including labels), allows for safe and effective use by the intended users for intended uses and 
 
9 As stated in section III.A., General Clinical Pharmacology Considerations, if the sponsor plans to collect PK 
samples for local drug exposure and characterize its PK profile, the sponsor should propose a reliable methodology 
or approach to accurately measure local drug concentrations and discuss the proposal with the Division early in 
development. 
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233  use environments.  Sponsors should refer to relevant FDA guidance documents that provide 
234  information on human factors and product design.10  
235   
236  C.  Trial Design 
237   
238  When a sponsor needs to conduct efficacy trial(s), the sponsor should consider the following:  
239   
240    The sponsor should design trials to demonstrate that the drug product is effective when 
241  used in each of the anatomical sites and surgical procedures for which an indication is 
242  sought.  Alternatively, the sponsor should provide justification for the extrapolation 
243  between anatomical sites and methods of administration. 
244   
245    The sponsor should select the primary outcome measure based on the proposed indication 
246  and the population being evaluated.  If several validated instruments are available to 
247  assess the outcome, the choice of instrument is at the discretion of the sponsor; however, 
248  the sponsor should provide a rationale for the selection.   
249   
250   The Agency distinguishes between indications for local anesthesia and local 
251  analgesia.  Local anesthesia is defined as the local loss of all sensation; local 
252  analgesia is defined as the local reduction or elimination of pain.  Therefore, 
253  instruments assessing level of pain will only support an analgesic indication.  
254  Evaluation of the drug products effects on the other sensory (e.g., temperature and 
255  pressure) and motor parameters will also be necessary in addition to the evaluation 
256  for pain sensation to adequately evaluate the safety profile of the drug product if an 
257  indication for local anesthesia is sought. 
258   
259    The sponsor should evaluate the drug in a patient population that reflects the 
260  demographics of the patient population to whom the drug product will ultimately be 
261  administered. 
262   
263    The sponsor should conduct blinded and randomized controlled trials to evaluate the 
264  doses, regimens, and methods of administration identified and evaluated in phases 1 and 
265  2 of the drug product development program.  
266   
267    To select the optimal dosing regimen for the indication, the Agency recommends that the 
268  sponsor conduct a dose ranging study or studies before the phase 3 clinical trial(s) or 
269  evaluate several doses in in an adequate and well-controlled phase 3 trial.  Sponsors 
270  should evaluate total dose (e.g., mg), volume, and concentration of the product. In 
 
10 Guidances on this topic include, but are not limited to, the guidance for industry Safety Considerations for 
Product Design to Minimize Medication Errors (April 2016), the guidance for industry and FDA staff Applying 
Human Factors and Usability Engineering to Medical Devices (February 2016), the guidance for industry Safety 
Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (May 2022), and 
the draft guidances for industry and FDA staff Contents of a Complete Submission for Threshold Analyses and 
Human Factors Submissions to Drug and Biologic Applications (September 2018) and Human Factors Studies and 
Related Clinical Study Considerations in Combination Product Design and Development (February 2016).  When 
final, these guidances will represent the FDAs current thinking on these topics.  
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271  addition, dose selection for local anesthetic drug product studies should take into 
272  consideration the pharmacologic properties of the drug product, target patient population, 
273  and probable concomitant medications. 
274   
275    Controls should include an immediate-release or modified-release local anesthetic drug 
276  product, or both if appropriate, which are already approved for the indication under study.  
277  In addition, one of the active comparators should reflect the current standard of care.  
278  Active-controlled trials can employ either superiority or noninferiority designs.  Sponsors 
279  should consult the Division regarding different aspects of trial design, including the 
280  noninferiority margin.   
281   
282   In certain instances, the drug product could also be compared to itself in trials 
283  designed to evaluate the efficacy of differing concentrations, doses, or dosing 
284  regimens.  In such trials, a significant difference (from both statistical and clinical 
285  perspectives) in efficacy between two treatment arms could serve as evidence of 
286  efficacy for the concentration, dose, or dosing regimen that was shown to be superior 
287  to another regimen evaluated. 
288   
289    Sponsors should consider current clinical practice (e.g., multimodal perioperative pain 
290  regimens) and incorporate these practices in both investigational drug and control arms, 
291  as appropriate, to obtain data, which are clinically meaningful and relevant to health care 
292  providers.   
293   
294    Trials should include an adequate subject follow-up period after drug product 
295  administration and assessments at appropriate time intervals to evaluate the following:  
296   
297   Systemic and local toxicity 
298   Clinical response, including clinically meaningful measures of benefit and function   
299   
300  D.  Clinical Evaluation  Efficacy 
301   
302  Early in the development program, the sponsor should decide which formulation and method of 
303  delivery will be marketed.  This includes, but is not limited to, the type of device design and 
304  whether it will be a generally available FDA-approved/cleared device or a device constituent part 
305  of a combination product.  To support approval, the sponsor should use the final to-be-marketed 
306  product (including drug product formulation and its delivery device, if applicable) and the dosing 
307  regimen proposed for inclusion in the drug product labeling in the PK studies and clinical trials.  
308  If a product other than the final to-be-marketed product is used, the sponsor may need to conduct 
309  bridging studies or provide justification to address differences in the formulations or devices.  
310   
311  1.  Pharmacodynamic Profile 
312   
313  Ideally, sponsors are able to characterize pharmacodynamics of the drug during phase 1 and 
314  phase 2 clinical trials and confirm with the findings in phase 3 trials.  The sponsor should 
315  characterize the onset and duration of action of the drug product for the proposed indication.  If 
316  the sponsor seeks more than one indication and the indications vary significantly in terms of the 
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317  route(s) of administration, the length of time for which anesthesia or analgesia is required, or the 
318  level of required anesthesia or analgesia (e.g., intraoperative versus postoperative anesthesia or 
319  analgesia), the sponsor should characterize the onset and duration of action of the drug product 
320  for each proposed indication.  This information should be the basis for determining the time to 
321  redosing, if redosing is appropriate.   
322   
323  In addition, for drug products that may be used on a variety of tissue types (e.g., epidermis, 
324  dermis, muscle, perineural, bone) and/or in anatomic compartments, which differ in size and 
325  vascularity (e.g., posterior capsule of the knee versus abdominal cavity versus thoracic cavity), 
326  the evaluations should determine if those uses lead to substantial differences in the onset or 
327  duration of action of the drug product.  The sponsor should include sufficient data about these 
328  differences in its NDA submission to adequately inform labeling and guide health care providers 
329  in the appropriate use of the drug product. 
330   
331  2.  Indications 
332   
333  In general, the indication of a local anesthetic drug product will be limited to the type of surgical 
334  models or anatomical sites studied in the drug product development program.  
335   
336  a.  Incisional infiltration/instillation 
337   
338  For a new local anesthetic drug product, if the sponsor is proposing a surgery-specific or an 
339  anatomical site-specific indication, at least two adequate and well-controlled studies will be 
340  necessary.  For a modified-release formulation of a previously approved local anesthetic drug 
341  product, if the sponsor is proposing a surgery-specific or an anatomical site-specific indication, 
342  at least one adequate and well-controlled trial will be necessary.  For a generalized incisional 
343  infiltration/instillation indication, at the minimum, the sponsor should establish efficacy in a 
344  bony compartment model, small and large soft tissue models, and a highly vascular compartment 
345  model (e.g., intercostal space).  However, additional models may be necessary based on the drug 
346  formulation, dosing and administration, and consistency in efficacy across models demonstrated 
347  in the drug product development program. 
348   
349  b.  Peripheral nerve block (e.g., interscalene nerve block) 
350   
351  There is a large variability in the types of peripheral nerve block procedures performed for 
352  surgical anesthesia and analgesia.  The ability to visualize and access the target nerve, which 
353  varies with the anatomy adjacent to the target nerve (including major vessels and other tissues), 
354  will potentially impact the dose and/or volume of drug product necessary to achieve the desired 
355  degree and duration of the block.  Therefore, extrapolation from one nerve block to another is 
356  difficult.  Consequently, the indication will likely be limited to nerve blocks for which safety and 
357  efficacy have been demonstrated in the drug product development program.  
358   
359  c.  Fascial plane block (e.g., transverse abdominis plane block) 
360   
361  The type of anatomical tissues exposed to the local anesthetic drug product in a fascial plane 
362  block (e.g., skin, subcutaneous tissues, fat, muscle) may differ significantly from incisional 
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363  infiltration/instillation (e.g., skin, subcutaneous tissues, fat only) and peripheral nerve block 
364  administration (e.g., skin, subcutaneous tissues, fat, muscle, nerve sheath, large vessels).  
365  Therefore, studies demonstrating both safety and efficacy in a fascial plane block model will be 
366  necessary to support such an indication.  If efficacy and safety of the drug product has already 
367  been established for an incisional infiltration/instillation indication or peripheral nerve block 
368  indication, at least one additional trial will be necessary to be considered for a fascial plane block 
369  indication.  Alternatively, the sponsor can provide an evidence-based rationale to support 
370  extrapolation from incisional infiltration/instillation or peripheral nerve block to a fascial plane 
371  block.  Sponsors should consult the Division regarding extrapolation. 
372   
373  d.  Neuraxial block (e.g., spinal or epidural block) 
374   
375  The development of local anesthetic drug product formulations with prolonged duration of effect 
376  for neuraxial use is challenging because of safety concerns, such as the potential for prolonged 
377  muscle weakness leading to increased risk of fall, the potential for cephalad spread leading to 
378  respiratory insufficiency or total spinal anesthesia, and spinal cord/spinal nerve toxicity because 
379  of prolonged exposure to the drug product.  Therefore, sponsors should consult the Division 
380  before initiating a neuraxial block drug product development program for a local anesthetic drug 
381  product with prolonged duration of effect. 
382   
383  3.  Fixed-Combination Drug Product 
384   
385  For purposes of this guidance, a fixed-combination drug product (FCDP) is one in which two or 
386  more active ingredients are combined at a fixed dosage in a single dosage form. When 
387  developing an FCDP, the sponsor must demonstrate that each active ingredient makes a 
388  contribution to the claimed effect of the combination drug product, as defined in 21 CFR 300.50.  
389  The demonstration of such contribution may require a properly designed factorial trial.  In 
390  addition, the benefit of the proposed combination of active ingredients must outweigh any 
391  additional risk posed by the combination.11, 12  
392   
393  4.  Combination Product 
394   
395  If developing a combination product, the design of the product user interface should be assessed 
396  in human factors studies, as appropriate, to demonstrate that the proposed combination product 
397  user interface allows for safe and effective use in addition to addressing human factors 
398  considerations (see section III.B., Human Factors Engineering Evaluation).  The application 
399  should address the safety and effectiveness of the to-be-marketed combination product including 
400  the device constituent part.  Also, combination products are subject to 21 CFR part 4 subpart A, 
401  Current Good Manufacturing Practice Requirements for Combination Products.13  The type of 
402  data to submit for the device constituent part is beyond the scope of this guidance.  Developers of 
 
11 For additional information, see the guidance for industry Codevelopment of Two or More New Investigational 
Drugs for Use in Combination (June 2013). 
 
12 See 21 CFR 300.50. 
 
13 See the guidance for industry and FDA staff Current Good Manufacturing Practice Requirements for 
Combination Products (January 2017).  
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403  local anesthetic combination products with prolonged duration of effect should request early 
404  development discussions with the Division.  
405   
406  5.  Efficacy Endpoints and Analyses 
407   
408  The recommended primary efficacy endpoint for the evaluation of the postoperative analgesic 
409  effect of a local anesthetic drug product is the AUC of pain scores.  The clinical pain scale(s) 
410  utilized to assess pain should be validated in the patient population(s) being studied.  The 
411  schedule of assessments should be appropriate to evaluate the clinical endpoints and reflect the 
412  PK and PD profiles of the proposed local anesthetic drug product.  Because the PK and PD 
413  profile may vary with each drug product, it is necessary to demonstrate superiority or 
414  noninferiority relative to the comparator during the entire proposed duration of effect, most 
415  importantly the later time points.  
416   
417  Efficacy analyses should include the following: 
418   
419    Comparison of primary endpoint(s) using the appropriate statistical methods. 
420   
421    Consideration of adjustment for prognostic covariates (e.g., baseline pain) to potentially 
422  improve precision of treatment effect estimate and study power if linear model 
423  assumption holds. 
424   
425    Prespecification of estimand of interest, including strategy for handling rescue 
426  medication use. 
427   
428    Planned sensitivity analyses to evaluate sensitivity to violations in missing data 
429  assumptions. 
430   
431    Presentation of mean pain scores over the entire treatment period.  These pain curves 
432  should demonstrate continuous benefit or similarity of the local anesthetic drug product 
433  relative to the comparator during a clinically meaningful trial period.  
434   
435   In general, comparison of the changes in the mean pain scores of treatment groups at 
436  a single time point is not an appropriate analysis of efficacy because such comparison 
437  may be difficult to interpret from a clinical perspective.  Therefore, the sponsor 
438  should evaluate a range of time points, specifically focusing on later time points, that 
439  can demonstrate an extended efficacy profile (e.g., 48 to 72 hours).  The sponsor can 
440  evaluate additional later time points, as appropriate. 
441   
442   The AUC approach is a weighted average across the specified time frame.  Weights 
443  are determined by the length of time between each observed pain score.  Benefits 
444  include the ability to vary the timing of planned observations (e.g., short intervals 
445  early in treatment to capture time to the onset of action) and to account for use of 
446  rescue medication by recording unscheduled pain scores before administration of 
447  rescue medication. 
448   
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449   Presentation of pain scores over time can: 
450   
451    Include the point estimate and the 95 percent confidence interval of the mean pain 
452  scores at each postsurgical time point when the pain curve over the entire 
453  postsurgical treatment period is presented.  
454   
455    Present pain score over the entire postsurgical time period by trial subject for the 
456  intent-to-treat subjects in one pain score graph. 
457   
458  At a particular time point, some trial subjects may fare well while others fare poorly in the same 
459  treatment group, and yet, the mean group response may be favorable.  One approach is to 
460  compare the number of subjects reaching prespecified criteria for success, i.e., a responder 
461  analysis.  It is important that a responder analysis incorporate a criterion of improvement in the 
462  primary endpoints along with criteria for use of rescue medication and other outcome measures.  
463  FDA encourages sponsors to explore a variety of outcome measures and responder definitions 
464  during phase 2 trials to provide a rationale for use of a responder analysis as the primary analysis 
465  in phase 3 trials. 
466   
467  Sponsors should contact the Division for recommendations on the adequacy of the trial endpoints 
468  and additional analyses for specific local anesthetic drug product development programs.  
469   
470  If a sponsor decides to pursue both surgical anesthesia and postoperative analgesia indications, 
471  the sponsor should discuss such plans with the Division early in the drug product development 
472  process. 
473   
474  E.  Clinical Evaluation  Safety 
475   
476  The sponsor should address the following safety aspects, as appropriate, for the proposed local 
477  anesthetic drug product with a prolonged duration of effect: 
478   
479    All established safety risks associated with the immediate-release local anesthetic drug 
480  product that is being developed into a modified-release formulation and the potential 
481  general safety implications of extending its duration of action.  
482   
483    The safety of any novel inactive ingredients in the drug product formulation or novel 
484  device or device constituent parts. 
485   
486    Risks of local exposure at the site of administration (e.g., infection, wound dehiscence, 
487  nerve toxicity). 
488   
489    Risks of systemic exposure (i.e., local anesthetic systemic toxicity assessments). 
490   
491    Risks of prolonged or permanent neurologic deficits, or any outcomes of 
492  unresolved/ongoing sensory or motor deficits (e.g., falls, inability to undergo physical 
493  rehabilitation).  Full recovery of both sensory and/or motor function must be 
494  demonstrated.  
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495   
496    Safety of repeated dosing, including time frame and dose adjustments, if necessary. 
497   
498    Safety and compatibility of concomitant drugs (e.g., coadministration with immediate-
499  release local anesthetic drug products, anesthetic adjuncts such as epinephrine). 
500   
501   
502  IV.  CONSIDERATIONS FOR LABELING CLAIMS 
503   
504  A.  Superiority Claims 
505   
506  For a claim of superiority in the prescribing information, the sponsor needs to demonstrate that 
507  the proposed local anesthetic drug product is superior to an approved drug product from both 
508  statistical and clinical perspectives using clinically relevant efficacy or safety endpoints in 
509  replicated adequate and well-controlled trials making direct comparison to the approved drug 
510  product for each proposed indication.14  In addition, to claim superiority, the sponsor must 
511  establish a positive benefit-risk profile of the proposed product compared to the approved drug 
512  product.   
513   
514  B.  Novel Endpoints 
515   
516  There is great public health interest in assessing additional, clinically meaningful endpoints such 
517  as reduction in hospitalization or rehospitalization, emergency department visits, or death caused 
518  by opioid abuse, as well as improvements in the ability to resume work, school, or other 
519  productive activities.  FDA recognizes that evaluating these outcomes could require larger trials 
520  than those usually conducted for marketing approval.  However, collecting data on clinically 
521  meaningful outcomes would be highly valuable, and FDA encourages sponsors to consider 
522  collecting such data even if not intended to support a regulatory decision.  Furthermore, using 
523  these outcomes as clinical trial endpoints could provide the basis for inclusion in the FDA-
524  approved labeling.   
525   
526  Sponsors should support novel endpoints with data demonstrating that the endpoints represent a 
527  clinically meaningful benefit.  Additional research may be necessary to develop or better define 
528  instruments to measure these patient-reported outcomes15 or other novel endpoints in clinical 
529  trials (e.g., improvement in rehabilitation or recovery).  For endpoints related to the reduction in 
530  opioid analgesic drug products use, opioid-sparing claims, and data needed to support such 
531  claims, sponsors should refer to the draft guidance for industry Development of Non-Opioid 
532  Analgesics for Acute Pain (February 2022).16   
533   
 
14 For additional information, see the guidance for industry Clinical Studies Section of Labeling for Human 
Prescription Drug and Biological Products  Content and Format (January 2006). 
 
15 See the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims (December 2009).  
 
16 When final, this guidance will represent the FDAs current thinking on this topic.   
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534  If a sponsor plans to include novel endpoints in a local anesthetic drug product development 
535  program, FDA strongly encourages the sponsor to discuss such plans with the Division early in 
536  the drug product development process.  
14