Diabetic Foot 
Infections:  
Developing Drugs for 
Treatment 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (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 Mayurika Ghosh at 301-796-4776.   
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
October 2023 
Clinical/Antimicrobial 
26138dft.docx 
10/04/23   
Diabetic Foot 
Infections:  
Developing Drugs for 
Treatment  
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Tel: 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) 
 
October 2023 
Clinical/Antimicrobial 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  DEVELOPMENT PROGRAM ............................................................................2 
A.  General Drug Development Considerations ................................................................... 3 
1.  Early Phase Development Considerations .......................................................................... 3 
2.  Drug Development Population ............................................................................................ 3 
3.  Efficacy Considerations ...................................................................................................... 3 
4.  Safety Considerations .......................................................................................................... 3 
B.  Phase 3 Efficacy Trial Considerations ............................................................................. 4 
1.  Trial Design ......................................................................................................................... 4 
2.  Trial Population .................................................................................................................. 4 
3.  Entry Criteria ...................................................................................................................... 4 
4.  Prior Antibacterial Drug Therapy ...................................................................................... 6 
5.  Clinical Microbiology Considerations ................................................................................ 6 
6.  Assessment for Osteomyelitis .............................................................................................. 6 
7.  Randomization, Stratification, Covariate Adjustment, and Blinding .................................. 7 
8.  Specific Populations ............................................................................................................ 7 
9.  Dose Selection ..................................................................................................................... 8 
10. Use of Active Comparators ................................................................................................. 8 
11. Concurrent Antibacterial Drug Therapy ............................................................................. 8 
12. Adjunctive Measures ........................................................................................................... 8 
13. Minimum Duration of Treatment: ....................................................................................... 8 
14. Intravenous to Oral Therapy Switch ................................................................................... 9 
15. Efficacy Endpoints ............................................................................................................... 9 
a.  Primary efficacy endpoint............................................................................................. 9 
b.  Secondary endpoint considerations .............................................................................. 9 
c.  Additional endpoint considerations .............................................................................. 9 
16. Trial Procedures and Timing of Assessments ................................................................... 10 
17. Statistical Considerations .................................................................................................. 10 
18. Labeling Considerations ................................................................................................... 12 
REFERENCES .................................................................................................................13 
APPENDIX:  JUSTIFICATION FOR A NONINFERIORITY MARGIN FOR 
DIABETIC FOOT INFECTIONS..................................................................................14 
APPENDIX REFERENCES ...........................................................................................19 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Diabetic Foot Infections:  Developing Drugs for Treatment  
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 create 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  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
17  treatment of diabetic foot infections (DFIs) without concomitant bone and joint involvement.2 
18  Specifically, this guidance addresses the Food and Drug Administrations (FDAs) current 
19  thinking regarding the overall development program and clinical trial designs for the 
20  development of drugs to support an indication for treatment of DFI. Development of drugs for 
21  the treatment of acute bacterial skin and skin structure infections, defined as cellulitis/erysipelas, 
22  wound infection, and major cutaneous abscess, is addressed in a separate guidance.3 
23   
24  This guidance does not contain discussion of the general issues of statistical analysis or clinical 
25  trial design. Those topics are addressed in the ICH guidances for industry E9 Statistical 
26  Principles for Clinical Trials (September 1998) and E10 Choice of Control Group and Related 
27  Issues in Clinical Trials (May 2001), respectively.4 Diabetic foot infections encompass cellulitis, 
28  ulcers, and bone and joint infections located at or distal to the malleoli. Bone and joint infections 
29  are excluded from the scope of this guidance. 
30   
31  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
32  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
33  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
 
1 This guidance has been prepared by the Division of Anti-Infectives in the Office of Infectious Diseases in the 
Office of New Drugs in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.  
 
2 For the purposes of this guidance, references to drugs, include drugs approved under section 505 of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) and biological products licensed under section 351 of 
the Public Health Service Act (PHS Act) (42 U.S.C. 262) that are regulated as drugs. 
 
3 See the guidance for industry Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment 
(October 2013). 
 
4 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs. In addition to consulting 
guidances, sponsors are encouraged to contact the Division to discuss specific issues that arise during drug 
development. 
1  Contains Nonbinding Recommendations 
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34  the word should in Agency guidances means that something is suggested or recommended, but 
35  not required.  
36   
37   
38  II.  BACKGROUND 
39   
40  Foot infections in diabetic patients account for substantial morbidity and often underlie the need 
41  for lower extremity amputations. Frequently, the inciting event is a superficial neuropathic foot 
42  ulcer. Diabetic peripheral neuropathy predisposes to foot ulcer formation, as many diabetic 
43  patients sustain repeated, localized foot trauma that is not perceived as being painful. 
44  Concomitant peripheral vascular insufficiency results in poor wound healing and predisposes 
45  superficial wounds to progress into deep ulcers before medical attention is sought. DFIs can be 
46  further complicated by the development of abscesses, joint infections, and osteomyelitis. 
47  Treatment is multifactorial, requiring debridement of devitalized tissue, drainage of any 
48  abscesses, reperfusion in cases of critical limb ischemia, off-loading (removing pressure on the 
49  infected wound), optimizing glycemic control, administration of appropriate antibacterial 
50  therapy, and application of dressings that allow for moist wound healing and control of excess 
51  exudation.  
52   
53  Important considerations for developing antibacterial drugs for DFI include the types of bacteria 
54  that are associated with DFI, which can be either monomicrobial or polymicrobial. 
55  Monomicrobial infections with aerobic gram-positive cocci such as Staphylococcus aureus or - 
56  hemolytic streptococci typically occur in patients who have not recently received antibacterial 
57  therapy.5 Patients who have chronic wounds or who have recently received antibacterial therapy 
58  are more prone to developing polymicrobial infections. These infections can involve pathogens 
59  such as aerobic gram-positive cocci, including methicillin-resistant Staphylococcus aureus, and 
60  gram-negative organisms, including drug-resistant gram-negative pathogens. Patients with limb 
61  ischemia or necrotic wounds may be infected by anaerobic pathogens.  
62   
63  Of note, the guidance for industry Acute Bacterial Skin and Skin Structure Infections: 
64  Developing Drugs for Treatment does not address DFI due to the differences between DFI and 
65  other ABSSSI related to definitions, clinical manifestations, microbiology, management, and 
66  measurement of clinical outcomes;6 therefore, a separate guidance was deemed necessary. 
67   
68   
69  III.  DEVELOPMENT PROGRAM 
70   
71  Sponsors should consider the following when developing drug products for diabetic foot 
72  infection. 
73   
 
5 Johns Hopkins ABX Guide. The Johns Hopkins University; 2022. 
 
6 See the guidance for industry Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment. 
2  Contains Nonbinding Recommendations 
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74  A.  General Drug Development Considerations 
75   
76  1.  Early Phase Development Considerations  
77   
78  In assessing the efficacy of antibacterial drugs for the treatment of DFI, the sponsor should 
79  consider providing phase 1 data demonstrating adequate drug penetration into the outer skin 
80  layers. We recommend sponsors discuss with the Agency the type of technique to evaluate drug 
81  penetration before study initiation.  
82   
83  2.  Drug Development Population 
84   
85  The drug development population should include subjects with diabetes mellitus who have a 
86  bacterial infection of the foot, located at or distal to the malleoli. Although DFI studies may 
87  include subjects with disease ranging from cellulitis to deep wounds, the study population should 
88  consist of subjects with comparable disease extent (note that development of drugs for bone and 
89  joint infections is out of the scope of this guidance).  
90   
91  The use of a classification system characterizing the extent of the lesion and systemic signs and 
92  symptoms may be considered to define the study population (Schaper 2004; Lipsky et al. 2020; 
93  Lipsky 2009; Senneville et al. 2023). 
94   
95   
96  3.  Efficacy Considerations 
97   
98  Noninferiority (NI) trials are interpretable and acceptable to support approval of a drug for the 
99  treatment of DFI, provided an acceptable NI margin is clearly justifiable. Superiority trials 
100  comparing the investigational drug to an active control are also readily interpretable and provide 
101  direct evidence of treatment benefit. 
102   
103  In general, two adequate and well-controlled trials are needed to support the effectiveness 
104  of the investigational drug. A single adequate and well-controlled trial supported by other 
105  independent confirmatory evidence, such as a trial in another related infectious disease indication 
106  (e.g., acute bacterial skin and skin structure infections), can potentially provide evidence of 
107  effectiveness in support of an indication for the treatment of DFI. Sponsors should discuss with 
108  the Agency the confirmatory evidence that could support findings from a single trial in DFI.7 
109   
110  4.  Safety Considerations 
111   
112  In general, a safety database of approximately 500 subjects or more is recommended to support 
113  approval of a drug for the treatment of DFI. If the same or greater dosage and duration of therapy 
114  were used in clinical trials for other infectious disease indications, the safety information from 
115  those clinical trials may be part of the overall preapproval safety database. For new drugs that 
116  have an important clinical benefit compared with existing therapies, depending on the benefit 
117  demonstrated, a smaller preapproval safety database may be appropriate. Sponsors should 
 
7 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products (May 1998). 
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118  discuss the appropriate size of the preapproval safety database with the FDA during clinical 
119  development. 
120   
121  B.  Phase 3 Efficacy Trial Considerations 
122   
123  Sponsors are encouraged to discuss proposed study designs and investigative approaches with 
124  the Agency before initiating clinical trials for antibacterial drugs for the treatment of DFI. 
125   
126  1.  Trial Design 
127   
128  Trials should be active-controlled, prospective, randomized, and double-blinded using an NI or 
129  superiority trial design. Add-on superiority trials can also be performed.  
130   
131  2.  Trial Population 
132   
133  The clinical trial population for efficacy trials should include subjects with DFIs of varying 
134  depths and extent of involvement. Surgical incision and drainage of abscesses or wound 
135  debridements could influence treatment outcomes among subjects with DFI. Planned surgical 
136  debridements should be performed during the first 48 hours after randomization. Subjects 
137  needing surgical debridement after 48 hours should be considered as having a clinical failure.8 
138  Topical antibacterial drugs should be avoided. Minor prespecified procedures performed at the 
139  bedside (e.g., suture removal, needle aspiration, superficial debridement of devitalized tissue, or 
140  routine wound care) are permitted.  
141   
142  3.  Entry Criteria  
143   
144  Subjects with type 1 or 2 diabetes mellitus with a foot infection that started at or below the 
145  malleoli and does not extend above the knee, without concomitant osteomyelitis and infectious 
146  arthritis, can be enrolled in DFI clinical trials. Infection should be defined by the presence of at 
147  least two of the following (Lipsky et al. 2012; Lipsky et al. 2019; Senneville et al. 2023):  
148   
149    Local swelling or induration  
150    Erythema >0.5 cm around the wound 
151    Local tenderness or pain  
152    Local warmth  
153    Purulent discharge (thick, opaque to white or sanguineous secretion) 
154   
155  Investigators should enroll subjects with moderate to severe DFIs, including patients who may 
156  have vascular insufficiency and neuropathy and who are representative of the population in 
157  which antibacterial drug treatment is recommended. Enrollment of subjects with mild infections 
158  could potentially drive results toward NI as these infections are associated with a higher 
159  incidence of spontaneous resolution.  
160   
 
8 Sponsors can discuss with the FDA a different window for planned surgical debridements. 
 
4  Contains Nonbinding Recommendations 
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161  The International Working Group on the Diabetic Foot (IWGDF) DFI criteria can be used to 
162  define moderate and severe infection (Lipsky 2019). Under this classification, moderate infection 
163  is defined as erythema extending 2 cm from the wound margin, and/or tissue involvement 
164  deeper than skin and subcutaneous tissues (e.g., muscles and tendons), and no systemic 
165  inflammatory response signs, while severe infection is defined as any foot infection associated 
166  with two or more of the following systemic manifestations: 
167   
168    Temperature >38C or <36C 
169    Heart rate >90 beats/min 
170    Respiratory rate >20 breaths/min or PaCO2 < 4.3 kPa (32 mmHg) 
171    White blood cell count >12 000/mm3, <4000/mm3, or >10% immature (band) forms  
172   
173  If the subject has multiple sites of DFI, the one with the highest IWGDF classification and the 
174  largest size will be designated as the primary DFI. 
175   
176  The method of measuring lesion size should be the same across all trial sites. Methods to assess 
177  lesion size include, but are not limited to, the following: (1) manual measurement of length and 
178  perpendicular width, (2) digital planimetry, and (3) computer-assisted tracings. 
179   
180  Recommended general exclusion criteria include the following:  
181   
182    Subjects with medical conditions that would alter the interpretation of the primary 
183  endpoint (e.g., subjects with severe neutropenia) 
184   
185    Subjects with suspected or confirmed osteomyelitis 
186   
187    Subjects with suspected or confirmed septic (infectious) arthritis 
188   
189    Subjects who have received more than 24 hours of effective antibacterial drug therapy for 
190  the treatment of DFI 
191   
192    Subjects with gangrene requiring amputation 
193   
194    Subjects with necrotizing fasciitis 
195   
196    Subjects with an infected prosthesis 
197   
198    Subjects likely to require revascularization of the primary site of infection or critical 
199  ischemia involving the infected limb 
200   
201    Subjects with a burn wound or an underlying inflammatory skin disease that may obscure 
202  determination of response, such as atopic dermatitis  
203   
204    Subjects with documented or suspected fungal, parasitic, or viral pathogens as a causative 
205  pathogen  
206   
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207    Subjects with acute gout, acute Charcot neuro-osteoarthropathy, acute fracture in the 
208  affected foot, or deep venous thrombosis of the affected extremity. 
209   
210  4.  Prior Antibacterial Drug Therapy 
211   
212  Ideally, subjects enrolled in a DFI noninferiority clinical trial would not have received prior 
213  antibacterial drug therapy for the current DFI episode because such therapy can obscure potential 
214  treatment differences between an investigational drug and a control drug and therefore bias 
215  toward a finding of no difference.  
216   
217  However, consideration can be given for the enrollment of a limited number of subjects who 
218  have received less than 24 hours of potentially active antibacterial therapy for the current DFI 
219  episode before enrollment (e.g., at most 25% of the patient population).  
220   
221  5.  Clinical Microbiology Considerations 
222   
223  All subjects should have pretherapy specimens obtained aseptically from acceptable sources such 
224  as leading-edge needle aspirates of an infected wound, surgically debrided tissue, abscess 
225  contents, and blood. DFI lesion cultures and/or blood cultures should be repeated only if 
226  clinically indicated (e.g., if a subject is deemed a clinical failure or if purulence and discharge 
227  from the DFI lesion continues at any time after screening). 
228   
229  An adequate clinical specimen for microbiological evaluation should be sent to the laboratory for 
230  microscopic examination (e.g., Gram stain) and culture. Specimens should be processed 
231  according to standard methods. In vitro antimicrobial susceptibility testing should be performed 
232  using standardized methods on appropriate bacterial isolates. Potential pathogenic isolates should 
233  be saved and sent to the central laboratory for final confirmation, antimicrobial susceptibility 
234  testing, and additional testing. Blood cultures should be obtained before administration of 
235  antibacterial therapy. 
236   
237  Wound swabs are generally not appropriate. Sinus tract cultures are unreliable and should be 
238  avoided. The sponsors approach to wound microbiology should be discussed with the Agency 
239  before study initiation.  
240   
241  The investigator should assess bacteria isolated from culture specimens as either pathogens, 
242  colonizers, or contaminants, and should provide a summary of the assessment.  
243   
244  Only bacteria designated as pathogens should be considered in determining the microbiological 
245  evaluability of an enrolled subject. A list of accepted pathogens should be discussed with and 
246  submitted to the Agency.  
247   
248  6.  Assessment for Osteomyelitis  
249   
250  Subjects should be screened for bone and joint infections before enrollment, and those with 
251  suspected or confirmed bone and joint infections should be excluded from DFI clinical trials as 
252  they may have less favorable outcomes resulting from slower healing times. Additionally, the 
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Draft  Not for Implementation 
253  management of these subjects may differ because they often require surgical resection and 
254  prolonged duration of antibacterial drug treatment. These factors can influence the selection of 
255  the primary endpoint, timing of evaluation of the endpoint, and justification of NI margins. A 
256  diagnosis of osteomyelitis may be established either by a positive probe to bone test or by 
257  imaging. In subjects with open, infected foot ulcers that do not probe to bone and for subjects 
258  with sepsis related to a foot infection, magnetic resonance imaging should be considered. 
259  Sponsors should discuss with the FDA before initiation of the trial if alternative methods of 
260  detection of osteomyelitis are planned.  
261   
262  7.  Randomization, Stratification, Covariate Adjustment, and Blinding 
263   
264  Trials should be controlled, randomized, and double-blinded. If subjects with ulcer and non-
265  ulcerrelated infections are enrolled in the trial, then the randomization and outcome analyses 
266  should be stratified by the presence or absence of a foot ulcer to account for the differences in the 
267  natural history of the disease entities. To improve the precision of treatment effect estimation and 
268  inference, sponsors may consider adjusting for prespecified prognostic baseline covariates (e.g., 
269  severity of infection, degree of vascular insufficiency) in the primary efficacy analysis and 
270  propose methods of covariate adjustment.9   
271   
272  8.  Specific Populations 
273   
274  Sponsors should include geriatric subjects without any upper age limit in clinical trials.10 Any 
275  exclusion criteria pertaining to comorbidities should be avoided unless essential for ensuring 
276  patient safety (e.g., because of important drug-drug interactions with drugs required in the 
277  treatment of a comorbidity). The trials should also include obese subjects (defined as body mass 
278  index of at least 30 kg/m2), as obese subjects with diabetes are at an increased risk of diabetic 
279  foot infection (Glovaci et al. 2019). Sponsors should characterize the pharmacokinetics of the 
280  drug in obese subjects before phase 3 studies to inform the selection of an appropriate dosage for 
281  this population. Adequate characterization of pharmacokinetics of the study drug in patients with 
282  renal insufficiency should be planned in early development (i.e., phase 1 studies) so such patients 
283  can be included with appropriate dosage modifications in phase 3 studies.11 Similarly, subjects 
284  with hepatic impairment should be enrolled, provided the pharmacokinetics of the drug have 
285  been evaluated in these subjects and/or appropriate dosage has been defined.12    
286   
287   
 
9 See the guidance for industry Adjusting for Covariates in Randomized Clinical Trials for Drugs and 
Biological Products (May 2023).  
 
10 See the ICH guidances for industry E7 Studies in Support of Special Populations: Geriatrics (August 1994) and 
E7 Studies in Support of Special Populations: Geriatrics; Questions and Answers (February 2012). 
 
11 See the draft guidance for industry Pharmacokinetics in Patients with Impaired Renal Function  Study Design, 
Data Analysis, and Impact on Dosing (September 2020). 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. 
 
12 See the guidance for industry Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data 
Analysis, and Impact on Dosing and Labeling (May 2003).   
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288  9.  Dose Selection 
289   
290  Sponsors should integrate the findings from animal models13 and information from phase 1 and, 
291  if appropriate, phase 2 trials for the purposes of selecting appropriate dosages, and duration of 
292  therapy to be evaluated in phase 3 clinical trials.  
293   
294  10.  Use of Active Comparators  
295   
296  In general, the active comparator used in clinical trials should be considered standard of care for 
297  this indication. When evaluating standard of care, sponsors should consider recommendations by 
298  authoritative scientific bodies (e.g., the Infectious Diseases Society of America) and other 
299  information that reflects current clinical practice.   
300   
301  11.  Concurrent Antibacterial Drug Therapy 
302   
303  Ideally, concurrent antibacterial drug therapy should be avoided except in an add-on trial when it 
304  is part of the study therapy. Concomitant antibacterial drug therapy with a spectrum of activity 
305  that overlaps with the spectrum of the investigational drug should not be administered during the 
306  trial, except as rescue therapy, as it will limit assessment of the efficacy of the investigational 
307  drug. The need for rescue therapy will generally be interpreted as failure of the study drug. 
308  Concomitant antibacterial drugs for bacteria that are not susceptible to the study drug may be 
309  acceptable. Sponsors should discuss with the FDA any plans for concomitant antibacterial drug 
310  therapy in advance of trial initiation. The ability to maintain study blinding with the use of 
311  concomitant antibacterial drug therapy should be addressed. 
312   
313  12.  Adjunctive Measures 
314   
315  As part of the current standard of care for DFI, various modalities are used in wound 
316  management to encourage healing and closure. Some examples of the measures that could be 
317  employed include non-weight bearing (off-loading) and debridement. The contribution of each 
318  modality to the overall treatment outcome can be difficult to assess. The sponsor should 
319  prespecify and document which adjunctive modalities are permitted under the protocol.  
320   
321  13.  Minimum Duration of Treatment: 
322   
323  In general, the minimal duration of treatment for DFI without concomitant osteomyelitis or 
324  septic arthritis is 7 to 14 days. For subjects who require a prolonged course of antibacterial drug 
325  therapy, the sponsor should define criteria for prolonging study drug treatment and discuss these 
326  with the Agency before study initiation. 
327   
 
13 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible. We 
encourage sponsors to consult with us if they wish to use a nonanimal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method is adequate to meet the regulatory 
need. 
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328  14.  Intravenous to Oral Therapy Switch 
329   
330  For drugs that only have an intravenous (IV) formulation available, we recommend that subjects 
331  receive the IV formulation alone until the assessment of the primary efficacy endpoint.  
332   
333  For drugs that have both an IV and an oral formulation, a switch to the oral formulation may be 
334  appropriate before the primary efficacy outcome assessment, provided that the pharmacokinetics 
335  of the oral formulation have been evaluated to ensure adequate exposure and to determine an 
336  appropriate dosage. If an IV-to-oral switch is incorporated into the protocol, the sponsor should 
337  specify the objective criteria necessary to permit the switch and discuss the criteria with the FDA 
338  before study initiation.  
339   
340  15.  Efficacy Endpoints 
341   
342  a.  Primary efficacy endpoint  
343   
344  The primary endpoint should be resolution or improvement of all signs and symptoms of DFI to 
345  the extent that no further antibacterial drug therapy is needed and none of the following events 
346  have occurred: receipt of rescue therapy, unplanned surgical debridement, amputation, or death. 
347  Sponsors should predefine these criteria to allow for uniformity of clinical assessments among 
348  investigators across sites. Alternative definitions of clinical response should be discussed with 
349  the FDA before initiation of clinical trials.   
350   
351  To preserve the integrity of randomization, the timing of all post-baseline assessments should be 
352  based on a window defined by the time from randomization (i.e., around a fixed time point) 
353  rather than a window defined by the time from the end of therapy (EOT). In general, the primary 
354  endpoint should be evaluated at the test-of-cure visit approximately 21 days post-randomization. 
355  The treatment effect should also be evaluated at the EOT and other follow-up visits to evaluate 
356  for durability of the treatment effect.  
357   
358  The investigators assessment of clinical response should be performed by the same investigator 
359  on the same subject throughout the study, whenever possible, to ensure uniformity of 
360  assessments. 
361   
362  b.  Secondary endpoint considerations 
363   
364  An endpoint defined as the composite of death, unplanned amputation, and infectious 
365  complications at 21 days post-randomization should be considered, as this objectively measures 
366  key patient benefits. Other secondary endpoints may include clinical response assessed at EOT 
367  or all-cause mortality at a fixed time point post-randomization (e.g., 21 days).  
368   
369  c.  Additional endpoint considerations 
370   
371  For the primary and secondary outcome classifications, subjects with any unplanned surgical 
372  debridement, except for minor prespecified procedures, or other unplanned adjunctive 
373  interventions after 48 hours, should be considered clinical failures. Subjects who have 
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374  amputations or who develop osteomyelitis of underlying bone despite study drug therapy would 
375  be considered clinical failures.  
376   
377  In instances where an overlying foot ulcer has healed completely without clinical evidence of 
378  infection, the subjects microbiological response would be presumptive eradication.  
379   
380  Endpoints based on patient-reported outcomes can be considered. Sponsors should discuss 
381  proposed patient-reported outcome instruments with FDA. 
382   
383  16.  Trial Procedures and Timing of Assessments 
384   
385  Entry visit 
386  At this visit sponsors should collect appropriate demographic, history, and physical examination 
387  information, including lesion size measurements, evaluation for osteomyelitis, neuropathy, 
388  peripheral vascular disease, microbiological specimens, safety laboratory tests, and imaging 
389  studies.  
390   
391  On-therapy visits 
392  At 48 to 72 hours after initiating study drug and other on-therapy visits, sponsors should provide 
393  a clinical assessment of the primary DFI site (including lesion size measurement) and assess all 
394  signs and symptoms as specified by the protocol. Safety and laboratory tests, as appropriate, 
395  should be evaluated.  
396   
397  EOT visit 
398  At this visit, sponsors should evaluate the lesion size in the same manner as at the entry and on-
399  therapy visits, as specified by the protocol. Safety and laboratory tests, as appropriate, should be 
400  evaluated. For subjects who discontinue study therapy prematurely, subjects should not be 
401  discontinued from the study but should continue to be followed per the protocol. The protocol 
402  should specify criteria to guide the duration of study treatment.  
403   
404  Test-of-cure visit 
405  This visit should occur at Day 21 plus/minus 2 days post-randomization, which would 
406  correspond to 7 to 14 days following the EOT. As indicated above, the primary endpoint should 
407  be evaluated at this visit. Sponsors should assess the maintenance of clinical response and any 
408  new safety effects, evaluate for osteomyelitis, and obtain safety laboratory tests, as appropriate, 
409  at this visit.  
410   
411  Day-28 post-randomization follow-up visit 
412  At this visit, all-cause mortality, durability of clinical response, and follow-up of any adverse 
413  events should be assessed. 
414   
415  17.  Statistical Considerations 
416   
417  The trial hypotheses, the estimands of interest, and the analysis methods should be prespecified 
418  in the protocol and in a detailed statistical analysis plan. The primary efficacy analysis should be 
419  based on the difference in the proportions of subjects achieving a successful clinical response. 
420  Subgroup analyses should assess the primary endpoint in the baseline subgroups of subjects who 
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421  did and did not receive prior antibacterial therapy. Additional sensitivity/exploratory analyses 
422  should be performed for factors that could modify the primary analysis findings.  
423   
424  Analysis populations 
425  The definitions for the statistical analysis populations are provided as follows:  
426   
427    Safety population  All subjects who received at least one dose of drug during the trial.  
428   
429    Intent-to-treat (ITT) population  All subjects who were randomized.  
430   
431    Microbiological intent-to-treat (micro-ITT) population  All subjects randomized to 
432  treatment who have a baseline bacterial pathogen known to cause DFI. Patients should 
433  not be excluded from this population based upon events that occur after randomization 
434  (e.g., lost to follow-up). 
435   
436    Per-protocol, clinically evaluable, or microbiologically evaluable populations  Subjects 
437  who follow important prespecified components of the trial can then be defined as part of 
438  a per-protocol or other evaluable population (i.e., ITT subjects who follow important 
439  components of the trial can be defined as the clinically evaluable population, or micro-
440  ITT subjects who follow important components of the trial can be defined as the 
441  microbiologically evaluable population). 
442   
443  For both NI and superiority trials, the primary analysis should be based on the ITT population. In 
444  general, the ITT population, instead of the micro-ITT population, should be the primary analysis 
445  population because the definitions of DFI described are most consistent with bacterial infection 
446  even for cases in which purulent material is not easily obtained (e.g., cellulitis). Generally, it is 
447  not appropriate to consider analyses of the per-protocol, clinically evaluable, or 
448  microbiologically evaluable populations as primary because population membership is based on 
449  post-randomization events or characteristics of subjects. However, consistency of the results 
450  should be evaluated in all populations.  
451   
452  Sample size 
453  The appropriate sample size for a clinical trial should be based on the number of subjects needed 
454  to answer the research question posed by the study. The sample size is influenced by several 
455  factors, including the prespecified type I (=.05, two-sided) and type II error (  0.2) rates, the 
456  expected clinical response rate, and the NI margin (for NI trial) or the magnitude by which the 
457  study drug is expected to be superior to the control in a superiority trial. Sample size should be 
458  based upon the number of subjects needed to draw conclusions in the ITT primary analysis 
459  population. 
460   
461  An estimate of the sample size for an NI trial with 1:1 randomization is approximately 442 
462  subjects per arm based on the following assumptions: (1) the NI margin is selected at 10%, (2) 
463  the two-sided type I error is 0.05, (3) the type II error is 0.10 (90% power), and (4) 70% of 
464  subjects achieve clinical response in both arms. 
465   
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466  Selection of NI14 margins 
467  If a sponsor chooses to design an NI trial for DFI, then the NI margin should be prespecified to 
468  determine an appropriate sample size for the trial. The NI margin that should be used in this 
469  circumstance is determined by the amount of potential loss of efficacy relative to the active 
470  control that the trial will attempt to rule out statistically. Sponsors should provide data to justify 
471  the selection of the NI margin. The selection of an appropriate NI margin should be based upon 
472  the following: 
473   
474    Previous evidence of the magnitude of the benefit of the control antibacterial drug over 
475  placebo from a compilation of all relevant placebo-controlled or superiority trials of an 
476  antibacterial drug over another antibacterial drug. The degree of benefit anticipated must 
477  account for the variability across previous trials in the degree of beneficial effect 
478  observed. The planned trial should be sufficiently similar to the studies considered in the 
479  historical evidence on important factors including inclusion criteria, patient and disease 
480  characteristics, clinical endpoint(s), duration of treatment, timing of assessment, and 
481  other relevant factors.  
482   
483    Consideration of the potential loss of efficacy relative to the control drug by an amount 
484  that is clinically acceptable. 
485   
486  In general, a 10% NI margin would be acceptable; however, sponsors can propose alternative NI 
487  margins with a justification provided for the acceptance of that margin.  
488   
489  The appendix provides an example of an NI margin justification. Sponsors should discuss with 
490  the FDA a clinically appropriate NI margin in advance of trial initiation. 
491   
492  18.  Labeling Considerations 
493   
494  The DFI treatment indication should include the approved age groups and information about the use 
495  of the drug in patients without concomitant osteomyelitis or septic arthritis. Additionally, this 
496  indication should list the genus and species of the bacteria identified in clinical trials that supported 
497  the indication. For example:  
498   
499  Drug X is indicated for the treatment of adults with diabetic foot infections (without 
500  concomitant osteomyelitis or septic arthritis) caused by ... [list genus and species of 
501  bacteria]. 
502   
 
14 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016). 
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503  REFERENCES 
504   
505  Glovaci D, W Fan, and ND Wong, 2019, Epidemiology of Diabetes Mellitus and Cardiovascular 
506  Disease, Curr Cardiol Rep, 21(4):21. 
507   
508  Lipsky BA, AR Berendt, PB Cornia, JC Pile, EJG Peters, DG Armstrong, H. Gunner Deery, JM 
509  Embil, WS Joseph, AW Karchmer, MS Pinzur, and E Senneville, 2012, Infectious Diseases 
510  Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot 
511  Infections, Clin Infect Dis, 54(12):e132e173. 
512   
513  Lipsky BA, AB Polis, KC Lantz, JM Norquist, and MA Abramson, 2009, The Value of a Wound 
514  Score for Diabetic Foot Infections in Predicting Treatment Outcome: A Prospective Analysis 
515  from the SIDESTEP Trial, Wound Rep Reg, 17(5):671677. 
516   
517  Lipsky BA, E Senneville, ZG Abbas, J Aragon-Sanchez, M Diggle, JM Embil, S Kono, LA 
518  Lavery, M Malone, SA van Asten, V Urbancic-Rovan, and EJG Peters, 2019, IWGDF Guideline 
519  on the Diagnosis and Treatment of Foot Infection in Persons with Diabetes, IWGDF. 
520   
521  Lipsky BA, E Senneville, ZG Abbas, J Aragon-Sanchez, M Diggle, JM Embil, S Kono, LA 
522  Lavery, M Malone, SA van Asten, V Urbancic-Rovan, and EJG Peters, 2020, Guidelines on the 
523  Diagnosis and Treatment of Foot Infection in Persons with Diabetes (IWGDF 2019 update), 
524  Diabetes Metab Res Rev, 36(S1):e3280. 
525   
526  Schaper NC, 2004, Diabetic Foot Ulcer Classification System for Research Purposes: A Progress 
527  Report on Criteria for Including Patients in Research Studies, Diabetes Metab Res Rev, 
528  20(S1):S1S95. 
529   
530  Senneville E, Z Albalawi, SA van Asten, ZG Abbas, G Allison, J Aragon-Sanchez, JE Embil, 
531  LA Lavery, M Alhasan, O Oz, I Uckay, V Urbancic-Rovan, ZR Xu, and EJG Peters, 2023, 
532  IWGDF/IDSA Guidelines on the Diagnosis and Treatment of Diabetes-related Foot Infections 
533  (IWGDF/IDSA 2023), Clin Infect Dis, epub ahead of print October 2, 2023, 
534  https://doi.org/10.1093/cid/ciad527. 
535   
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536  APPENDIX:  
537  JUSTIFICATION FOR A NONINFERIORITY MARGIN 
538  FOR DIABETIC FOOT INFECTIONS 
539   
540   
541  Background 
542   
543  The first step in the consideration for a noninferiority (NI) trial design is determining the 
544  treatment effect of the active-comparator drug that can be reliably distinguished from placebo 
545  (M ). This determination is based on the evidence from previously conducted trials using reliable 
1
546  efficacy endpoints. Because no historical, randomized, placebo-controlled trials for patients with 
547  diabetic foot infection (DFI) could be identified, direct estimation of the treatment effect was not 
548  possible. Therefore, we considered retrospective case series comparing the pre- with the post-
549  antibacterial drug era. Various outcome measures were considered, including control of infection 
550  rates, mortality rates, and rates of major amputations.  
551   
552  Retrospective case series comparing the pre- with the post-antibacterial drug era: 
553   
554  Two publications (McKittrick 1946; Regan et al. 1949) discussed the treatment effect of 
555  antibacterial drugs on amputations in patients with DFI as assessed by the treating physicians in 
556  the pre- and post-antibacterial drug era. An additional publication (McKittrick 1949) assessed 
557  infection control in the post-antibacterial drug era. These studies generally included subjects with 
558  serious DFI, such as infections with gangrene and presumably osteomyelitis for which 
559  amputation was often required. Patients with osteomyelitis are not considered for this guidance 
560  because they require a prolonged duration of antibacterial drug therapy, typically 4 to 6 weeks, 
561  usually in conjunction with surgical intervention.    
562   
563  Regan (1949) stated that changes in surgical procedures with more aggressive surgeries likely 
564  led to a strong reduction in the infection rate. For example, 105/140 (75%) of the amputations 
565  performed between 1930 and 1939 resulted in infections of the stump after amputation versus 
566  1/28 (3.5%) of amputations performed between 1940 and 1944 using a more aggressive surgical 
567  approach. The potential for confounding is also observed by the reduction in mortality for all 
568  amputations performed from 1933 to 1939 (35.0%) versus 1940 to 1944 (8.8%), which was 
569  primarily attributed to improvements in surgical protocols, although sulfonamide use appeared to 
570  be an additional factor (Regan et al. 1949).  
571   
572  Outcome of major amputations 
573  Table 1 shows for both studies the proportion of major amputations out of all amputations of 
574  lower extremities in diabetic patients before and after the introduction of penicillin. These results 
575  show that a substantial reduction in major amputations occurred after the introduction of 
576  penicillin. The treatment difference (before and after penicillin) was 30.7% in McKittrick (1946) 
577  and 41.2% in Regan et al. (1949) (Table 1). In Figure 1, a meta-analysis of both studies using a 
578  random effect model based on the DerSimonian-Laird approach shows a treatment difference of 
579  35.0% (95% CI: 24.9%, 45.1%).  
580   
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581  Table 1: Proportion of Patients with Amputations Receiving Major Amputations, Pre-
582  Penicillin Versus Post-Penicillin 
  Before 
Publication  Penicillin1  After Penicillin2 
n/N (%) 
 
n/N (%) 
McKittrick 1946  680/1036 (65.6%)  80/229 (34.9%) 
Regan et al. 1949  99/140 (70.7%)  36/122 (29.5%) 
583  n = Number of patients with major amputations, N = Number of patients with any type of amputation (major or minor). 
584  1 Before Penicillin refers to years of 1923 to 1941 (McKittrick 1946) and 1933 to 1939 (Regan et al. 1949).  
585  2 After Penicillin refers to 1944 to1945 (McKittrick 1946) and 1945 to 1948 (Regan et al. 1949).  
586   
587   
588  Figure 1: Meta-Analysis of the Proportion of Major Amputations Performed, Pre-
589  Penicillin Versus Post-Penicillin 
590   
591   
592  Outcome of mortality 
593  The two publications discussed above (McKittrick 1946; Regan et al. 1949) also discuss the 
594  mortality of patients undergoing amputations. Table 3 shows post-amputation mortality rates pre 
595  and post the use of penicillin. These results show that a modest reduction occurring after the 
596  introduction of penicillin. The treatment difference was 7.1% in McKittrick (1946) and 4.7% in 
597  Regan et al. (1949) (Table 2). In Figure 2, a meta-analysis of both studies shows a treatment 
598  difference of 6.7% (95% CI: 4.2%, 9.2%) using a random effects model. The reduction in 
599  mortality rate post penicillin use helps to support an overall treatment benefit attributable to 
600  antibacterial drug use. 
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601   
602  Table 2: Mortality Rates After Amputation,1 Before Penicillin Versus After Penicillin 
Publication  Mortality Rate   
Before Penicillin2  After Penicillin3  Difference 
n/N (%)  n/N (%)  (%) 
McKittrick (1946)  101/1036 (9.7%)  6/229 (2.6%)  7.1% 
Regan et al. (1949)  12/136 (8.8%)  5/122 (4.1%)  4.7% 
603  1 Amputations include both minor and major amputations. 
604  2 Before Penicillin refers to 1923 to 1941 (McKittrick 1946) and 1940 to 1944 (Regan et al. 1949)  
605  3After Penicillin refers to 1944 to 1945 (McKittrick 1946) and 1945 to 1948 (Regan et al. 1949) 
606   
607   
608  Figure 2: Meta-Analysis of Mortality Rates Following Amputation 
609   
610   
611  Outcome of control of infection rates 
612  Regan et al. (1949) discussed the treatment effect of antibacterial drugs on the control of 
613  diabetic lower extremity infection rates in patients receiving minor amputations in the pre- and 
614  post-antibacterial drug era. McKittrick (1949) also discussed control of infection rates after the 
615  introduction of penicillin. In Regan et al. (1949), control of infection required that the wound 
616  heal completely, or stumps take skin grafts without subsequent re-amputation. In McKittrick 
617  (1949), control of infection required that the wound heal without need of re-amputation or 
618  death. 
619   
620  These results show that a substantial improvement in control of infection rates occurred after the 
621  introduction of penicillin. The treatment difference in Regan et al. (1949) was 39.7% (21.0% to 
622  58.4%). Treatment comparisons could not be made based on the 1949 McKittrick paper; 
623  however, control of infection rates in the after-penicillin period were observed to be 72.1%.   
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624   
625  Table 2: Control of Infection Rates Among Cases with Local (Minor) Amputations 
Publication  Pre-Penicillin  Post-Penicillin  Difference 
(19331939)  (19451948)  (95% CI) 
n/N (%)  n/N (%) 
Regan et al. (1949)  19/41 (46.3%)  74/86 (86.0%)  39.7% (21.0-58.4) 
McKittrick et al.  NA  155/215 (72.1%)   
(1949) 
626   
627  Discussion 
628   
629  There are major limitations with determining an NI margin for patients with DFIs. For example, 
630  the older studies of antibacterial drug treatment in diabetic lower extremity infections (Regan et 
631  al. 1949; McKittrick 1946; McKittrick et al. 1949) were not performed in a prospective and well-
632  controlled manner but rather were based on retrospective analyses of case series. Analyses of 
633  case series can involve treatment imbalances, uncontrolled confounding variables, lack of 
634  standardized methodologies, missing/unreported data, and various types of biases (e.g., evaluator 
635  biases, recall biases). These studies also lacked details regarding important study design features 
636  such as inclusion/exclusion criteria, baseline characteristics, extent of antibacterial drugs used 
637  (e.g., extent of sulfonamide use during early 1940s), and definitions used for control of 
638  infection (e.g., timing of assessment and the success/failure criteria). These studies were also 
639  conducted in a much earlier time period involving large differences with respect to treatment 
640  modalities, including management of diabetes mellitus patient populations and disease etiologies. 
641  This can result in higher baseline mortality/morbidity rates and estimated treatment effects 
642  compared with what would be observed in current clinical trials for DFI.   
643   
644  There are also limitations specific to the analyses of the treatment effect using major amputations 
645  and mortality, which may not be applicable in current clinical trials of DFIs. Analyses using 
646  mortality may be affected by low incidence rates resulting in smaller estimates of the treatment 
647  effect. Analyses using major amputations may involve serious confounding because of 
648  improvements in surgical protocols that were attributed to reduced mortality and postoperative 
649  incidence of infections from 1940 to 1945 (Regan et al. 1949).  
650   
651  These studies also included patients with more serious infections, including those with gangrene, 
652  and presumably osteomyelitis where amputation was often required. Current populations 
653  addressed in this guidance have less serious infections (e.g., no osteomyelitis) and are less likely 
654  to have an amputation. Despite these differences, these publications strongly point to a large 
655  effect of antibacterial drugs in the treatment of DFI. 
656   
657  Summary and Selection of Noninferiority Margin for DFI 
658   
659  Data from the Regan et al. (1949) study support a difference of at least 20% based on the lower 
660  95% confidence limit for the difference in control of infection rates between the pre-penicillin 
661  and post-penicillin periods. These scientific data provide support for the selection of an NI 
662  margin of 10% that preserves some of M  based on an endpoint of control of infection. Sponsors 
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663  should discuss the selection of an NI margin with the FDA in advance of trial initiation, in 
664  particular for a margin selected at greater than 10%.   
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665  APPENDIX REFERENCES 
666   
667  McKittrick LS, 1946, Recent Advances in the Care of the Surgical Complications of Diabetes 
668  Mellitus, NEJM, 235(26): 929932. 
669   
670  McKittrick LS, JB McKittrick, and TS Risley, 1949, Transmetatarsal Amputation for Infection 
671  or Gangrene in Patients with Diabetes Mellitus, Ann Surg, 130(4):826840. 
672   
673  Regan JS, BD Bowen, and PA Fernbach, 1949, Reduction in Mortality and Loss of Limbs in 
674  Diabetic Gangrene and Infection, Arch Surg 1949, 59(3):594600. 
675   
676  Snodgrass WR and T Anderson, 1937, Prontosil in the Treatment of Erysipelas: A Controlled 
677  Series of 312 Cases, BMJ, 2(3993):101104. 
678   
679  Snodgrass WR and T Anderson, 1937, Sulphanilamide in the Treatment of Erysipelas: A 
680  Controlled Series of 270 Cases, BMJ, 2(4014):11561159. 
681   
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