Antibacterial Therapies for 
Patients With an Unmet 
Medical Need for the 
Treatment of Serious 
Bacterial Diseases  Questions 
and Answers (Revision 1) 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Peter Kim (CDER) 301-796-0741. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2022 
Clinical/Antimicrobial 
Revision 1 
45312611dft.docx 
05/17/22   
Antibacterial Therapies for 
Patients With an Unmet 
Medical Need for the 
Treatment of Serious 
Bacterial Diseases  Questions 
and Answers (Revision 1) 
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) 
 
May 2022 
Clinical/Antimicrobial 
Revision 1 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  QUESTIONS AND ANSWERS ....................................................................................... 3 
BIBLIOGRAPHY ....................................................................................................................... 15 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Antibacterial Therapies for Patients With an Unmet Medical Need 
2  for the Treatment of Serious Bacterial Diseases  Questions and 
3  Answers (Revision 1) 
4  Guidance for Industry1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA office 
12  responsible for this guidance as listed on the title page.   
13   
14   
15   
16  I.  INTRODUCTION  
17   
18  This guidance is intended to assist sponsors in the clinical development of new antibacterial 
19  drugs.2  Specifically, the guidance explains the FDAs current thinking about possible 
20  development programs and clinical trial designs for antibacterial drugs to treat serious bacterial 
21  diseases in patients with an unmet medical need, including patients with a serious bacterial 
22  disease for which effective antibacterial drugs are limited or lacking.3  Antibacterial drugs that 
23  are active against only a single species or few species within a genus of bacteria can be 
24  developed for the treatment of serious bacterial diseases in patients with an unmet medical need.4  
25  For products that have the potential to address an unmet medical need, a more flexible 
26  development program may be acceptable to facilitate development.  
27   
28  Section 3042 of the 21st Century Cures Act (Public Law 114-255) established a limited 
29  population pathway for certain antibacterial and antifungal drugs (LPAD) that are intended to 
30  treat a serious or life-threatening infection in a limited population of patients with unmet medical 
 
1 This guidance has been prepared by the Division of Anti-Infectives in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products regulated in CDER unless otherwise specified.  
 
3 For example, effective antibacterial drugs can be limited because resistance to several antibacterial drugs has 
developed.  Patients who have allergies or intolerance to several antibacterial drugs also may be considered as 
having an unmet medical need.  See the guidance for industry Expedited Programs for Serious Conditions  Drugs 
and Biologics (May 2014), section III. C., Unmet Medical Need.  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. 
 
4 For a detailed discussion of regulatory programs intended to expedite development and review of drugs (e.g., fast 
track, breakthrough) and their attendant criteria and definitions, see the guidance for industry Expedited Programs 
for Serious Conditions  Drugs and Biologics.   
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31  needs.5  Antibacterial and antifungal drugs developed to address unmet medical need may also 
32  be considered for approval under the LPAD pathway.6  Sponsors are encouraged to discuss 
33  proposed approaches with the Agency. 
34   
35  This draft guidance revises the guidance for industry Antibacterial Therapies for Patients With 
36  an Unmet Medical Need for the Treatment of Serious Bacterial Diseases (August 2017).  After it 
37  has been finalized, this draft guidance will replace the August 2017 guidance.  Significant 
38  changes in this draft guidance from the 2017 version include the possibility to conduct 
39  noninferiority trials that include subjects with infections caused by certain drug-resistant 
40  pathogens since effective active controls are now available.  More detail is also provided for the 
41  currently used noninferiority trial designs that may be used with a wider noninferiority margin, 
42  including cases for which the trial population is enriched for subjects with infections caused by 
43  certain drug-resistant organisms. 
44   
45  This draft guidance does not contain discussion of the general issues of statistical analysis or 
46  clinical trial design.  Those topics are addressed in the ICH guidances for industry E9 Statistical 
47  Principles for Clinical Trials (September 1998) and E10 Choice of Control Group and Related 
48  Issues in Clinical Trials (May 2001), respectively.  
49   
50  The contents of this document do not have the force and effect of law and are not meant to bind 
51  the public in any way, unless specifically incorporated into a contract.  This document is 
52  intended only to provide clarity to the public regarding existing requirements under the law. 
53  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
54  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
55  Agency guidances means that something is suggested or recommended, but not required.  
56   
57   
58  II.  BACKGROUND 
59   
60  Antibacterial drug resistance continues to be a public health concern.  It has led to an increasing 
61  number of patients with serious bacterial diseases, such as hospital-acquired bacterial 
62  pneumonia, ventilator-associated bacterial pneumonia, and complicated urinary tract infections, 
63  who may not respond to currently available antibacterial drugs.7   
64   
65  Conducting clinical trials to evaluate antibacterial drugs for the treatment of subjects with a 
66  serious bacterial disease can be challenging for a number of reasons, including (1) the need to 
67  promptly initiate empiric antibacterial therapy to reduce the risk of morbidity and mortality, 
68  which may obscure the effect of the antibacterial drug under study because empiric antibacterial 
69  therapy administered to some subjects before enrollment in the trial may be effective; (2) the 
70  severity of the acute illness in subjects (e.g., delirium in the setting of acute infection) may make 
71  obtaining informed consent and performing other trial enrollment procedures difficult; (3) the 
 
5 See section 506(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).   
 
6 See the guidance for industry Limited Population Pathway for Antibacterial and Antifungal Drugs (August 2020). 
 
7 See the Bibliography at the end of this guidance.  
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72  diagnostic uncertainty with respect to the etiology of the subjects underlying disease, including 
73  the specific bacterial etiology; and (4) the potential need for concomitant antibacterial drug 
74  therapy (often empiric) with a spectrum of activity that may overlap with the activity of the 
75  antibacterial drug being studied can make assessment of the efficacy of the investigational drug 
76  difficult. 
77   
78  Given the urgent need for development of new antibacterial drugs to treat serious bacterial 
79  diseases, sponsors should be aware of the recognized need for flexibility in meeting the 
80  requirements for substantial evidence of effectiveness in such situations, as stated in 21 CFR part 
81  312, subpart E (Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses), 
82  below.     
83   
84  The Food and Drug Administration (FDA) has determined that it is appropriate 
85  to exercise the broadest flexibility in applying the statutory standards, while 
86  preserving appropriate guarantees for safety and effectiveness.  These procedures 
87  reflect the recognition that physicians and patients are generally willing to accept 
88  greater risks or side effects from products that treat life-threatening and severely-
89  debilitating illnesses, than they would accept from products that treat less serious 
90  illnesses.  These procedures also reflect the recognition that the benefits of the 
91  drug need to be evaluated in light of the severity of the disease being treated.8 
92   
93   
94  III.  QUESTIONS AND ANSWERS  
95   
96  The following questions and answers are provided to explain the FDAs current thinking on 
97  flexible development programs that may be appropriate for development of antibacterial drugs to 
98  treat serious bacterial diseases in patients with an unmet medical need.  
99   
100  1.  What types of antibacterial drugs may be appropriate for a more flexible 
101  development program?  
102   
103  Candidates for a flexible development program are antibacterial drugs intended to treat serious 
104  bacterial infections in patients who have few or no available treatments.9  Such drugs are likely 
105  to have (1) a new mechanism of action that preserves antibacterial activity against bacteria that 
106  have mechanisms of resistance to other available antibacterial drugs, (2) an added inhibitor that 
107  neutralizes a mechanism of resistance, (3) an alteration in the structure of the molecule that 
108  makes the drug no longer susceptible to the mechanisms of resistance to existing drugs, or (4) 
109  some other characteristic that has a potential to lead to enhanced effectiveness.  A drug that has 
110  slightly greater potency (e.g., more active by 2- to 3-fold dilutions based on in vitro testing) 
111  generally would not be considered a drug that addresses an unmet medical need. 
112   
 
8 See 21 CFR 312.80. 
 
9 For a more general discussion of the concepts of unmet medical need and serious conditions, see the guidance for 
industry Expedited Programs for Serious Conditions  Drugs and Biologics.   
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113  2.  Can a drug that treats a single species of bacteria be a candidate for a flexible 
114  development program? 
115   
116  Yes, a drug that treats a single species (or a few species) of bacteria is a candidate for a more 
117  flexible development program.  For an antibacterial drug active against only a single species (or 
118  few species) within a genus, possible clinical trial design recommendations are discussed below.  
119  When planning for such a drug development program, sponsors should consider the following 
120  factors for clinical trials: 
121   
122    The frequency with which the bacterial species of interest causes serious infections 
123    The use and availability of rapid diagnostic tests to promptly identify subjects with the 
124  bacterial etiology of interest as the cause of their infection 
125    The codevelopment of a rapid diagnostic test for use in clinical practice10 
126   
127  3.  What are important nonclinical considerations in a flexible development program 
128  for an antibacterial drug for the treatment of patients with serious bacterial diseases 
129  and an unmet medical need? 
130   
131  Sponsors should evaluate the antibacterial activity of the new drug, mechanism of action, 
132  mechanism or mechanisms of resistance, and whether the new drug is affected by mechanisms 
133  that confer resistance to other drugs and its potential as a candidate for the treatment of patients 
134  with serious infections and few or no treatment options. 
135   
136  To the extent that a flexible clinical development program involves smaller, shorter, or fewer 
137  clinical trials, it is likely that less safety data will be generated, and the nonclinical studies may 
138  assume an even more important role in contributing to the evaluation of the safety of an 
139  antibacterial drug.  Thus, the nonclinical evaluations generally should not be abbreviated.  In 
140  certain circumstances, an abbreviated nonclinical program may be applicable (see Question 6 
141  below).  A sponsor developing a drug using a flexible clinical development program must still 
142  provide adequate data to demonstrate that the drug is safe and effective to meet the statutory 
143  standards for approval.11  Other guidances for industry discuss the important elements of the 
144  nonclinical safety evaluation.12  Sponsors are encouraged to discuss their nonclinical safety 
145  program with the Agency early in the development process.  
 
10 The Center for Devices and Radiological Health regulates devices for the purpose of use in the clinical care of 
patients.  Sponsors should discuss with the FDA whether an investigational in vitro diagnostic device is intended to 
be used with a corresponding drug as a companion diagnostic device.  See the guidance for industry and Food and 
Drug Administration staff In Vitro Companion Diagnostic Devices (August 2014) and the guidance for industry and 
Food and Drug Administration staff Coordinated Development of Antimicrobial Drugs and Antimicrobial 
Susceptibility Test Devices (February 2019). 
 
11 See 21 U.S.C. 355(d). 
 
12 See, for example, the ICH guidances for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human 
Clinical Trials and Marketing Authorization for Pharmaceuticals (January 2010), S6 Preclinical Safety Evaluation 
of Biotechnology-Derived Pharmaceuticals (July 1997), and S7B Nonclinical Evaluation of the Potential for 
Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (October 2005), and the 
guidances for industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of 
 
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146   
147  Flexible drug development programs that address an unmet medical need for serious bacterial 
148  infections may include clinical trials with smaller sample sizes and greater uncertainty.  The 
149  nonclinical data package should provide information about the investigational drug, including the 
150  following: 
151   
152    In vitro activity of the investigational drug, including the minimum inhibitory 
153  concentration (MIC) from a representative sample of target bacterial pathogens13   
154   
155    Activity in appropriate animal models of infection14  
156   
157    Evidence for the antibacterial drugs ability to achieve appropriate concentrations in 
158  relevant tissue sites from nonclinical studies (e.g., from appropriate animal models of 
159  infection) 
160   
161    The mechanism of action and whether mechanisms of resistance to other drugs affect its 
162  antibacterial activity 
163   
164    The evaluation of pharmacokinetic/pharmacodynamic (PK/PD) relationships from animal 
165  models of infection, such as the PK/PD index that is associated with activity in a relevant 
166  animal model and/or in vitro model or models based on (1) the area under the unbound 
167  plasma concentration time curve over the MIC, (2) maximum unbound plasma 
168  concentration over the MIC, (3) time above the MIC, or (4) other appropriate metrics  
169   
170    The target value of the PK/PD index that is associated with activity in the animal model 
171   
172    Dose and frequency of administration that was evaluated in in vitro models of infection 
173  based on PK parameters obtained from human PK studies 
174   
175  4.  What are clinical trial design considerations in a more flexible development 
176  program? 
177   
178  Different approaches can be used to evaluate an antibacterial drug for the treatment of a serious 
179  bacterial disease in patients with an unmet medical need.  The approaches outlined below are 
180  provided as examples that sponsors may consider using.  These approaches are not all inclusive, 
181  and some approaches may be used together.  As the therapeutic armamentarium and the unmet 
182  medical need for serious bacterial diseases are continuously evolving, sponsors are encouraged to 
 
Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products (November 1995) and INDs for 
Phase 2 and Phase 3 Studies:  Chemistry, Manufacturing, and Controls Information (May 2003). 
 
13 See the guidance for industry Microbiology Data for Systemic Antibacterial Drugs  Development, Analysis, and 
Presentation (February 2018). 
 
14 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible.  FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
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183  discuss their development plans early with the Agency.  The following are examples of trial 
184  design considerations. 
185   
186  a.  Noninferiority clinical trials 
187   
188  For serious bacterial diseases for which there are existing treatment options, efficacy of an 
189  investigational drug can be established in a noninferiority trial.15  The active comparator used in 
190  the trial should provide effective therapy for the population enrolled in the clinical trial.  The 
191  clinical trial population should include subjects with illness severity and comorbid conditions 
192  that reflect the patient population with unmet medical need to ensure the generalizability of a 
193  finding of safety and efficacy.  A randomized trial design is needed because both comparative 
194  safety and efficacy evaluations can be performed.  The randomized clinical trial data can be 
195  supported by confirmatory evidence from nonclinical studies demonstrating the activity of the 
196  investigational drug against resistant phenotypes.   
197   
198  Given that the antibacterial drug would be indicated for use only in patients who have limited 
199  treatment options, the characterization of efficacy in a noninferiority trial could be based on a 
200  larger noninferiority margin than is typically recommended in the disease-specific guidances, but 
201  acceptance of the noninferiority margin would depend on the type and degree of unmet need.  
202  Under these circumstances, a drug meeting the margin would still be considered effective 
203  compared with a hypothetical placebo but would retain less than the usual fraction of the efficacy 
204  of the comparator.16  The primary analysis of noninferiority should exclude subjects with 
205  baseline pathogens resistant to the control drug.17   
206   
207  A trial could be enriched to enroll subjects with the pathogen or pathogens of interest.  As new 
208  treatment options have become available, it is now possible to enroll subjects with infection 
209  caused by certain antibacterial drug-resistant phenotypes of interest that are susceptible to both the 
210  active comparator and the study drug.  
211   
212  b.  Superiority clinical trials  
213   
214  An investigational drug can be compared with best-available active control therapy in a single 
215  randomized controlled superiority trial with confirmatory evidence to meet substantial evidence 
216  of effectiveness.  Sponsors should discuss with the FDA the type of trial design, for example, a 
217  trial enrolling subjects who have a particular type of infection (e.g., ventilator-associated 
218  bacterial pneumonia) or who have more than one type of infection (e.g., ventilator-associated 
219  bacterial pneumonia and complicated intra-abdominal infection) and inferential statistical 
220  evaluations for a finding of superiority.   
221   
 
15 The existence of treatment options may not preclude using a flexible development program; please refer to 
comments under Question 16 for further discussion. 
 
16 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016). 
 
17 A hierarchical nested noninferiority/superiority analysis can be considered if a sufficient number of subjects with 
infection caused by bacteria resistant to the control drug are expected to be enrolled in the trial.  See the response in 
Question 4.c., Nested noninferiority/superiority clinical trials. 
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222  Typically, superiority trials compare an investigational drug with an inactive placebo using a 
223  standard statistical significance level to control the risk of falsely declaring efficacy.  However, 
224  in some circumstances, superiority against an active control that is considered best available 
225  therapy is more acceptable.  Best available therapy may be expected to have some treatment 
226  benefit, although there may not be reliable and reproducible evidence to quantify this effect.  In 
227  this situation, a superiority finding using a prospectively planned and agreed upon significance 
228  level corresponding to a less stringent type I error rate could be acceptable as evidence of 
229  efficacy.   
230   
231  A superiority trial design can also be used to test for drug activity against a single species (or a 
232  few species) of bacteria.  A sufficient number of subjects for enrollment in a trial of a particular 
233  type of infection (e.g., ventilator-associated bacterial pneumonia) may not be available.  Subjects 
234  with infections at more than one body site caused by the bacterial species of interest can be 
235  enrolled in the trial, with inferential statistical testing for superiority.18  
236   
237  c.  Nested noninferiority/superiority clinical trials 
238   
239  Subjects can be included in a nested, active-controlled noninferiority/superiority trial design.  In 
240  this trial design, the first step should be to demonstrate noninferiority of the investigational drug 
241  to the control treatment in the population of subjects who have a baseline bacterial isolate 
242  susceptible to the control drug.  If noninferiority is demonstrated, the second step should be to 
243  evaluate superiority in subjects subsequently confirmed to be infected with a baseline bacterial 
244  isolate resistant to the control drug.19  This hierarchical nested design does not require any 
245  multiplicity adjustments to control the overall type I error rate.20  Given the sequential nature of 
246  the preplanned testing, there would be no statistical penalty for the evaluation of superiority if 
247  superiority testing is conducted only after noninferiority is established.  
248   
249  One could consider enriching the trial for pathogens of the resistance phenotype of interest as 
250  long as the comparator drug is likely to be effective as empiric therapy pending culture and 
251  susceptibility results.  Subjects may be randomized to the investigational drug or the control drug 
252  before the availability of the results of antibacterial drug susceptibility testing of the baseline 
253  pathogens.  The trial should include provisions for adjusting the control regimen to provide 
254  appropriate therapy based on the susceptibility test results.  It is essential that adequate 
255  procedures be in place to protect subjects enrolled in this trial from avoidable exposure to less 
256  effective therapy. 
257   
258   
 
18 See the response to Question 17 for additional discussion on labeling considerations. 
 
19 See, for example, the nested noninferiority/superiority design in Infectious Diseases Society of America, 2012, 
White Paper:  Recommendations on the Conduct of Superiority and Organism-Specific Clinical Trials of 
Antibacterial Agents for the Treatment of Infections Caused by Drug-Resistant Bacterial Pathogens, Clin Infect Dis, 
55(8):10311046. 
 
20 See Huque MF, T Valappil, and G Soon, 2014, Hierarchical Nested Design for Demonstrating Treatment Efficacy 
of New Antibacterial Drugs in Patient Populations with Emerging Bacterial Resistance, Stat Med, 33(25):4321
4336. 
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259  5.  Can subjects who have infections at different body sites be enrolled in the same 
260  clinical trial?  If so, what are examples of primary efficacy endpoints and analysis 
261  considerations? 
262   
263  Yes.  Superiority trials may be appropriate when enrollment of subjects with infections across 
264  body sites is preferred for study feasibility; for example, an antibacterial drug with activity 
265  against a single species (or a few species) of bacteria.  Assuming noninferiority margins can be 
266  justified, a noninferiority trial design may be acceptable when closely related infections 
267  associated with similar disease severity and causative pathogens are combined, such as 
268  ventilator-associated bacterial pneumonia and bloodstream infections. 
269   
270  There may be several options to consider for a primary efficacy endpoint across multiple body 
271  sites.  One option is to use different clinical efficacy endpoints based on each body site infection.  
272  Each subject would be counted as a success or failure, depending on the outcome specific to 
273  each body site infection, and results would be examined by each body site (recognizing the 
274  limited numbers available for each site).  Another option for a primary efficacy endpoint is all-
275  cause mortality if the types of infections in the trial are often fatal when untreated. 
276   
277  A more flexible development program that includes a trial enrolling subjects with infections at 
278  different body sites may not be able to identify antibacterial drugs that are less effective in some 
279  body sites compared with others.  There have been several recent instances where unexpected 
280  results from clinical trials revealed reduced performance of an antibacterial drug for the 
281  treatment of severe infections at some body sites.21  Trials should enroll subjects who have 
282  greater severity of illness to address concerns regarding the potential for reduced performance in 
283  some body sites. Sponsors should discuss with the Agency stratified enrollment or other 
284  approaches to ensure that a sufficient number of subjects with infections at certain body sites, 
285  such as the lung, are enrolled.  
286   
287  For example, such a trial of an investigational drug with activity against gram-negative bacteria 
288  could enroll subjects receiving care in an intensive care unit with one of the following different 
289  infections: (1) ventilator-associated bacterial pneumonia, (2) hospital-acquired bacterial 
290  pneumonia requiring mechanical ventilation or nonventilated hospital-acquired bacterial 
291  pneumonia with hypotension and/or bacteremia, (3) complicated intra-abdominal infection plus 
292  hypotension and/or bacteremia, and (4) complicated urinary tract infection plus hypotension 
293  and/or bacteremia.  In this example, we recommend that subjects who have ventilator-associated 
294  bacterial pneumonia or hospital-acquired bacterial pneumonia requiring mechanical ventilation 
295  should comprise approximately 50 percent or more of the total subject population to adequately 
296  represent patients with more severe infections.  Sponsors are encouraged to discuss plans for 
297  multisite studies with the FDA before they begin the trial.  
298   
299  Frequentist or Bayesian modeling approaches for assessing subgroup-specific treatment effects 
300  may be useful in trials designed to enroll subjects with body site infections that have different 
301  severity and associated comorbid conditions.  Modeling approaches provide a measure of 
302  internal consistency of treatment effect among the subgroups of each body site. 
 
21 See Cox E, S Nambiar, L Baden, 2019, Needed: Antimicrobial Development, N Engl J Med. 380(8):783785. 
 
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303   
304  6.  What are examples of statistical approaches or randomization strategies in a flexible 
305  clinical program? 
306   
307  Group sequential designs can be useful and flexible for early stopping based on efficacy or 
308  futility.  Adaptive design clinical trials or trial designs with features, such as those discussed 
309  below, can be considered.22   
310   
311  A cluster randomization strategy is one possible approach that could be explored.  With 
312  appropriate informed consent procedures, cluster randomization may facilitate trial enrollment.  
313  Subjects enrolled at sites randomized to the standard-of-care arm would be treated consistent 
314  with the standard of care at that site, while subjects enrolled at sites randomized to the 
315  investigational drug arm would be treated with the investigational drug.  This strategy is best 
316  suited for trials with a large number of clinical centers, each enrolling a relatively small number 
317  of subjects.  With adequate numbers of clinical centers, randomization should ensure balance 
318  between the treatment groups with respect to both site and subject-level characteristics. 
319   
320  Clinical trial networks also might simplify trial conduct and enhance feasibility for evaluating 
321  new antibacterial drugs.  Innovative clinical trial approaches such as platform or umbrella trials 
322  are also possibilities that could be considered.23 
323   
324  Collaboration between sponsors may assist in the development of antibacterial drugs with spectra 
325  of activity that do not overlap.  For instance, if investigational Drug A and investigational Drug 
326  B are active against different species of bacteria and use of Drug A and Drug B together could be 
327  considered as complete empiric coverage for possible bacterial pathogens causing the infection, 
328  then a trial comparing Drug A plus Drug B to the best-available active control therapy could be 
329  used to evaluate each drug in the prespecified primary analysis populations based on the baseline 
330  bacterial species.  Sponsors pursuing this approach should discuss with the FDA the safety data 
331  that would be needed to assess the individual antibacterial drugs. 
332   
333  Factorial designs are another consideration.  Clinical trials are often conducted in intensive care 
334  units to evaluate interventions whose mechanisms of action differ from antibacterial drugs (e.g., 
335  anti-inflammatory therapies).  A factorial design would simultaneously randomize subjects in 
336  such a trial to one of two different antibacterial drug regimens and one of two different 
337  nonantibacterial interventions, and thus allow the single trial to answer two questions.  Sponsors 
338  interested in using a factorial design should discuss with the FDA whether any interactions are 
339  expected between the antibacterial and nonantibacterial interventions.  
 
22 Clinical trial designs with adaptive features may enhance the efficiency of the trial; sponsors who are considering 
an adaptive design are encouraged to consult the guidance for industry Adaptive Designs for Clinical Trials of Drugs 
and Biologics (December 2019).  
 
23 Some trials may feature an adaptive design that includes several investigational drugs, each as a different 
treatment arm that is compared with a common control arm representing standard-of-care treatment. An example of 
an innovative trial design is the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging 
And MoLecular Analysis 2 (I-SPY 2 TRIAL).  Information about the trial can be found at 
http://www.ispytrials.org/home. 
 
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340   
341  7.  What is the importance of PK/PD (exposure-response) data in a more flexible 
342  development program? 
343   
344  Information on the distribution of MICs for the relevant bacteria based on recent surveillance 
345  data, the results of PK/PD (exposure-response) assessments in animal models, and results from 
346  human PK trials should be integrated to help identify the appropriate dose and frequency of 
347  administration for evaluation in clinical trials.24  In some previously conducted clinical trials, 
348  wider variability in exposure was observed in subjects who were seriously ill, compared with 
349  those who were less seriously ill.  Additionally, increased variability in exposure has also been 
350  noted by the type of infection (e.g., ventilator-associated bacterial pneumonia).  Thus, it is 
351  important that adequate evaluation of the PK and dose justification be provided for patients with 
352  an unmet medical need who have the infection type to be evaluated.  PK information from 
353  humans should include information about the distribution of the drug to the site of action (e.g., 
354  epithelial lining fluid).  Although it is ideal to evaluate drug penetration to the site of action in 
355  the intended patient population, given the challenges of conducting such a study in subjects, the 
356  information on drug penetration to the site of action can be obtained in healthy subjects.  
357  Comparison of human and animal exposure data should include correction for any differences in 
358  plasma protein binding and distribution to the site of action.   
359   
360  Collection of PK data in clinical trials (e.g., sparse sampling in all subjects enrolled in clinical 
361  trials) may help address potential questions about efficacy or safety that arise and help describe 
362  the effects of intrinsic and extrinsic factors on pharmacokinetics and pharmacodynamics.  
363  Patients with serious bacterial diseases with an unmet medical need often have important 
364  comorbidities, notably renal or hepatic impairment, and, therefore, an increased likelihood of 
365  alterations in PK.  An important consideration in drug development is to characterize PK in such 
366  subjects.  For example, understanding the PK of the investigational drug in subjects with renal or 
367  hepatic impairment early in development could facilitate enrollment of such subjects in clinical 
368  trials (e.g., by providing guidance on dosing).    
369   
370  8.  What is the size of the premarketing safety database in a flexible development 
371  program?  
372   
373  The premarketing safety database of an investigational drug should be adequate in light of its 
374  potential benefit.  In general, a safety database for a drug that is the subject of a more flexible 
375  development program should include approximately 300 subjects at the dose and duration of 
376  therapy proposed for marketing.  This safety database could include subjects from all phases of 
377  clinical development and include subjects who do not have an unmet medical need.25   
 
24 See the guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and Regulatory 
Applications (April 2003) and the ICH guidance for industry E4 Dose-Response Information to Support Drug 
Registration (November 1994).   
 
25 Nonclinical data and early safety data can inform the size of the premarketing safety database; see, for example, 
ICH guidances for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential 
for Non-Antiarrhythmic Drugs (October 2005) and E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs  Questions and Answers (R1) (October 2012). 
 
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378   
379   
380  9.  What other safety regulatory requirements should be considered in a flexible 
381  development program? 
382   
383  Section 901 of the Food and Drug Administration Amendments Act of 2007 (Public Law 110-
384  85) created sections 505(o) and 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C 
385  Act).  Section 505(o)(3) of the FD&C Act authorizes the FDA to require certain postmarketing 
386  studies and clinical trials for prescription drug products.26  Section 505-1 authorizes the FDA to 
387  require a risk evaluation and mitigation strategy (REMS) if the FDA determines that a REMS is 
388  necessary to ensure that the benefits of a drug outweigh the risks of the drug.27   
389   
390  As described earlier, a more flexible development program may include a relatively small safety 
391  database.  In some instances, this may lead to uncertainties about findings of a potential serious 
392  risk (e.g., strength of the association of the risk with drug treatment; the rate of occurrence of the 
393  risk).  In these cases, when the approval standard has been met, the FDA may determine that a 
394  postmarketing study or clinical trial is needed to further characterize the risk.   
395   
396  10. Will the FDA accept greater toxicity for drugs that treat patients with a serious 
397  bacterial disease and an unmet medical need?  
398   
399  The safety of a drug is assessed by weighing its risks against its benefits.  Drugs with risks that 
400  would be unacceptable for a broad population may be acceptable for patients with a serious 
401  bacterial disease who do not have other treatment options.  As stated previously, acceptance of 
402  greater uncertainty or higher risk in patients with a serious bacterial disease and an unmet 
403  medical need is an appropriate approach to the risk-benefit assessment.28   
404   
405  11. Does a more flexible development program for antibacterial drugs result in a lower 
406  regulatory standard for drug approval? 
407   
408  No.  Drugs approved on the basis of a more flexible development program must, among other 
409  things, meet the statutory standards for safety and effectiveness set forth in section 505(d) of the 
410  FD&C Act.  A finding of effectiveness must be supported by substantial evidence based on 
411  adequate and well-controlled clinical investigations.29  A finding of safety must be supported by 
 
26 For further information on the FDAs current thinking on this topic, see the draft guidance for industry 
Postmarketing Studies and Clinical TrialsImplementation of Section 505(o)(3) of the Federal Food, Drug, and 
Cosmetic Act (October 2019).  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. 
 
27 For further information on REMS, see the revised draft guidance for industry Format and Content of a REMS 
Document (October 2017).  When final, this guidance will represent the FDAs current thinking on this topic. 
 
28 See 21 CFR part 312, subpart E, Drugs Intended to Treat Life-threatening and Severely-debilitating Illnesses. 
 
29 See section 505(d) of the FD&C Act ([T] the term substantial evidence means evidence consisting of adequate 
and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and 
 
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412  sufficient information (including adequate tests) to determine whether the drug is safe for use 
413  under conditions prescribed, recommended, or suggested in the proposed labeling.30   
414   
415  As noted previously, use of a flexible antibacterial drug development program is consistent with 
416  the philosophy first formally articulated in regulations codified at 21 CFR part 312, subpart E.31  
417  This philosophy reflects the FDAs commitment to expediting the availability of drugs for 
418  serious diseases for patients as soon as it can be concluded that the drugs benefits exceed its 
419  risks, especially when these patients have unmet medical needs, while preserving appropriate 
420  standards for safety and effectiveness.   
421   
422  12. Why is it important for the FDA and for sponsors to emphasize to the health care 
423  community the risks and benefits of drugs developed under a more flexible 
424  development program for the treatment of serious bacterial diseases in patients with 
425  an unmet medical need? 
426   
427  To obtain approval, a sponsor must, among other things, demonstrate that the drug is safe and 
428  effective for use under the conditions prescribed, recommended, or suggested in its labeling 
429  (section 505(d)(1) of the FD&C Act).  Therefore, drug labeling should identify the approved 
430  indication, including the targeted patient population.  Furthermore, it is important to emphasize 
431  the following points:   
432   
433    Product labeling for such drugs should include not only the known risks and benefits of 
434  the drug but also a description of the limitations of the available information that 
435  supported approval 
436   
437    It is important for the health care community to be informed on how to use the drug 
438  appropriately (i.e., make clear the approved patient population for which the FDA has 
439  determined the benefits of the drug outweigh the risks) 
440   
441    Postmarketing monitoring (or, in some cases, continued development of the drug) can 
442  help to further define the drugs safety and efficacy profile (see the responses to 
443  Questions 9 and 11) 
444   
445  For all drugs, but particularly for drugs approved with a smaller safety database, important 
446  findings regarding safety may first become apparent in the postmarketing period.   
 
experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be 
concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions 
of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.  If the Secretary 
determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and 
confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the 
Secretary may consider such data and evidence to constitute substantial evidence for the purposes of the preceding 
sentence.).  See also the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and 
Biological Products (May 1998). 
 
30 See section 505(d)(1) of the FD&C Act. 
 
31 See 21 CFR 312.80. 
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447   
448  13. Is the animal rule an appropriate consideration for a more flexible development 
449  program? 
450   
451  When human clinical effectiveness trials can be conducted, drugs are not eligible for approval 
452  under the so-called animal rule, a term that refers to the regulatory pathway set forth in 21 CFR 
453  part 314 subpart I (or, for biologics, 21 CFR part 601 subpart H) for approving drugs when 
454  human efficacy studies are not ethical or feasible.  
455   
456  14. What is the role of a rapid diagnostic in more flexible antibacterial drug 
457  development programs? 
458   
459  The use of bacterial detection methods, such as urinary antigen tests, serology, and polymerase 
460  chain reaction, may help identify the baseline bacterial pathogen or pathogens.  These methods 
461  could be particularly helpful for drugs that have a narrow spectrum of activity (e.g., drugs 
462  active against a single species or a few species within a genus).   
463   
464  The clinical trial for a candidate antibacterial drug may provide an opportunity to contribute to 
465  the development and evaluation of a new diagnostic test.  Sponsors are encouraged to discuss 
466  these approaches with the Agency and the appropriate review division in the Center for Devices 
467  and Radiological Health.    
468   
469  15. Can an antibacterial drug approved for patients with an unmet medical need using 
470  a flexible development program be subsequently developed for other indications? 
471   
472  Yes, a sponsor can use a flexible development approach to obtain approval of an indication that 
473  addresses an unmet medical need, and subsequently develop the drug for other indications.  
474  Depending on the indication, a flexible or a traditional development approach may be used.  
475   
476  16. Does the approval of one drug for the treatment of a serious bacterial disease in 
477  patients with an unmet medical need preclude approval of another drug for the 
478  same indication using a flexible development program? 
479   
480  No.  The approval of an antibacterial drug for the treatment of serious bacterial diseases in 
481  patients with an unmet medical need does not necessarily preclude the development of a 
482  subsequent drug for the same or similar indication using a flexible development program.  
483  Provided below are some examples for when an antibacterial drug may be considered to address 
484  an unmet medical need when there is an already approved treatment for the same indication: 
485   
486    The first drug approved has serious adverse effects limiting its use. 
487   
488    The adverse effects of the approved drug could affect its utility in certain subpopulations 
489  (e.g., a drug with the potential to cause nephrotoxicity would be a less than ideal choice 
490  in a patient with impaired renal function).  A subsequent drug with a different adverse 
491  effect profile could provide a treatment option for these patients. 
492   
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493    The approval of more than one therapy addresses an emerging or anticipated public 
494  health need, such as a drug shortage or the development of antibacterial resistance.  For 
495  instance, a drug may have a novel mechanism of action and not be affected by existing 
496  mechanisms of resistance.  
497   
498  17. Are there special considerations for the product labeling? 
499   
500  The labeled indication for a drug approved under a flexible development program should reflect 
501  the patient population for which the drug is approved (e.g., the patient population with a serious 
502  infection caused by a bacterial pathogen that the drug is intended to treat for which the patient has 
503  no treatment options or limited alternative treatment options available).  The INDICATIONS 
504  AND USAGE section should also summarize the limitations of available data that supported the 
505  approval (e.g., limited efficacy and/or safety data).32  If the development program is based on 
506  trials that enroll subjects with infections at different body sites, as discussed in Questions 4(b) 
507  and 5, then the indication or indications may depend on numbers of subjects enrolled with 
508  different diseases, results in disease-specific subgroups, and consistency of effects across these 
509  subgroups. 
510   
511  The following example represents wording for an indication based on use of a flexible 
512  development program for patients who have a serious infection in the setting of limited 
513  therapeutic options or no alternative treatment options: 
514   
515  DRUG-X is indicated, in [age groups (e.g., adult)] patients [who have limited or no 
516  alternative treatment options (include as appropriate)] for the treatment of [serious bacterial 
517  diseases such as hospital-acquired bacterial pneumonia, ventilator-associated bacterial 
518  pneumonia, complicated intra-abdominal infections, complicated urinary tract infections 
519  (include as appropriate)] caused by the following susceptible microorganism(s): [list the 
520  genus and species of the bacterial pathogen(s)].  Approval of this indication is based on 
521  [summarize the limitations of available data that supported the approval].  
522   
523  The FDA has issued a final guidance regarding LPAD, including specific labeling-related 
524  information.33,34 
525   
 
32 Sponsors are obligated to comply with the content and format requirements of labeling for antibacterial drugs 
under 21 CFR 201.24, 201.56(d), and 201.57.  See the guidance for industry Labeling for Human Prescription Drug 
and Biological ProductsImplementing the PLR Content and Format Requirements (February 2013). 
 
33 See section 506(h)(3)(A) of the FD&C Act (as amended by the 21st Century Cures Act). 
 
34 See the guidance for industry Limited Population Pathway for Antibacterial and Antifungal Drugs. 
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