Pulmonary Tuberculosis:  
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Ramya Gopinath at 
Ramya.Gopinath@fda.hhs.gov.  
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2022 
Clinical/Antimicrobial 
Revision 1 
16856dft.docx 
12/09/22   
Pulmonary Tuberculosis:  
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  
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) 
 
December 2022 
Clinical/Antimicrobial 
Revision 1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  General Considerations ................................................................................................................. 2 
1. Early Phase Clinical Development Considerations ......................................................................... 2 
a.  EBA ........................................................................................................................................... 3 
b.  Phase 2 evaluations ................................................................................................................... 3 
2. Efficacy Considerations ................................................................................................................... 3 
3. Safety Considerations ...................................................................................................................... 3 
B.  Specific Efficacy Trial Considerations ......................................................................................... 4 
1. Trial Designs .................................................................................................................................... 4 
2. Trial Population ............................................................................................................................... 5 
3. Inclusion and Exclusion Criteria ..................................................................................................... 6 
4. Randomization, Stratification, and Blinding .................................................................................... 7 
5. Specific Populations......................................................................................................................... 7 
a.  Pediatric populations ................................................................................................................. 7 
b.  Pregnant females ....................................................................................................................... 8 
c.  Other specific populations ......................................................................................................... 9 
6. Dose Selection .................................................................................................................................. 9 
7. Choice of Comparators .................................................................................................................... 9 
8. Efficacy Endpoints ........................................................................................................................... 9 
9. Trial Procedures and Timing of Assessments ................................................................................ 11 
a.  Entry visit ................................................................................................................................ 11 
b.  Visits during therapy and after therapy completion ................................................................ 12 
10.  Statistical Considerations .......................................................................................................... 12 
11.  Accelerated Approval Considerations ....................................................................................... 13 
C.  Other Considerations ................................................................................................................... 13 
1. Microbiological Considerations .................................................................................................... 13 
a.  In vitro studies ......................................................................................................................... 13 
b.  In vivo (animal models) .......................................................................................................... 14 
c.  Drug resistance and cross-resistance ....................................................................................... 14 
d.  Types of culture media to identify M. tuberculosis ................................................................ 15 
e.  Differentiate relapse from reinfection or new infection .......................................................... 15 
2. Relevant Nonclinical Safety Considerations .................................................................................. 15 
3. PK/PD Considerations................................................................................................................... 16 
a.  Phase 1/phase 2 PK trials ........................................................................................................ 16 
b.  Drug interactions ..................................................................................................................... 16 
c.  Exposure response ................................................................................................................... 17 
d.  In vitro hollow fiber system models ....................................................................................... 17 
4. Foreign Clinical Data .................................................................................................................... 17 
5. Data standards for TB ................................................................................................................... 17 
6. Labeling Considerations ................................................................................................................ 18 
REFERENCES ............................................................................................................................ 19 
APPENDIX .................................................................................................................................. 21 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Pulmonary Tuberculosis:   
2  Developing Drugs for Treatment 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  The purpose of this guidance is to assist sponsors in the clinical development of investigational 
18  drugs for the treatment of pulmonary tuberculosis (TB) under section 505 of the Federal Food, 
19  Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355 and FDA regulations at 21 CFR part 312 
20  and part 601.2  Specifically, this guidance provides the FDAs current recommendations 
21  regarding the overall development program for a new investigational drug or drugs to be used in 
22  combination with approved drugs or as a new treatment regimen that includes one or more 
23  investigational drugs to support an indication for the treatment of pulmonary TB.  This guidance 
24  does not address the development of drugs for latent TB infection or for extrapulmonary TB. 
25   
26  Sponsors should also refer to the guidance for industry Codevelopment of Two or More New 
27  Investigational Drugs for Use in Combination (June 2013).3  Sponsors are encouraged to discuss 
28  with FDA the programs and pathways facilitating drug development that might be applicable for 
29  their development program.4  
30   
31  This guidance revises and replaces the draft guidance for industry of the same name issued in 
32  November 2013.  This revision includes more detail regarding nonclinical models, early phase 
33  studies, and trial design considerations, including the demonstration of efficacy using superiority 
34  or noninferiority (NI) trial designs.  Additionally, updates are made regarding inclusion of 
35  pediatric subjects in trials, endpoint and safety considerations, and labeling.  The Appendix 
36  containing the NI margin justification has also been updated. 
 
1 This guidance has been prepared by the Division of Anti-Infectives in the Center for Drug Evaluation and 
Research 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 unless otherwise specified. 
 
3 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 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014). 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
37   
38  This guidance does not contain discussion of the general issues of statistical analysis or clinical 
39  trial design.  Those topics are addressed in the International Council for Harmonisation (ICH) 
40  guidances for industry E9 Statistical Principles for Clinical Trials (September 1998) and E10 
41  Choice of Control Group and Related Issues in Clinical Trials (May 2001) (ICH E10), 
42  respectively. 
43   
44  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
45  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
46  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
47  the word should in Agency guidances means that something is suggested or recommended, but 
48  not required.  
49   
50   
51  II.  BACKGROUND 
52   
53  Infections caused by Mycobacterium tuberculosis (M. tuberculosis) are diagnosed in the United 
54  States and are endemic in many parts of the world.  Resistance to multiple drugs and coinfection 
55  with human immunodeficiency virus (HIV) pose challenges in the management of TB.  Drugs 
56  with new mechanisms of action, improved safety profiles, fewer drug-drug interactions, and 
57  treatment-shortening combination regimens are needed to manage TB.   
58   
59   
60  III.  DEVELOPMENT PROGRAM 
61   
62  A.  General Considerations 
63   
64  1.  Early Phase Clinical Development Considerations 
65   
66  Nonclinical evaluations provide valuable information for the development of investigational 
67  drugs (see section III.C.1., Microbiology Considerations, section III.C.2., Relevant Nonclinical 
68  Safety Considerations, and section III.C.3., PK/PD Considerations).  
69   
70  Activity of antimycobacterial drugs can be evaluated in trials of early bactericidal activity (EBA) 
71  and/or in phase 2 trials that evaluate microbiological outcomes at early time points.  For a 
72  combination regimen, the sponsor should evaluate the contribution of each drug to the treatment 
73  effect.5 This can be evaluated in phase 2 clinical development and in nonclinical studies (see 
74  section III.C.1., Microbiology Considerations).  Treatment of pulmonary TB includes more than 
75  one drug in a treatment regimen, and sponsors may be developing more than one investigational 
76  drug as part of a new combination regimen.  Sponsors should consult with the Agency early in 
77  development regarding plans to demonstrate the contribution of the investigational drug(s) as 
78  part of a combination regimen. 
79   
 
5 The recommendations in this guidance are relevant to demonstrating the contribution of the individual new 
investigational drugs to the effect(s) of the combination regimen and are consistent with the requirements of 21 CFR 
300.50, Fixed-combination prescription drugs for humans. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
80  a.  EBA 
81   
82  If applicable to the investigational drug under study, EBA trials evaluating the quantitative 
83  counts of viable M. tuberculosis from daily collections of sputum can provide information on the 
84  bactericidal activity of antimycobacterial drugs.  These trials are intended to evaluate 
85  antimycobacterial activity of investigational drugs alone or in combination over a brief time 
86  course (e.g., 7 to 14 days).  EBA trials can provide preliminary evidence for the contribution of 
87  each drug to the treatment effect of the combination regimen.  Appropriate subjects for 
88  enrollment in EBA trials include immunocompetent subjects, treatment-naive adult subjects at 
89  low risk of infection with drug-resistant TB, and subjects with no evidence of extra-pulmonary 
90  disease, who can begin standard-of-care treatment for pulmonary TB at the completion of the 
91  EBA trial.   
92   
93  b.  Phase 2 evaluations 
94   
95  Sponsors should conduct phase 2 trials to assess the antimycobacterial activity of an 
96  investigational drug regimen.  In addition, if feasible, a phase 2 development program should 
97  include a dose ranging study or studies to assist in determining the most appropriate dose 
98  regimen to be taken into phase 3.  Phase 2 exploratory endpoints can include, but are not limited 
99  to, the following: (1) 8-week evaluation for absence of acid-fast bacilli (AFB) in sputum; (2) 
100  time to sputum culture negativity for M. tuberculosis; (3) symptom improvement; and/or (4) a 
101  biomarker intended to predict clinical benefit.  The Agency recommends that as part of phase 2 
102  trial designs, sponsors include long-term follow-up with collection of clinical endpoints in 
103  addition to earlier time points. 
104   
105  2.  Efficacy Considerations 
106   
107  An investigational drug can be evaluated for efficacy when added to combination regimens of 
108  already approved drugs.  Additionally, an entirely new combination regimen comprised of 
109  investigational drugs can be evaluated for efficacy.  A single adequate and well-controlled trial 
110  in subjects with pulmonary TB, supported by other confirmatory evidence (e.g., evidence of 
111  antimycobacterial activity from nonclinical data, EBA, and phase 2 trials), may provide evidence 
112  of effectiveness when the single trial demonstrates a clinically meaningful and statistically robust 
113  treatment effect.6  See section III., B., Specific Efficacy Trial Consideration, below for further 
114  discussion regarding efficacy considerations. 
115   
116  3.  Safety Considerations 
117   
118  The evaluation of the safety profile of an investigational drug can be challenging because 
119  patients with pulmonary TB often have comorbid conditions.  Sponsors should evaluate potential 
120  drug-drug interactions that may occur during coadministration with other antimycobacterial 
121  drugs or other concomitant medications (e.g., antiretroviral drugs).   
 
6 See the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products (December 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. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
122   
123  Hepatotoxicity and QT interval prolongation are common adverse reactions with 
124  antimycobacterial drugs.  Sponsors should evaluate investigational drugs for their potential to 
125  cause hepatotoxicity, QT prolongation, and arrhythmias.7, 8  
126   
127  Sponsors should discuss the size of the preapproval safety database with the FDA during drug 
128  development.  For assessment of risks and benefits in subjects with an unmet medical need, a 
129  smaller safety database of approximately 300 subjects treated at (or greater/longer than) the 
130  proposed intended dose and duration may be sufficient. If safety signals are identified, a larger 
131  safety database may be needed. 
132   
133  B.  Specific Efficacy Trial Considerations 
134   
135  1.  Trial Designs 
136   
137  Sponsors can use the following trial designs to demonstrate superiority:  
138   
139    A regimen that includes one or more investigational drugs is compared to a standard 
140  regimen, with efficacy demonstrated by showing superiority of the investigational drug 
141  regimen over the standard regimen.9   
142   
143    The investigational drug(s) plus the optimized background regimen (OBR) is compared 
144  to the matching placebo plus the OBR, with efficacy demonstrated by showing 
145  superiority of the investigational drug regimen over the placebo-containing regimen.  
146  Optimized background antimycobacterial treatment should be based on epidemiologic 
147  information and in vitro susceptibility testing, when available.   
148   
149  Sponsors can use the following trial designs to demonstrate NI:  
150   
151    An investigational drug regimen is compared to a standard regimen.  NI would be 
152  demonstrated by showing that the investigational regimen performs within a prespecified 
153  margin of the performance of the standard regimen. 
154   
155    The investigational drug replaces one of the drugs in a standard combination regimen.  
156  The investigational drug regimen should perform within an acceptable NI margin that is 
157  based on the known quantitative and reliable contribution of the drug that has been 
 
7 See the guidance for industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation (July 2009). 
 
8 See the ICH guidances for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs (October 2005); E14 Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs  Questions and Answers (R3) (June 2017);  S7B 
Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by 
Human Pharmaceuticals (October 2005); and M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical 
Trials and Marketing Authorization for Pharmaceuticals (January 2010). 
 
9 See the guidance for industry Codevelopment of Two or More New Investigational Drugs for Use in Combination.  
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
158  replaced to the standard regimen.  This NI trial design determines the efficacy 
159  contribution of the investigational drug to the regimen. 
160   
161  Interpretation of the results of an NI trial relies on a justified NI margin.  This margin, which is 
162  highly dependent on the specific design of the NI trial, including the control regimen, is based, in 
163  part, on data from previously conducted trials to evaluate for historical evidence of sensitivity to 
164  drug effects (HESDE) and estimate the effect of the active control.10  The Appendix contains an 
165  example of an NI margin justification for a trial of a 4-month regimen for drug-susceptible TB.   
166   
167  The FDA has not estimated an exact numerical treatment effect for the standard regimen of 2 
168  months of treatment with ethambutol, isoniazid, rifampin, and pyrazinamide followed by 4 
169  months of treatment with isoniazid and rifampin (abbreviated terminology: 2EHRZ/4HR) for 
170  patients with drug-susceptible pulmonary TB.  However, considering the historical data on 
171  management and outcomes of patients with pulmonary TB in the era before antibacterial drug 
172  therapy and the highly successful results following treatment with 2EHRZ/4HR, there is support 
173  for the selection of an NI margin based on the large degree of clinical benefit.  For example, 
174  given that the success rates of 2EHRZ/4HR exceed 90 percent, the numerical treatment effect is 
175  likely to far exceed 10 percent (Nahid et al. 2016).  Therefore, based on clinical judgement, a 10 
176  percent NI margin is clinically relevant and has appropriate preservation of the treatment effect 
177  for an NI trial to determine the efficacy of an investigational drug regimen as a whole based on 
178  comparison to this 6-month standard regimen.  
179   
180  Depending on the new investigational drug regimen, study design of the NI trial, potential impact 
181  (e.g., ability to fulfill an unmet medical need), and safety profile of the regimen, it may be 
182  appropriate to set a wider NI margin and still plan for a trial design that is feasible and provides a 
183  reasonable preapproval safety database.  The Agency encourages sponsors to discuss their 
184  clinical trial designs and NI margin justifications with the FDA.11 
185   
186  For both superiority trials and NI trials that assess the activity of the investigational drug regimen 
187  as a whole, the sponsor will also need to address the added contribution of the components of the 
188  regimen.9  This may be accomplished through nonclinical trials, EBA studies, phase 2 trials 
189  and/or as part of the pivotal efficacy trials. 
190   
191  2.  Trial Population 
192   
193  The trial population should include adult subjects and if appropriate, pediatric subjects with 
194  pulmonary TB.  The presence of extrapulmonary disease may require longer durations of 
195  treatment than pulmonary TB and assessment of endpoints that evaluate the extrapulmonary 
196  site(s).  Trials can include subjects with either drug-susceptible or drug-resistant pulmonary TB 
197  depending on the anticipated effectiveness of the antimycobacterial drugs being evaluated. 
198   
 
10 See ICH E10 for a discussion of HESDE. 
 
11 See also the article Four-Month Moxifloxacin-Based Regimens for Drug-Sensitive Tuberculosis (Gillespie et al. 
2014). 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
199  Protocols should specify how subjects will be handled after in vitro susceptibility results are 
200  available, both in the conduct of the trial and in the analysis of the results.  
201   
202  Enrichment strategies regarding trials for drug-resistant TB can include a focus on contacts of 
203  subjects with drug-resistant TB, subjects from areas with a high prevalence of drug resistance, 
204  subjects who relapse after previous treatment, and subjects with disease progression on a 
205  standard regimen.   
206   
207  3.  Inclusion and Exclusion Criteria 
208   
209  The FDA recommends the following inclusion criteria for subjects with pulmonary TB: 
210   
211    Presence of AFB in a sputum specimen detected by smear microscopy or other rapid 
212  diagnostic test.  Microbiological diagnosis of TB should be confirmed by culture from at 
213  least one sputum sample obtained at the time of enrollment. 
214   
215    Chest radiographic findings consistent with active pulmonary TB, for example, cavitary 
216  lesions, apical or other infiltrates, or hilar lymphadenopathy. 
217   
218    A minimum of two of the following signs or symptoms that have been present for at least 
219  2 weeks: 
220   
221   Sputum production 
222   
223   Cough 
224   
225   One or more episodes of hemoptysis 
226   
227   Fever (e.g., oral temperature greater than or equal to 38.0 degrees Celsius on at least 
228  two occasions) 
229   
230   Pleuritic chest pain 
231   
232   Weight loss 
233   
234   Night sweats 
235   
236  Use of rapid diagnostic or nonculture tests may help identify a subject for enrollment in a TB 
237  trial.  If the tests being used are not FDA cleared, sponsors should provide sufficient information 
238  about the performance characteristics of the tests determined from analytical validation studies. 
239   
240  The FDA recommends the following as exclusion criteria for subjects with pulmonary TB: 
241   
242    One or more weeks of therapy for the current episode of active TB (unless being enrolled 
243  in a trial targeting drug-resistant TB and there is documented lack of response to therapy 
244  based on clinical and microbiological findings) 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
245   
246    Significant concurrent illness other than HIV (e.g., lung cancer) that may affect outcome 
247  assessment 
248   
249    Unwillingness to comply with recommendations from local public health authorities for 
250  the management of patients with pulmonary TB 
251   
252  4.  Randomization, Stratification, and Blinding 
253   
254  Trials should be randomized and double-blind unless a sponsor can provide a scientifically 
255  adequate explanation why blinding cannot be accomplished.  If trials are single blind or open 
256  label, sponsors should discuss potential biases with the FDA and how these biases will be 
257  addressed.  If the trial cannot be fully blinded, the sponsor should maintain the maximum 
258  possible level of blinding within the trial with blinded assessors, blinded databases until database 
259  lock, etc.  
260   
261  Sponsors should consider stratification of subjects based on certain baseline characteristics (e.g., 
262  by the presence or absence of cavitary disease, HIV infection).  The sponsor should include in 
263  the protocol a discussion of how the analyses will account for the stratified randomization.12 
264   
265  5.  Specific Populations 
266   
267  a.  Pediatric populations 
268   
269  The FDA encourages sponsors to begin discussions about their pediatric clinical development 
270  plans as early as is feasible.  The additional safeguards of 21 CFR part 50, subpart D, for 
271  enrolling children in clinical investigations, affect the timing and design of trials that support 
272  pediatric drug development.  In accordance with these requirements, sponsors can enroll 
273  pediatric subjects in trials if sufficient safety, antimycobacterial activity, pharmacokinetic (PK), 
274  and efficacy data in adult subjects are available and appropriate dosing regimens for pediatric 
275  subjects have been characterized.13  Sponsors can include adolescent subjects with pulmonary 
276  TB in phase 3 clinical trials, if appropriate.14 
277   
278  Sponsors must submit pediatric study plans no later than 60 calendar days after the date of the 
279  end-of-phase 2 meeting or another time as agreed upon by the FDA and the sponsor unless the 
 
12 See the draft guidance for industry Adjusting for Covariates in Randomized Clinical Trials for Drugs and 
Biological Products (May 2021).  When final, this guidance will represent the FDAs current thinking on this topic.   
 
13 For example, see the article Towards Earlier Inclusion of Children in Tuberculosis (TB) Drug Trials: Consensus 
Statements from an Expert Panel (Nachman et al. 2015). 
 
14 See the guidance for industry Development of Anti-Infective Drug Products for the Pediatric Population 
(December 2021). 
 
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
280  investigational drug has been granted an orphan designation.15  Pediatric formulation 
281  development should begin as soon as results from the adult phase 2b trials are known and the 
282  sponsor has determined an appropriate dosing regimen.  
283   
284  Extrapolation of adult efficacy for the treatment of pulmonary TB to pediatric populations is 
285  acceptable for most pediatric populations, with the exception of very young children, who have 
286  different clinical and pathophysiologic characteristics.  Sponsors should provide PK and safety 
287  information in a sufficient number of pediatric subjects to support the appropriate dose for 
288  treatment of children with pulmonary TB.  Cohorts for pediatric studies can be defined based on 
289  chronological age or weight-based criteria, particularly for oral drugs.  Studies of drugs across 
290  the pediatric spectrum of ages/weights can be conducted in parallel rather than sequentially 
291  unless there are specific safety or PK properties that warrant a different approach.  If existing 
292  animal studies have identified potential developmental concerns for target organs (toxicology or 
293  pharmacology), juvenile animal toxicity testing may be appropriate.16, 17 
294   
295  Pediatric development plans for new TB investigational drugs could include children living with 
296  HIV provided there are no safety or drug-drug interaction issues that cannot be managed.  
297   
298  Sponsors should discuss their pediatric development programs with the FDA, especially if they 
299  include very young children (e.g., those younger than 5 years of age) because of differences in 
300  clinical manifestations (e.g., increased likelihood of extrapulmonary disease) and 
301  pathophysiologic characteristics.  
302   
303  b.  Pregnant females 
304   
305  Sponsors can include pregnant females in clinical trials once all female reproduction toxicity 
306  studies and the standard battery of genotoxicity tests have been conducted.18  Infants born to 
307  female subjects who received the investigational drug(s) should be followed by investigators for 
308  an appropriate length of time; sponsors should discuss the duration with the FDA before trial 
309  conduct.19   
 
15 See section 505B(e)(2)(A) of the FD&C Act (21 U.S.C. 355c(e)(2)(A)).  For additional information, see the 
guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans 
and Amended Initial Pediatric Study Plans (July 2020) and the ICH guidance for industry E11 Clinical Investigation 
of Medicinal Products in the Pediatric Population (December 2000). 
 
16 See the guidance for industry Nonclinical Safety Evaluation of Pediatric Drug Products (February 2006). 
 
17 We support the principles of the 3Rs (reduce, refine, and replace) for animal use in testing when feasible.  We 
encourage sponsors to consult with the review division when considering using a nonanimal testing method they 
believe is suitable, adequate, validated, and feasible.  We will consider if such an alternative method could be 
assessed for equivalency to an animal test method.   
 
18 See the draft guidance for industry Pregnant Women: Scientific and Ethical Considerations for Inclusion in 
Clinical Trials (April 2008).  When final, this guidance will represent the FDAs current thinking on this topic. 
 
19 For recommendations regarding treatment of women during pregnancy or breastfeeding, see the American 
Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America 
guidelines for treatment of TB (Nahid et al. 2016), available at 
https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm.  
8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
310   
311  c.  Other specific populations 
312   
313  Sponsors should include in trials geriatric subjects,20 subjects with renal insufficiency, diabetes 
314  mellitus, and subjects with hepatic impairment, if feasible.  Because of the high incidence of TB 
315  in patients coinfected with HIV, subjects with HIV should be included in trials.   
316   
317  6.  Dose Selection 
318   
319  When selecting a dosing regimen to be evaluated in phase 3 clinical trials, sponsors should 
320  consider target PK/pharmacodynamic (PD) parameters (e.g., area under the curve/minimum 
321  inhibitory concentration (MIC), maximal concentration/MIC, time above the MIC) based on 
322  in vitro models (see section III.C.1.a., In vitro studies) and animal models of TB, results from 
323  early clinical trials (e.g., EBA and/or trials of AFB clearance from sputum at early time points), 
324  and results from exposure-response evaluations.  PK/PD evaluations should include evaluations 
325  based on free drug concentrations. 
326   
327  7.  Choice of Comparators 
328   
329  The choice of comparator or background regimen depends in part on the subject population that 
330  the sponsor will enroll in the trial (e.g., the likelihood of infection with drug-susceptible or drug-
331  resistant M. tuberculosis).  In general, sponsors should choose comparator regimens that contain 
332  FDA-approved drugs and represent standard of care.  Before trial initiation, sponsors should 
333  discuss with the FDA the use of comparator regimens based on local practice outside of the 
334  United States, or the use of drugs that are not FDA-approved. 
335   
336  8.  Efficacy Endpoints 
337   
338  Sponsors can use the following efficacy endpoints in clinical trials of investigational drugs 
339  intended to treat pulmonary TB: 
340   
341    A primary clinical efficacy endpoint that is comprised of survival and evaluation of 
342  M. tuberculosis growth on serial sputum culture examinations at a fixed time point 
343  following randomization for all treatment arms and includes a period of follow-up 
344  after completion of the planned treatment period.  The FDA defines clinical success 
345  and failure as follows:  
346   
347  Clinical success is assigned to subjects who are alive, achieved M. tuberculosis culture 
348  negativity on serial sputum examinations, did not experience relapse or recurrence of 
349  pulmonary TB, and otherwise did not meet a definition of clinical failure.  In general, 
 
20 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). 
9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
350  protocol-defined serial sputum examinations should occur every 2 weeks or once a month 
351  during treatment, and every 3 months following completion of treatment.21 
352   
353  Clinical failure is defined as having one or more of the following: 
354   
355   Protocol-defined clinical progression of pulmonary disease during treatment  
356   
357   Switch in antimycobacterial therapy because of tolerability issues or clinical 
358  progression of pulmonary TB 
359   
360   Signs or symptoms of active TB, including radiographic worsening compared to 
361  baseline findings, resulting in reinitiation of antimycobacterial therapy during 
362  follow-up22 
363   
364   Death during treatment or follow-up 
365   
366   Growth of M. tuberculosis on sputum culture outlined as follows: 
367   
368    Failure to achieve M. tuberculosis culture negativity in serial sputum specimens 
369  during the treatment period 
370   
371    Failure to maintain culture negative status after a specific time point defined in 
372  the trial (in general, this is expected to be any time after two consecutive negative 
373  sputum cultures, taken at least 28 days apart) on therapy or in follow-up 
374   
375   Any growth of M. tuberculosis from an extrapulmonary site during the trial 
376   
377    A surrogate endpoint based on results of M. tuberculosis sputum cultures during 
378  treatment.  Demonstration of treatment effect on sputum culture conversion from 
379  positive to negative during treatment, either as a time-to-conversion analysis or at a fixed 
380  time point (e.g., at 2 months from randomization), could be considered as surrogate 
381  endpoints reasonably likely to predict clinical benefit under the accelerated approval 
382  statutory and regulatory provisions.23  Additional considerations related to accelerated 
383  approval regarding verification and description of clinical benefit, including the 
384  durability of the treatment effect are discussed in section III.B.11., Accelerated Approval 
385  Considerations.  Sponsors should obtain serial cultures at specific time points during 
386  treatment (e.g., every 2 weeks or every month).  The time to sputum culture conversion is 
387  the time to the first sterile culture, verified by M. tuberculosis culture negativity in at 
 
21 The protocol-defined timing of serial examinations of sputum for culture may differ from clinical practice, which 
often depends on local treatment guidelines and respiratory isolation procedures.   
 
22 In some circumstances, antimycobacterial therapy may be restarted though there is diagnostic uncertainty whether 
relapse has occurred, but therapy is subsequently stopped when an alternative diagnosis is established.  Protocols 
should define the duration of retreatment therapy that will be used to define clinical failure to avoid labeling all trial 
subjects in this situation as failures. 
 
23 Section 506(c) of the FD&C Act and 21 CFR 314.510 or 21 CFR 601.41. 
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388  least two subsequent consecutive sputum specimens taken at least 14 days apart (e.g., 
389  three consecutive negative sputum cultures).  Sputum cultures can be evaluated on either 
390  solid or liquid media (see section III.B.11., Accelerated Approval Considerations).  
391   
392    Secondary and exploratory endpoints.  Sponsors should consider the following: 
393   
394   A well-defined and reliable evaluation of symptoms, which can be included in the 
395  clinical trial as a secondary or exploratory endpoint.  Of note, symptom evaluation in 
396  certain patient populations may be more difficult to interpret, for example, among 
397  patients coinfected with HIV who experience immune reconstitution inflammatory 
398  syndrome or non-HIV-infected individuals with paradoxical reactions (Rangaka et al. 
399  2012).  
400   
401   Molecular or other biochemical evaluations to ascertain whether a positive culture for 
402  M. tuberculosis after drug treatment represents relapse or reinfection (e.g., an 
403  exploratory endpoint analysis that treats relapse of the baseline M. tuberculosis 
404  infection as a failure of the original study treatment and treats reinfection with a new 
405  M. tuberculosis isolate as a success of the original study treatment). 
406   
407  9.  Trial Procedures and Timing of Assessments 
408   
409  a.  Entry visit 
410   
411  Sponsors should obtain baseline demographic information, current medications, and complete 
412  physical examinations at the entry visit.  In addition, sponsors should obtain the following at 
413  entry: 
414   
415    Clinical signs and symptoms of pulmonary TB (e.g., cough, sputum production, episodes 
416  of hemoptysis, fever, pleuritic chest pain, weight loss, night sweats). 
417   
418    Baseline safety laboratory evaluations. 
419   
420    HIV serology and, if HIV positive, viral load and CD4 cell count. 
421   
422    Imaging results (standard posterior to anterior view and lateral chest radiographs or 
423  computed tomography scans) describing the extent and severity of pulmonary disease. 
424   
425    Sputum specimens for AFB smears and mycobacterial culture obtained by one of the 
426  following: spontaneous expectoration, induction with hypertonic saline, bronchoscopy, or 
427  gastric lavage (e.g., for pediatric subjects).  When applicable, baseline specimens for 
428  quantitative cultures should be collected in a standardized manner (e.g., single early 
429  morning induced sputum, pooled 24-hour sputum). 
430   
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431  b.  Visits during therapy and after therapy completion 
432   
433  In general, clinical assessments should occur weekly or biweekly during the first months of 
434  therapy, followed by monthly assessments until therapy completion.  After completion of 
435  therapy, assessments should occur approximately every 3 months until the assessment of the 
436  primary efficacy endpoint is complete (e.g., at 12 months after randomization).  Assessments of 
437  signs and symptoms, adverse effects, and laboratory tests, as appropriate, should occur at these 
438  visits.  In addition, targeted physical examinations should be performed.   
439   
440  During therapy, sponsors should obtain sputum specimens for AFB smears and culture at least 
441  monthly.  Depending on the investigational drug regimen and design, a shorter interval between 
442  specimen collections (e.g., 2 weeks) may be appropriate for certain periods of the trial.  
443   
444  If subjects are not able to expectorate sputum spontaneously at follow-up visits after therapy 
445  completion, sponsors should consider other methods to obtain sputum (e.g., sputum induction). 
446   
447  10.  Statistical Considerations 
448   
449  In general, the sponsor should include in the protocol a detailed statistical analysis plan stating 
450  the trial hypotheses and the efficacy analysis methods.   
451   
452  Sponsors should consider the following definitions of analysis populations: 
453   
454    Safety population:  all subjects who received at least one dose of the investigational 
455  drug during the trial. 
456   
457    Intent-to-treat (ITT) population:  all randomized subjects. 
458   
459    Microbiological ITT (micro-ITT) population:  all randomized subjects with a positive 
460  culture for M. tuberculosis from a pretreatment prerandomization sample.  For trials 
461  intended to focus on subjects with drug-resistant TB, sponsors can choose for the primary 
462  analysis a micro-ITT population of all randomized subjects with a positive culture for a 
463  drug-resistant isolate of M. tuberculosis in the pretreatment prerandomization sample.  
464   
465    Per-protocol population:  all randomized subjects with a positive culture from a 
466  pretreatment sample who achieve a prespecified level of compliance with the protocol 
467  (e.g., presence at all or a high percentage of follow-up visits). 
468   
469  In general, the analysis population of greatest interest in the determination of efficacy is the 
470  micro-ITT population.  In addition, sponsors should evaluate consistency of results for efficacy 
471  in the ITT and per-protocol populations.  If there are notable differences between outcomes for 
472  the ITT and per-protocol populations, the sponsor should investigate reasons for these 
473  differences.   
474   
475  All subjects should be followed completely for the duration of the trial even if they discontinue 
476  the investigational drug(s).  Sponsors should make every effort to minimize the loss to follow-up 
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477  throughout the trial.  Given that missing data are nonetheless likely to occur, the protocol should 
478  state how missing data will be handled in the primary efficacy analysis.  Additionally, the 
479  statistical analysis plan should define additional methods for handling missing data.  The study 
480  report should include an assessment of the dependence of the trial results on the specific method 
481  for handling missing data. 
482   
483  To improve the precision of treatment effect estimation and inference, sponsors should consider 
484  adjusting for prespecified baseline factors that are anticipated to be prognostic of the outcome.  If 
485  randomization is stratified by baseline covariates, the analysis should account for the stratified 
486  randomization. 
487   
488  11.  Accelerated Approval Considerations 
489   
490  In some circumstances, approval under 21 CFR part 314, subpart H, or 21 CFR part 601, subpart 
491  E, may be applicable to drugs developed for the treatment of TB that provide clinically 
492  meaningful benefit over existing treatments.  An endpoint based on conversion of sequential 
493  M. tuberculosis sputum cultures to negative (e.g., percent conversion at a prespecified time 
494  point) can be used as a surrogate endpoint that is reasonably likely to predict clinical benefit 
495  (Wallis et al. 2010; Wallis et al. 2013; Phillips et al. 2013; Wallis, Peppard, and Hermann 2015; 
496  Wallis and Peppard, 2015; Phillips et al. 2016; Meyvisch et al. 2018).  A sponsor may consider 
497  other surrogate endpoints (e.g., biomarkers) that are also reasonably likely to predict clinical 
498  benefit.  When a drug is approved under accelerated approval, FDA will require that the sponsor 
499  study the drug further, to verify and describe its clinical benefit24 including the durability of 
500  the treatment effect.  Sponsors considering sputum culture conversion or other surrogate 
501  endpoints that are reasonably likely to predict clinical benefit should consult with the Agency as 
502  the clinical trial is being planned.  
503   
504  C.  Other Considerations 
505   
506  1.  Microbiological Considerations 
507   
508  Sponsors of investigational drugs being evaluated for the treatment of TB should have supportive 
509  data from in vitro and in vivo (animal model) microbiological studies.  These studies may 
510  provide data to inform selection of the regimen of antimycobacterial drugs to be evaluated in 
511  clinical trials and to assess the contribution of each drug to the investigational drug regimen. 
512   
513  a.  In vitro studies 
514   
515  In vitro studies should encompass the following: 
516   
517    Investigations of drug activity (inhibiting growth or killing) against metabolically active, 
518  dormant, and intracellular stages of M. tuberculosis.   
519   
 
24 21 CFR 314.510 for drugs and 21 CFR 601.41 for biological products. 
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520    Susceptibility testing against metabolically active bacilli from drug-susceptible laboratory 
521  strains, laboratory strains with known patterns of drug resistance, and clinical isolates 
522  representing different geographical regions.  
523   
524    Standardized methods for susceptibility testing such as those recommended by the 
525  Clinical Laboratory Standards Institute (CLSI).25   
526   
527    If nonstandard methods are being employed in the trial, prior submission for FDA review 
528  of a complete description of the methods and the performance characteristics of the assay 
529  in the actual laboratory where testing will be done.     
530   
531    Establishment of quality control parameters for susceptibility testing before 
532  determination of in vitro activity.26   
533   
534  If two or more new investigational drugs are under evaluation simultaneously, the sponsor 
535  should conduct factorial design studies evaluating the new investigational drugs and provide the 
536  results to the FDA.9  The FDA encourages testing against multiple strains of M. tuberculosis.  
537  See section III.C.3.d., In vitro hollow fiber system models, for methods of assessment of the 
538  contribution of individual drugs in a combination regimen. 
539   
540  b.  In vivo (animal models) 
541   
542  Appropriate animal models can serve as an important bridge between the identification of 
543  in vitro antimycobacterial effects of an investigational drug and the initiation of clinical trials.  
544  PK assessments and changes in drug susceptibility in animal model studies may inform clinical 
545  trial designs.  Sponsors should consider evaluations of the investigational drug, and/or 
546  combinations of investigational drugs, using different animal models and more than one 
547  strain/isolate of M. tuberculosis to study mycobacterial burden and sterilizing activity.  In vivo 
548  studies conducted using a factorial design using clinically relevant exposures can provide 
549  information on the contribution of the individual drugs to the combination regimen. 
550   
551  c.  Drug resistance and cross-resistance 
552   
553  Sponsors should examine the potential of M. tuberculosis isolates to develop resistance to the 
554  investigational drug in appropriate in vitro and/or animal models and should evaluate the 
555  potential for cross-resistance to drugs in the same class or in other classes used for the treatment 
556  of TB.  If resistance is demonstrated, it is important to identify the mechanism(s) of resistance.  
 
25 For examples, see the guidance for industry and FDA Class II Special Controls Guidance Document:  
Antimicrobial Susceptibility Test (AST) Systems (August 2009) and CLSIs Susceptibility Testing of Mycobacteria, 
Nocardiae, and Other Aerobic Actinomycetes; Approved Standard  Third Edition, (available at 
https://clsi.org/standards/products/microbiology/documents/m24/).  For the most recent version of a class II special 
controls guidance document, check the FDA class II special controls guidance document web page at 
https://www.fda.gov/medical-devices/guidance-documents-medical-devices-and-radiation-emitting-products/class-
ii-special-controls-documents.  
 
26 For more details, see the guidance for industry Microbiology Data for Systemic Antibacterial Drugs  
Development, Analysis, and Presentation (February 2018).  
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557  Sponsors should attempt to evaluate the clinical significance of any changes in phenotype (e.g., 
558  in vitro susceptibility to the investigational drug) or genotype observed in nonclinical studies by 
559  correlating such changes with efficacy outcomes.  
560   
561  d.  Types of culture media to identify M. tuberculosis 
562   
563  Solid media (e.g., Lowenstein-Jensen medium, Middlebrook 7H10 or 7H11 agar media) and 
564  liquid media (e.g., mycobacteria growth indicator tube) are culture assay methods used to 
565  identify and characterize M. tuberculosis.  Sponsors can include other newer molecular 
566  methodologies to detect M. tuberculosis and its susceptibility profile in trials for microbiological 
567  evaluations.  Sponsors should specify the methods used to culture and identify M. tuberculosis as 
568  well as the in vitro susceptibility testing methods that will be employed in the trial.   
569   
570  For baseline evaluations, the Agency recommends using both solid and liquid media.  The 
571  advantages to this approach are (1) more rapid observation of mycobacterial growth in liquid 
572  media (e.g., less than 2 weeks) and (2) that growth of pure culture on solid media is already 
573  underway for (a) the biochemical confirmation of M. tuberculosis and (b) the evaluation of in 
574  vitro susceptibility.  
575   
576  For the evaluation of subjects on treatment and after treatment completion, sponsors can use 
577  solid or liquid culture media.  Within a clinical trial, the culture methodologies among trial sites 
578  should be consistent to evaluate all subjects in the trial.  Other types of culture evaluations can be 
579  informative as secondary or exploratory endpoints (e.g., quantitative culture techniques).   
580   
581  e.  Differentiate relapse from reinfection or new infection 
582   
583  As a secondary analysis, sponsors should aim to utilize molecular methods to evaluate whether 
584  clinical failure is caused by relapse of the original infection or by development of a new 
585  infection, especially in subjects living in endemic areas.  If any of these methods are used in a 
586  clinical trial, the sponsor should include details of the methods used as well as performance 
587  characteristics of all assays in the clinical protocol.  
588   
589  2.  Relevant Nonclinical Safety Considerations 
590   
591  Combination regimens remain the standard of care for the treatment of TB.  Individual drugs 
592  may be developed for treatment of active disease although they would be used as part of a 
593  combination regimen.  Nonclinical studies to characterize the safety profile of individual drugs 
594  or a combination regimen and to support clinical trials and approval of a marketing application 
595  will vary, depending on the information available on each drug and the intended patient 
596  population.27  The Agency encourages sponsors to discuss with the FDA the available toxicology 
 
27 For guidance on when to conduct nonclinical combination studies to support clinical trials of combination 
regimens, see the following: (1) guidance for industry Nonclinical Safety Evaluation of Drug or Biologic 
Combinations (March 2006); (2) ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials and Marketing Authorization for Pharmaceuticals; (3) ICH guidance for industry S6(R1) 
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (May 2012); and (4) guidance for industry 
Codevelopment of Two or More New Investigational Drugs for Use in Combination.  
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597  data for each investigational drug and a proposal for the clinical development of the combination 
598  regimen. 
599   
600  Sponsors should conduct nonclinical toxicology studies of a combination regimen consisting of  
601  two or more investigational (unapproved) drugs before initial administration of that combination 
602  regimen to humans based on the following: 
603   
604    The availability of clinical experience with the individual drugs 
605   
606    The availability of relevant nonclinical toxicology data for each of the individual drugs 
607  for the proposed duration of the combination regimen 
608   
609    The existence of a significant toxicological concern and the safety margin between the no 
610  observed adverse effects level (NOAEL) for each of the individual drugs in the animal 
611  toxicology studies and the proposed human exposure to each of the investigational drugs 
612  in the combination regimen 
613   
614    The potential for drug-drug interactions based on the absorption, distribution, 
615  metabolism, and excretion of each of the drugs 
616   
617    The potential for adverse effects to involve the same organ system (overlapping 
618  toxicities) or synergistic toxicities based on a review of accumulated data from each of 
619  the investigational drugs 
620   
621  Sponsors should discuss with the FDA the type, duration, and timing of nonclinical toxicology 
622  studies needed to support clinical development of the combination regimen.  
623   
624  3.  PK/PD Considerations 
625   
626  a.  Phase 1/phase 2 PK trials 
627   
628  The PK of the investigational drug should be fully characterized in single-dose PK, multiple-
629  dose PK, and phase 2 PK/PD evaluations.  The FDA recommends characterization of PK in 
630  specific populations, including subjects who have renal or hepatic impairment, as well as an 
631  evaluation of the drug effect on the QT interval.28  
632   
633  b.  Drug interactions 
634   
635  Sponsors should conduct in vitro studies to determine the potential of the investigational drug to 
636  act as a substrate, inhibitor, or inducer of major human metabolizing enzymes and relevant 
637  transporters.29  Based on these results, drug interaction evaluations between one or more of the 
 
28 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs  Questions and Answers (R1) (October 2012). 
 
29 See the guidance for industry In Vitro Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions (January 2020). 
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638  antimycobacterial drugs used in the planned combination regimen, or with drugs unrelated to the 
639  treatment of TB but likely to be used concomitantly for other indications (e.g., antiretroviral 
640  therapy for treatment of HIV; antiviral therapy for treatment of hepatitis B or C), may be needed 
641  before initiating clinical efficacy trials.30  The Agency strongly recommends that sponsors 
642  consult the FDA during drug development regarding appropriate drug interaction evaluations.  
643   
644  c.  Exposure response 
645   
646  Sponsors should explore exposure-response relationships during early phases of drug 
647  development to aid in the selection of optimal dosing strategies for evaluation in later trials.31  
648  The FDA encourages sponsors to explore exposure-response relationships for both sputum and 
649  serum drug concentrations and markers of activity (e.g., the time-to-sputum-conversion or 
650  sputum conversion rate at 2 months in subjects with pulmonary TB). 
651   
652  d.  In vitro hollow fiber system models 
653   
654  The results from hollow fiber system models, combined with other sources of nonclinical data, 
655  can help inform the selection of antimycobacterial drug regimens to begin clinical evaluation 
656  (Chilukuri et al. 2015).  The hollow fiber system models can be used to simulate PK 
657  characteristics of drugs intended to treat TB and allows for the exploration of concentration-
658  effect relationships potentially relevant to the treatment of TB in the clinical setting.  These 
659  models are expected to provide key information on regimen selection for further evaluation.  
660  These models may also play an important role in evaluating the contribution of each drug (at 
661  clinically relevant exposures) to the treatment effect. 
662   
663  4.  Foreign Clinical Data32 
664   
665  FDA regulations permit the acceptance of foreign clinical trials in support of a new drug 
666  application (NDA) or biologics license application (BLA) approval (21 CFR 312.120).  
667   
668  5.  Data standards for TB 
669   
670  Study data standards describe a standardized way to exchange clinical and nonclinical research 
671  data between computer systems.  Data standards have been developed for TB to provide a 
 
30 See the guidance for industry Clinical Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-
Mediated Drug Interactions (January 2020). 
 
31 See the guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and Regulatory 
Applications (April 2003).  
 
32 See the guidance for industry and FDA staff FDA Acceptance of Foreign Clinical Studies Not Conducted Under 
an IND Frequently Asked Questions (March 2012). 
 
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672  consistent general framework for organizing study data, including templates for datasets, 
673  standard names for variables, and standard ways of doing calculations with common variables.33   
674   
675  6.  Labeling Considerations 
676   
677  Generally, the labeled indication should reflect the patient population enrolled in the clinical 
678  trials.  For example, sponsors should consider the following: 
679   
680  Drug X is indicated in combination with Drugs Y and Z for the treatment of pulmonary 
681  tuberculosis. 
682   
683  or  
684   
685  Drug X is indicated in combination with other antimycobacterial drugs for the treatment 
686  of pulmonary tuberculosis. 
687   
688  For drugs approved under accelerated approval, the sponsor must include additional information 
689  in the INDICATIONS AND USAGE section (see 21 CFR 201.57(c)(2)(i)(B)).34  For drugs 
690  approved under the limited population pathway for antibacterial and antifungal drugs, additional 
691  information is available for specific labeling requirements and recommendations.35, 36
 
33 See, for example, the TB Therapeutic Area User Guide version 2 available at 
https://www.cdisc.org/standards/therapeutic-areas/tuberculosis/tuberculosis-therapeutic-area-user-guide-v2-0 and 
FDAs Study Data Standards Resources web page available at 
https://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm. 
 
34 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics. 
 
35 See section 506(h)(3)(A) of the FD&C Act (as amended by the 21st Century Cures Act). 
 
36 See the guidance for industry Limited Population Pathway for Antibacterial and Antifungal Drugs (August 2020). 
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692  REFERENCES 
693   
694  Bark, CM, R Dietze, A Okwera, et al., 2011, Clinical Symptoms and Microbiological Outcomes 
695  in Tuberculosis Treatment Trials, Tuberculosis, 91(6):601604. 
696   
697  Chilukuri, D, O McMaster, K Bergman, et al., 2015, The Hollow Fiber System Model in the 
698  Nonclinical Evaluation of Antituberculosis Drug Regimens, Clin Infect Dis, 61 (Suppl 
699  1):S32-S33. 
700   
701  DerSimonian, R and N Laird, 1986, Meta-Analysis in Clinical Trials, Controlled Clin Trials, 
702  7(3):177188. 
703   
704  East African/British Medical Research Council, 1981, Controlled Clinical Trial of Five Short-
705  Course (4-Month) Chemotherapy Regimens in Pulmonary Tuberculosis, Am Rev Respir Dis, 
706  123(2):165170. 
707   
708  East and Central Africa/British Medical Research Council Fifth Collaborative Study, 1983, 
709  Controlled Clinical Trial of 4 Short-Course Regimens of Chemotherapy (Three 6-Month and 
710  One 8-Month) for Pulmonary Tuberculosis, Tubercle, 64(3):153166. 
711   
712  Gillespie, SH, AM Crook, TD McHugh, et al., 2014, Four-Month Moxifloxacin-Based Regimens 
713  for Drug-Sensitive Tuberculosis, New Engl J Med, 371(17): 15771587. 
714   
715  Johnson, JL, DJ Hadad, R Dietze, et al., 2009, Shortening Treatment in Adults With Noncavitary 
716  Tuberculosis and 2-Month Culture Conversion, Am J Respir Crit Care Med, 180(6):558563. 
717   
718  Makuch, RW and RM Simon, 1980, Sample Size Considerations for Non-Randomized 
719  Comparative Studies, J Chron Dis, 33(3):175181. 
720   
721  Meyvisch, P, C Kambili, K Andries, et al., 2018, Evaluation of six months sputum culture 
722  conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial, PLoS One, 
723  13(7):e0200539. 
724   
725  Nachman, S, A Ahmed, F Amanullah, et al., 2015, Towards Earlier Inclusion of Children in 
726  Tuberculosis (TB) Drug Trials: Consensus Statements from an Expert Panel, Lancet Infect Dis, 
727  15(6):711720. 
728   
729  Nahid, P, SE Dorman, N Alipanah, et al., 2016, Official American Thoracic Society/Centers for 
730  Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice 
731  Guidelines: Treatment of Drug-Susceptible Tuberculosis, Clin Infect Dis, 63(7):853867. 
732   
733  Nunn, AJ, PPJ Phillips, and SH Gillespie, 2008, Design Issues in Pivotal Drug Trials for Drug 
734  Sensitive Tuberculosis (TB), Tuberculosis; 88(Suppl 1):S85S92. 
735   
736  Perez-Velez, CM and BJ Marais, 2012, Tuberculosis in Children, New Engl J Med, 367(4):348
737  361. 
19  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
738  Phillips, PPJ, CM Mendel, DA Burger, AM Crook, AJ Nunn, R Dawson, et al., 2016, Limited 
739  Role of Culture Conversion for Decision-making in Individual Patient Care and for Advancing 
740  Novel Regimens to Confirmatory Clinical Trials, BMC Med, 14:19. 
741   
742  Phillips, PPJ, K Fielding, and AJ Nunn, 2013, An Evaluation of Culture Results During 
743  Treatment for Tuberculosis as Surrogate Endpoints for Treatment Failure and Relapse, PLoS 
744  ONE, 8(5):e63840. 
745   
746  Rangaka, MX, RJ Wilkinson, JR Glynn, et al., 2012, Effect of Antiretroviral Therapy on the 
747  Diagnostic Accuracy of Symptom Screening for Intensified Tuberculosis Case Finding in a 
748  South African HIV Clinic, Clin Infect Dis, 55(12):16981706. 
749   
750  Singapore Tuberculosis Service/British Medical Research Council, 1986, Long-Term Follow-up 
751  of a Clinical Trial of Six-Month and Four-Month Regimens of Chemotherapy in the Treatment 
752  of Pulmonary Tuberculosis, Am Rev Respir Dis, 133(5):779783. 
753   
754  Wallis, RS, and T Peppard, 2015, Early Biomarkers and Regulatory Innovation in Multidrug-
755  Resistant Tuberculosis, Clin Infect Dis, 61 (Suppl 3):S160S163. 
756   
757  Wallis, RS, C Wang, TM Doherty, P Onyebujoh, M Vahedi, H Laang, et al., 2010, Biomarkers 
758  for Tuberculosis Disease Activity, Cure, and Relapse, Lancet Infect Dis,10(2): 6869. 
759   
760  Wallis, RS, C Wang, D Meyer, and N Thomas, 2013, Month 2 Culture Status and Treatment 
761  Duration as Predictors of Tuberculosis Relapse Risk in a Meta-Regression Model PLoS ONE, 
762  8(8): e71116. 
763   
764  Wallis, RS, T Peppard, and D Hermann, 2015, Month 2 Culture Status and Treatment Duration 
765  as Predictors of Recurrence in Pulmonary Tuberculosis: Model Validation and Update, PloS 
766  ONE, 10(4):e0125403. 
767   
768  Wejse, C, P Gustafson, J Nielson, et al., 2008, TBscore:  Signs and Symptoms from Tuberculosis 
769  Patients in a Low-Resource Setting Have Predictive Value and May Be Used to Assess Clinical 
770  Course, Scand J of Infect Dis, 40(2):111120.
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771  APPENDIX 
772  Example of a Justification for a Noninferiority Margin  
773  in a Treatment-Shortening Clinical Trial of Pulmonary Tuberculosis 
774   
775  This appendix provides an example of a noninferiority (NI) margin justification.  As stated in 
776  this guidance, NI margin justifications are dependent on the specific design of the NI trial.  This 
777  justification is for a specific NI trial that would compare an investigational drug regimen 
778  consisting of a new investigational drug plus the first 4 months of the standard regimen to the 
779  standard 6-month regimen in subjects with drug-susceptible tuberculosis (TB).  The effect of the 
780  investigational drug essentially replaces the effect of Months 5 and 6 of the standard regimen.  
781  Using historical data, this justification determines the effect of these 2 months of therapy 
782  (historical evidence of sensitivity to drug effects (HESDE)) to determine if the new 
783  investigational drug is effective based on the results of the NI trial.  Additional information is 
784  available regarding a complete discussion of NI trials and justifications of margins.1 
785   
786  We identified two trials that allowed for an estimate of the effect of Months 5 and 6 in the 
787  standard regimen for drug-susceptible TB, based on a comparison of the standard-of-care 
788  regimen (2 months of treatment with ethambutol (or streptomycin), isoniazid, rifampin, and 
789  pyrazinamide followed by 4 months of treatment with isoniazid and rifampin, which is often 
790  described in abbreviated terminology as 2EHRZ/4HR or 2SHRZ/4HR) to a 4-month regimen of 
791  2EHRZ/2HR or 2SHRZ/2HR.2  The endpoint of unfavorable outcome was defined as one of the 
792  following: (1) subjects who never become sputum culture negative for M. tuberculosis while on 
793  therapy; (2) subjects who had microbiological confirmation of relapse of pulmonary TB within a 
794  12-month period of observation following therapy completion; or (3) subjects who died at any 
795  time within the clinical trial drug administration period and 12-month period of observation 
796  following therapy completion. 
797   
798  Table A, below, contains the results from the two trials among subjects randomized to receive 
799  the 6-month regimen or the 4-month regimen.  A comparison of the two regimens gives an 
800  estimate of the effect of the final 2 months of the 6-month regimen of 8.4 percent with a lower 
801  bound of the 95 percent confidence interval of 4.8 percent; 4.8 percent can be used as a 
802  conservative estimate of the treatment effect of Months 5 and 6 of treatment. 
803   
 
1 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016).  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. 
 
2 See Singapore Tuberculosis Service/British Medical Research Council 1986; East and Central Africa/British 
Medical Research Council Fifth Collaborative Study 1983; and East African/British Medical Research Council 
1981. 
21  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
804  Table A:  The Results of Two Treatment-Shortening Studies* 
805   
Study**  6-Month  Unfavorable  4-Month  Unfavorable  Treatment Effect (4-
Regimen  Outcome  Regimen  Outcome  Month Regimen 
Minus 6-Month 
Regimen) and 95% CI 
1  2SHRZ/4HR(Z)  1.2% (2/158)  2SHRZ/2HR(Z)  9.6% (15/156)  8.4% (3.8%, 14.2%) 
2  2SHRZ/4HR  4.7% (8/172)  2SHRZ/2HR(Z)  13.2% (28/212)  8.6% (2.4%, 14.6%) 
  Summary Estimate and 95% CI***  8.4% (4.8%, 12.1%) 
806  * CI = confidence interval; 2SHRZ/4HR(Z) = 2 months of treatment with streptomycin, isoniazid, rifampin, and 
807  pyrazinamide followed by 4 months of treatment with isoniazid and rifampin (and pyrazinamide); 2SHRZ/2HR(Z) = 
808  2 months of treatment with streptomycin, isoniazid, rifampin, and pyrazinamide followed by 2 months of treatment 
809  with isoniazid and rifampin (and pyrazinamide). 
810  ** The number of deaths is unknown for Study 1 and therefore is not included in the outcome.  The 6-month and 4-
811  month regimens in Study 2 are from separate trials; however, they were similarly designed and conducted, and 
812  occurred close in time.  Study 1: Singapore Tuberculosis Service/British Medical Research Council, 1986, Long-
813  Term Follow-up of a Clinical Trial of Six-Month and Four-Month Regimens of Chemotherapy in the Treatment of 
814  Pulmonary Tuberculosis, Am Rev Respir Dis, 133(5):779783.  Study 2: East and Central Africa/British Medical 
815  Research Council Fifth Collaborative Study, 1983, Controlled Clinical Trial of 4 Short-Course Regimens of 
816  Chemotherapy (Three 6-Month and One 8-Month) for Pulmonary Tuberculosis, Tubercle, 64(3):153166; and East 
817  African/British Medical Research Council, 1981, Controlled Clinical Trial of Five Short-Course (4-Month) 
818  Chemotherapy Regimens in Pulmonary Tuberculosis, Am Rev Respir Dis, 123(2):165170. 
819  *** Random effect model per DerSimonian, R and N Laird, 1986, Meta-Analysis in Clinical Trials, Controlled Clin 
820  Trials, 7(3):177188. 
821   
822  In an NI trial in subjects with drug-susceptible pulmonary TB where a treatment-shortening 
823  regimen is compared to a standard 6-month regimen, the selection of an NI margin of 4.8 percent 
824  can be supported by the historical data.  The NI margin justification presented here is a 
825  modification of the justification presented in Nunn et al. 2008.3   
826   
827  Although an NI margin of 4.8 percent may seem overly conservative, the fact that a very high 
828  proportion of subjects achieve a successful primary efficacy outcome with standard of care 
829  provides for a reasonable estimate of the sample size for an NI trial.  Additionally, given the high 
830  proportion of subjects achieving a successful outcome, there is interest in maintaining this high 
831  proportion in new investigational drug regimens.  For example, we identified a trial (Johnson et 
832  al. 2009)4 that described halting of the trial by a data monitoring committee based on an 
833  approximately 5 percentage point estimate difference between the standard regimen and a 
834  treatment-shortening regimen, indicating that there is a clinical expectation that there should be a 
835  high proportion of subjects achieving successful outcomes in both treatment groups, making the 
836  selection of an NI margin of 4.8 percent a feasible consideration.   
837   
 
3 Nunn, AJ, PPJ Phillips, and SH Gillespie, 2008, Design Issues in Pivotal Drug Trials for Drug Sensitive 
Tuberculosis (TB), Tuberculosis; 88(Suppl 1):S85S92. 
 
4 Johnson, JL, DJ Hadad, R Dietze, et al., 2009, Shortening Treatment in Adults With Noncavitary Tuberculosis and 
2-Month Culture Conversion, Am J Respir Crit Care Med, 180(6):558563. 
 
22  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
838  The following example provides a framework for discussion with the FDA about sample size 
839  estimation for an NI trial evaluating a treatment-shortening regimen (Makuch and Simon 1980).5  
840  The total sample size of enrolled subjects is approximately 480 subjects per arm based on the 
841  following assumptions: (1) the identification of Mycobacterium tuberculosis in 90 percent of 
842  enrolled subjects (primary analysis population is approximately 430 subjects per arm); (2) a two-
843  sided type I error of 0.05 and power of 90 percent; (3) for both arms, a rate of 5 percent of 
844  subjects who have the endpoint of failure to convert to negative sputum cultures, or who 
845  experience relapse of TB, or death at a 12-month period of observation; and (4) an NI margin of 
846  4.8 percent. 
847   
848  Sponsors should discuss with the FDA appropriate NI margins for specific NI trials being 
849  proposed. 
 
5 Makuch, RW and RM Simon, 1980, Sample Size Considerations for Non-Randomized Comparative Studies, J 
Chron Dis, 33(3):175181. 
23