Nontuberculous Mycobacterial 
Pulmonary Disease Caused by 
Mycobacterium avium Complex: 
Developing Drugs for Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
September 2023 
Clinical/Antimicrobial 
   
Nontuberculous Mycobacterial 
Pulmonary Disease Caused by 
Mycobacterium avium Complex:  
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) 
 
September 2023 
Clinical/Antimicrobial 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DRUG DEVELOPMENT CONSIDERATIONS ........................................................... 2 
A.  Trial Design and Conduct ............................................................................................................. 2 
B.  Trial Population ............................................................................................................................. 3 
C.  Efficacy Endpoints ......................................................................................................................... 4 
 
  Contains Nonbinding Recommendations 
Nontuberculous Mycobacterial Pulmonary Disease  
Caused by Mycobacterium avium Complex:  
Developing Drugs for Treatment 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors in the clinical development of drugs2 for the 
treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) caused by 
Mycobacterium avium complex (MAC).  
 
Specifically, this guidance addresses the Food and Drug Administrations (FDAs) current 
thinking regarding clinical trial design issues, choice of trial population, and endpoints for the 
treatment of naive and refractory NTM-PD caused by MAC. The design of clinical trials of new 
drugs for the treatment of NTM-PD was discussed during an FDA public workshop.3 
 
This guidance does not contain discussion of the general issues of statistical analysis or clinical 
trial design. Those topics are addressed in the International Council for Harmonisation (ICH) 
guidances for industry E9 Statistical Principles for Clinical Trials (September 1998), E9(R1) 
Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in 
Clinical Trials (May 2021), and E10 Choice of Control Group and Related Issues in Clinical 
Trials (May 2001).4 In addition, this guidance does not address drugs intended to treat patients 
with NTM-PD caused by pathogens other than MAC because the clinical characteristics of these 
patients may differ from patients with NTM-PD caused by MAC. Sponsors interested in 
 
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 Workshop materials can be found at https://www.fda.gov/drugs/development-antibacterial-drugs-treatment-
nontuberculous-mycobacterial-disease-04082019-04082019.  
 
4 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
1  Contains Nonbinding Recommendations 
developing drugs targeting non-MAC NTM-PD should discuss their plans with the Division of 
Anti-Infectives (the Division).  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND 
 
NTM-PD is a chronic and progressive pulmonary disease resulting in respiratory and 
nonrespiratory symptoms, such as cough, shortness of breath, and fatigue. In addition, NTM-PD 
decreases lung function and overall health-related quality of life. Most cases of NTM-PD are 
caused by MAC, but other species of NTM, such as M. kansasii and M. abscessus, can also cause 
lung disease. There are two main forms of NTM-PD: a nodular bronchiectatic form that has been 
classically associated with middle-aged and older nonsmoking females and a fibrocavitary form 
typically associated with preexisting pulmonary diseases such as chronic obstructive pulmonary 
disease. NTM-PD also occurs in patients with cystic fibrosis and certain types of 
immunodeficiencies. Treatment for NTM-PD involves multidrug regimens with durations lasting 
months to years that often cause drug-drug interactions and adverse reactions such as 
hepatotoxicity, nephrotoxicity, ocular toxicity, and skin reactions. Microbiological response to 
treatment, such as conversion of sputum culture to negative, is variable. Patients with treatment-
naive NTM-PD, who usually have macrolide-susceptible isolates, generally have high rates of 
microbiological response. In contrast, patients with NTM-PD caused by macrolide-resistant 
isolates generally have lower rates of microbiological response with salvage treatment regimens. 
In addition, microbiological recurrence (relapse or reinfection) and recurrence of NTM-PD 
associated symptoms are common after treatment cessation. 
 
 
III.  DRUG DEVELOPMENT CONSIDERATIONS 
 
To support approval, FDA expects that drugs will provide benefit on a clinically meaningful 
endpoint. Sponsors considering a microbiological outcome as a surrogate endpoint that is 
reasonably likely to predict clinical benefit should discuss this with the Division. 
 
A.  Trial Design and Conduct 
 
Sponsors should consider the following in their development programs for the treatment of 
NTM-PD caused by MAC: 
 
2  Contains Nonbinding Recommendations 
Early Clinical Studies: 
 
  Short-term, randomized, placebo-controlled proof-of-concept studies evaluating a single 
drug with subjects subsequently starting standard combination treatment may be 
appropriate in select subjects, provided there is adequate monitoring. 
 
Phase 3: 
 
  In general, sponsors should conduct two randomized, double-blind phase 3 trials. 
However, a single adequate and well-controlled trial showing robust evidence of efficacy 
with confirmatory evidence may also demonstrate substantial evidence of effectiveness.5 
Sponsors intending to seek approval of their drugs on the basis of a single trial and 
confirmatory evidence should discuss both the proposed phase 3 trial and a detailed and 
specific proposal for what they intend to provide as confirmatory evidence with the 
Division.  
 
  The following are possible designs for phase 3 trials; however, there may be other 
acceptable options. Sponsors should discuss their clinical development plans with the 
Division. 
 
  Comparison of a standard-of-care (SOC) regimen plus the investigational drug to 

SOC plus placebo in a superiority trial. Sponsors should discuss acceptable SOC 
regimens with the Division and define them in the trial protocol. 
 
  Comparison of a new combination regimen to SOC in a superiority trial. In this case, 

sponsors should justify the contribution of each component of the combination to the 
overall efficacy.6  
 
  Comparison of a new combination regimen to placebo in a superiority trial in an 

appropriate population such as treatment-naive subjects, provided that there are 
appropriate criteria for instituting rescue therapy. Sponsors should justify the 
contribution of each component of the combination to the overall efficacy.6   
 
B.  Trial Population 
 
Sponsors developing drugs for the treatment of NTM-PD caused by MAC should consider the 
following regarding trial population: 
 
 
5 See section 505(d) of the Federal Food, Drug, and Cosmetic Act and the guidance for industry Providing Clinical 
Evidence of Effectiveness for Human Drug and Biological Products (May 1998); see also 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. 
 
6 See the guidance for industry Codevelopment of Two or More New Investigational Drugs for Use in Combination 
(June 2013).  
3  Contains Nonbinding Recommendations 
Early Clinical Studies: 
 
  Including both nodular bronchiectatic subjects and fibrocavitary subjects may be 
acceptable in early clinical studies to assess the response in each patient population. 
These trials will help to determine which patient population may be further studied in 
phase 3 trials. 
 
Phase 3: 
 
  Trial entry criteria should include a positive respiratory culture for MAC at screening 
plus a history of a positive culture in the past 6 months. 
 
  Different NTM-PD patient populations (i.e., nodular bronchiectatic versus fibrocavitary 
or treatment naive versus treatment refractory) may have different disease manifestations 
and different responses to treatment and may require different trial endpoints. 
 
  Sponsors should consider whether phase 3 trials should limit enrollment based on 

subject characteristics such as disease form (nodular bronchiectatic versus 
fibrocavitary), treatment experience (naive versus refractory), and comorbidities. 
 
  If sponsors wish to develop their drugs for both the nodular bronchiectatic and the 

fibrocavitary forms of NTM-PD, they should discuss with the Division the need for 
separate trials in each patient population, based on the endpoint or endpoints of 
interest (see section III. C., Efficacy Endpoints). Given the differences between these 
subtypes of NTM-PD, the labeled indication will reflect the patient population 
studied. However, a single trial in each subtype of NTM-PD could be used to support 
a broader indication. 
 
  Trials should include trial entry criteria defining the minimal baseline severity for NTM-
PD-related symptoms. 
 
  Racial and ethnic minorities should be represented in clinical trials. Sponsors should 
employ methods to recruit diverse populations to ensure representativeness of racial and 
ethnic minorities in clinical trials. However, FDA advises sponsors to seek diversity in 
clinical trial enrollment beyond populations defined by race and ethnicity, including other 
underrepresented populations defined by demographics such as sex, gender identity, age, 
socioeconomic status, disability, pregnancy status, lactation status, and comorbidity. 
 
C.  Efficacy Endpoints 
 
As discussed below, phase 3 studies in the treatment of NTM-PD caused by MAC should 
generally have a clinical endpoint as the primary endpoint, with a microbiological endpoint as a 
key secondary endpoint. Sponsors should consider the following regarding efficacy endpoints: 
 
4  Contains Nonbinding Recommendations 
  Primary efficacy endpoints should be based on clinical outcome assessments,7 such as a 
Patient-Reported Outcome (PRO) instrument assessing symptoms of NTM-PD. Sponsors 
should discuss with the Division other appropriate clinical outcomes that could be used, 
such as observer-reported outcomes, clinician-reported outcomes, and performance 
outcomes. In addition to use in the primary efficacy endpoint, other clinical outcome 
assessments may also be appropriate for use in secondary endpoints. 
 
  Microbiological endpoints, such as sputum culture conversion, are not generally 
recommended alone as primary endpoints for a phase 3 trial intended for traditional 
approval. There are limited data available, based mainly on retrospective, nonrandomized 
studies or exploratory analyses from nonrandomized subgroups, on the relationship of 
sputum culture conversion to clinical outcomes. The main limitation of these data is the 
difficulty in assessing if there are differences in subject characteristics between the 
converters and nonconverters that might impact the clinical outcomes. However, sponsors 
should include a microbiological endpoint that assesses sputum culture conversion as a 
key secondary endpoint. A discrepancy between the clinical and microbiological 
endpoints would be a review issue. 
 
  Sponsors considering a microbiological outcome as a surrogate endpoint that is 
reasonably likely to predict clinical benefit should discuss this approach with the Division 
as clinical trials are being planned. If sponsors wish to use a microbiological endpoint as 
a coprimary endpoint, they should discuss their proposal with the Division. 
 
  Currently, FDA is not aware of any specific PRO instruments that have been 
demonstrated to be fit-for-purpose8 to assess symptoms of NTM-PD to support 
regulatory decision-making and medical product labeling.9 Sponsors should discuss 
existing, new, or modified PRO instruments for this use with the Division. 
 
  Based on the role of the PRO instrument and data obtained during its development, 
establishing a range of a priori thresholds (i.e., the change in the individual PRO score 
over a predetermined time period that should be interpreted as a clinically meaningful 
within-patient change) is useful, as options for the primary endpoint are considered. A 
variety of primary endpoint options are appropriate. For example, if a total symptom 
score can be computed for the PRO, possible endpoints might include time to sustained 
 
7 See the draft guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug Development: 
Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments (June 2022). When final, this 
guidance will represent the FDAs current thinking on this topic. 
 
8 For additional information on the definition of fit-for-purpose, refer to the BEST (Biomarkers, EndpointS, and 
other Tools) Resource glossary, available at https://www.ncbi.nlm.nih.gov/books/NBK338448/def-
item/glossary.fitforpurpose/. Additional information on FDAs Fit-for-Purpose Initiative is available at 
https://www.fda.gov/drugs/development-approval-process-drugs/drug-development-tools-fit-purpose-initiative.  
 
9 See the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims (December 2009). 
 
5  Contains Nonbinding Recommendations 
resolution of symptoms or meeting a prespecified extent of improvement. Sponsors 
should discuss endpoints with the Division. 
 
  Sponsors should consider the following when developing, modifying, or selecting a PRO 
for NTM-PD trials. Additional information on PRO instrument development can be 
found at FDAs Patient-Focused Drug Development Guidance Series.10 
 
  Sponsors should evaluate commonly reported symptoms for patients, which include 

cough, shortness of breath, fatigue, night sweats, and chest pain.3 
 
  Heterogeneity in patients symptoms (e.g., some patients have predominantly fatigue 

symptoms whereas others have predominantly pulmonary symptoms) may suggest an 
individualized endpoint approach.11 One possible approach would be for subjects, at 
baseline, to identify their most bothersome symptom or symptoms and use the change 
from baseline in the symptom or symptoms as the primary efficacy endpoint or at 
least as part of the endpoint. It is recognized that there are challenges with this 
approach, including that as one symptom resolves, other symptoms may emerge as 
more bothersome. Individualized endpoint methods and determination of which 
symptom(s) would be a part of this individualized endpoint approach should be 
discussed early in the drug development process with the Division. 
 
  Piloting the proposed PRO instrument in phase 2 trials provides an opportunity to 

evaluate the instruments measurement properties (reliability, validity, and ability to 
detect change), to evaluate clinically meaningful within-patient change in scores 
(using methods such as anchor-based methods), and to confirm the endpoint 
definition before use in phase 3 trials.10 
 
  The timing of the primary endpoint assessment and duration of follow-up will depend 

on the nature of the chosen trial population and treatment effect of the drug or drugs. 
Sponsors should discuss these issues with the Division. 
 
10 Information on this guidance series is available at https://www.fda.gov/drugs/development-approval-process-
drugs/fda-patient-focused-drug-development-guidance-series-enhancing-incorporation-patients-voice-medical.  
 
11 Duke Margolis Center for Health Policy. Report of an event on April 5, 2017. Developing Personalized Clinical 
Outcome Assessments, available at https://healthpolicy.duke.edu/sites/default/files/2020-
03/meeting_summary_4_5_17.pdf, accessed March 3, 2021. 
6