Nontuberculous Mycobacterial Pulmonary Disease Caused by Mycobacterium avium Complex: Developing Drugs for Treatment : Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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
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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 Administration’s (FDA’s) current
thinking regarding clinical trial design issues, choice of trial population, and endpoints for the
treatment of naïve 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.

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developing drugs targeting non-MAC NTM-PD should discuss their plans with the Division of
Anti-Infectives (the Division).
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s 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-
naïve 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:

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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-naïve 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 FDA’s 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).

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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 naïve 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 (naïve 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, sex 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:

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• 	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 FDA’s 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 FDA’s 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).

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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 FDA’s 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 instrument’s 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.