Chest
Volume 159, Issue 2, February 2021, Pages 537-543
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Chest Infections: Special Features
Development of Drugs for Nontuberculous Mycobacterial Disease: Clinicians’ Interpretation of a US Food and Drug Administration Workshop

https://doi.org/10.1016/j.chest.2020.08.2055Get rights and content

The US Food and Drug Administration convened a workshop to discuss clinical trial design challenges and considerations related to the treatment of nontuberculous mycobacterial pulmonary disease, to include topics such as clinical trial end points, duration, and populations. The clinicians participating in the meeting provide here their interpretation of the discussion, which included US Food and Drug Administration and industry representatives. The treatment of nontuberculous mycobacterial pulmonary disease typically includes multiple antibiotics for a prolonged period and can be difficult to tolerate; there is a great need for new treatment options. Most individuals have a microbiologic response to therapy, but data correlating decreasing bacillary load with patient-reported outcomes or measured functional improvement are lacking. Accordingly, trial designs for new therapeutic agents should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary end points, and placebo control arms was highlighted during the workshop.

Section snippets

Current State of Diagnosis and Treatment of NTM-PD

The reader is referred to other sources for a more complete description of the epidemiology, risk factors, and treatment outcomes in NTM-PD.2 The diagnosis of NTM-PD is based on clinical symptoms, radiographic findings, and the identification of NTM in cultures of respiratory specimens. Signs and symptoms may be pulmonary (eg, persistent cough, sputum production, hemoptysis) or systemic (eg, fever, night sweats, weight loss, fatigue). Radiographic features include nodular or tree-in-bud

Development of Antibacterial Drugs for NTM: A Patient Perspective

Patient perspectives regarding treatment of NTM-PD have been obtained from a number of sources. An NTM Research Consortium Workshop engaged patients to define research priorities and features of study design.11 The priorities identified with respect to treatment of infection included promoting quality-of-life measures for assessing the effectiveness of treatment and a need to reduce the burden of antibiotic treatment. Prior to this workshop, NTM Info & Research, a non-profit US organization

Development of Antibacterial Drugs for NTM: A Regulatory Perspective

The FDA mandate for development of new drugs is the demonstration of sufficient safety and efficacy, the latter defined as improving how a patient feels, functions, and/or survives. Accelerated approval of a drug was recently granted based on sputum culture conversion, but there are limited data evaluating the relationship between this microbiologic end point and clinical benefits. A review of the literature was conducted to establish whether culture conversion could be used as a surrogate end

Patient Population Heterogeneity

Previous studies have included heterogeneous subject populations (Table 2), but subjects recruited for a study should have disease manifestations that have the potential to respond to the treatment; that is, disease that is neither so indolent nor far advanced that treatment effects would be difficult to measure. The underlying condition and comorbidities may be highly relevant in predicting a response to treatment; patients with cystic fibrosis were excluded from a Phase III study14 based on

Conclusions

The clinicians on the panel concluded that NTM-PD is a condition in great need of new treatment options. Considerable knowledge has accrued in the past several years that has clarified the challenges that must be addressed in trial designs. These include selection of appropriate candidate subjects for clinical trials as well as proper outcome measures. There will always be interest in the microbiologic end points, but there is a need to define a clinical outcome measure to be used in NTM

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: P. A. F. reports grants and personal fees from Insmed, Savara Pharmaceuticals, and the Cystic Fibrosis Foundation; grants from Novoteris; and personal fees from Janssen Research & Development and from Merck, outside of the submitted work. D. E. G. reports grants, personal fees, and nonfinancial support from Insmed Inc.; and personal fees from Spero, Merck, and Johnson & Johnson, outside of the submitted work.

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    FUNDING/SUPPORT: This publication was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute/National Institutes of Health and in part by the National Center for Advancing Translational Sciences of the National Institutes of Health [Grant UL1 TR001450].

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