Abstract
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.
Key Words: clinical trials, drug development, mycobacteria
Abbreviations: 6MWT, 6-min walk test; FDA, US Food and Drug Administration; MAC, Mycobacterium avium complex; NTM, nontuberculous mycobacterial; PD, pulmonary disease; PRO, patient-reported outcome
The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections has increased considerably in the last decade.1 Published guidelines offer recommendations for diagnosis and treatment,2 but currently there are only two products approved by the US Food and Drug Administration (FDA) to treat NTM: amikacin liposome inhalation suspension for the treatment of refractory infection due to Mycobacterium avium complex (MAC); and macrolides for the treatment of disseminated MAC infection in patients with HIV. New therapies for NTM pulmonary disease (NTM-PD) are needed to improve clinical outcomes. Achieving this goal will require repurposing existing medications and/or the development of novel drugs. Developing an evidence base for new drugs to meet regulatory requirements necessitates clinical trial designs that can show efficacy and safety in studies that are feasible and ethical.
The FDA convened a workshop in April 2019 to discuss clinical trial design challenges and considerations related to the treatment of NTM-PD, to include topics such as trial end points, duration, and populations. In the current document, the clinicians participating in the hearing report the challenges and areas of controversy, as well as proposed solutions, highlighted during this meeting. All invited panelists are listed in the Acknowledgments.
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 densities, consolidation, and cavities, frequently in the setting of bronchiectasis or emphysema. Of key importance is that these signs and symptoms are not specific for NTM-PD, and it is common that patients experience symptoms for years prior to the diagnosis of NTM-PD being made.3 Nearly 200 different NTM species have been identified, although many have not been associated with disease in humans. MAC, which includes M avium, Mycobacterium intracellulare, and Mycobacterium chimaera, is the most frequently isolated group of NTM pathogens and causes 80% to 90% of all NTM-PD in the United States; however, there are other NTM pathogens known to cause disease in humans as well, especially Mycobacterium abscessus.2 Although the principles discussed during this workshop are applicable to other NTM, most of the discussion focused on MAC-PD.
Published recommendations are available for the management of NTM-PD.2 When antimycobacterial antibiotics are deemed necessary, the treatment generally involves multiple medications administered for a prolonged period. The guidelines recommend treatment with the intent to achieve long-term sputum culture conversion, defined as consistently negative respiratory cultures, implying successful reduction in bacterial burden and, potentially, cure. Accordingly, antibiotic treatment is recommended for a full 12 months following sputum culture conversion. The success of treatment varies based on the specific NTM species being treated, the amount of structural lung disease (eg, cavities), the antibiotics used to treat the infection, and the ability of the patient to remain on that treatment. Best-case scenarios have reported culture conversion of > 80% for MAC infections, but a systematic review and meta-analysis reported a sustained conversion rate of 65% in those who took a three-drug, guideline-recommended regimen for a least 1 year,4 attesting to the need for more effective therapies. Furthermore, 25% to ≥ 50% of patients experience microbiologic recurrence due to relapse or reinfection, generally within 3 years of stopping antibiotic therapy.5, 6, 7
Monitoring patients for evidence of treatment response or the occurrence of adverse reactions during therapy includes periodic microbiologic assessment, radiologic evaluations, and assessment of patient subjective symptoms and functional status. Clinical experience suggests that most patients experience improvement in their cough and fatigue during therapy,8 and some patients have improvement in other aspects of their symptoms (eg, improved exercise tolerance, less dyspnea).9 Although long-term treatment is planned, many patients will experience improvement in their symptoms within the first few months of therapy. Adverse effects of medications can diminish quality of life, and it is not uncommon to stop specific antibiotics within a regimen and/or start new ones if a regimen is not being tolerated.10
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 advocating for patients with NTM-PD, conducted a survey of patients, of whom 84% had been treated with antibiotics (Table 1). There is wide disparity in the types of symptoms (respiratory vs systemic) and considerable overlap of symptoms attributed to the infection and the treatment. There was clear interest in the microbiologic end point, as noted when subjects were asked: “if your treatment could change one thing about your NTM-PD, what would you want that one thing to be?” By a large margin, the preference was for culture conversion. This likely correlates with the patients’ view that the objective of treatment is cure with return of normal health and cessation of medications, and the only path to cessation of medication is associated with culture conversion.
Table 1.
Key Findings From Surveys of Patients With NTM-PD
| Most common symptoms associated with their condition | |
| Fatigue | 77% |
| Cough productive of sputum | 71% |
| Dyspnea | 67% |
| Coughing without sputum | 51% |
| Night sweats | 49% |
| Weight loss | 43% |
| Hemoptysis | 34% |
| Lack of appetite | 33% |
| Chest pain | 32% |
| Anxiety | 32% |
| Preferences for treatment outcomes | |
| Improved quality of life | 97% |
| Increased energy/less fatigue | 84% |
| Culture conversion | 72% |
| Reduce coughing | 53% |
| Improvement in dyspnea | 42% |
| Repair lung damage | 28% |
| Improve lung function | 27% |
| Reduce progression of disease | 21% |
| Reduce mucus/sputum | 20% |
| Most common reported adverse effects of treatment | |
| Fatigue | |
| Dry mouth | |
| Cough | |
| Tinnitus | |
| Decreased appetite | |
| Dyspnea | |
| Nausea | |
| Dysphonia | |
| Cognitive dysfunction | |
| Weight loss | |
| Diarrhea |
Results from 465 respondents in a survey conducted by NTM Info & Research. NTM-PD = nontuberculous mycobacterial-pulmonary disease.
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 point for clinical benefit. Although there were hints of an association, there was no definitive evidence to support surrogacy of the microbiologic end point. Retrospective, nonrandomized studies suggested higher mortality rates in patients with MAC-PD who remained culture positive despite treatment compared with those who convert to culture negative.12,13 A retrospective analysis of treatment response in a cohort of patients with nodular/bronchiectatic MAC-PD showed that both improvement in semi-quantitative sputum culture scores and sputum conversion correlated with symptomatic improvement, especially cough.8 However, studies were from single centers or included a specific subtype of MAC-PD, which limits generalizability to the overall population. A primary limitation of using microbiologic end points as a surrogate for clinical benefit is the lack of prospective randomized controlled trial data examining this idea. Two studies of treatment-refractory MAC-PD suggested that culture conversion correlates with improvements in 6-min walk test (6MWT), although neither study exhibited an association between conversion and symptoms or quality of life as measured by using questionnaires in the study.9,14
These observations do not mean that culture conversion does not correlate with improved clinical outcomes; rather, it means only that existing data have not clearly shown that the microbiologic outcome can serve as a surrogate marker for clinical benefit as defined by “feels, functions, or survives.” The cumulative clinical experience of the expert panelists suggests that sputum culture conversion is a necessary end point for the assessment of treatment response and that it does associate with improved symptoms. The lack of data may be due to the orphan nature of the condition, limited “natural history” data on what happens to symptoms of patients who are not treated, overlapping symptoms with underlying lung diseases (eg, bronchiectasis), and symptoms associated with the treatment itself. The heterogeneity of symptoms in NTM-PD also makes the consistent demonstration of benefit challenging, particularly as currently used instruments to assess patient-reported outcomes (PROs) were not designed for use in patients with NTM-PD. Also, successful treatment does not implicitly mean cure, or eradication of the infection; it may be necessary to establish a definition of disease control or low disease activity. Regardless, the panel overwhelmingly reiterated that for the treatment of an infectious disease, a decrease in the burden of infection (ie, a decrease in bacillary load as defined by using sputum microbiologic results) is an essential aspect of decision-making for clinical care and is therefore a critical outcome in clinical trials.
Trial Design Considerations
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 previous results in which the few patients with cystic fibrosis studied did not achieve culture conversion.9 Patients with advanced structural lung disease, especially cavities, are believed to be less likely to achieve culture conversion compared with those patients with nodules or bronchiectasis without cavities.15 The pathogen and its susceptibility, defined by using standard laboratory methods, may also predict responsiveness to treatment. Macrolide-resistant MAC is associated with a lower rate of culture conversion.4 Of note, subjects whose MAC exhibited a high level of amikacin resistance were excluded from studies of amikacin liposome inhalation suspension.14 Finally, the treatment history is highly relevant. Studies have enrolled subjects who met criteria for “treatment-refractory” disease (ie, defined as positive cultures despite ≥ 6 months of a guideline-based multidrug regimen), but these are different from a population naive to antibiotic treatment. Even in the treatment-refractory cohorts, there were widely disparate treatment regimens and durations of treatment. Although there are recommendations for drug regimens in MAC-PD, evidence suggests they are infrequently followed in actual clinical practice.16,17
Table 2.
Heterogeneous Factors Complicating NTM Clinical Trials
| Subject factors |
| Underlying disease and comorbidities |
| History of treatment of NTM infection (eg, naive, refractory to treatment) |
| Radiographic features (eg, nodules, presence of cavities) |
| Pathogen and antimicrobial susceptibility |
| Clinical end points |
| Baseline symptoms (ie, able to detect change?) |
| Baseline functional status (eg, 6-min walk distance) |
| Study design parameters |
| Duration of the study |
| Superiority vs noninferiority statistical analysis |
| Blinding and monitoring |
| Companion drugs |
See Table 1 legend for expansion of abbreviation.
Enriching for Responders
Subjects enrolled into a trial should have baseline measures of clinical outcomes that suggest they could show improvement (or worsening), or in other words, they should have the capacity to change. In one study, there was a wide range of baseline symptom scores and functional status (as measured by 6MWT).14 Some patients had relatively few symptoms (ie, normal score) and a 6MWT distance in the normal range for healthy subjects, therefore leaving little or no room for symptomatic or functional improvement.
Duration of Study
Although treatment guidelines recommend a duration of 12 months following culture conversion, this recommendation does not mean that a drug assessment requires a study of this duration. If a drug is efficacious, a clinical and microbiologic response should be expected within a much shorter period in most instances. Clinicians on the panel suggested strong consideration for limiting trials to 3 to 6 months or even less, as they desire the opportunity to change treatment if there is a perceived lack of efficacy. Therefore, if a study is to be based on clinical outcomes, then it was believed that the primary end point should be assessed earlier than the end of treatment. The observation, described earlier, that symptoms often improve in the first few months of therapy suggest that symptomatic improvements in short-term studies would be demonstrable. This presumes that the outcome measure is not caused by the drug (eg, cough due to inhaled therapies). Long study durations also increase the likelihood of significant changes to background regimens that will affect assessment of both the efficacy and safety of the studied drug.
Comparator and Companion Drugs
The study of a drug requires comparison vs something, whether an active comparator or a placebo, to determine safety and efficacy. For the subjects who have treatment-naive NTM-PD, several options could be considered. Monotherapy could be compared vs a placebo, but depending on the drug and its mechanism, there may be discomfort using a single drug against NTM for fear of selecting for resistance, although perhaps this fear could be overcome with short study durations. Alternatively, the study drug could be combined with others to mitigate potential generation of drug resistance and compared vs a placebo regimen. This option perhaps is the most acceptable, as in clinical practice, we often do not start patients needing therapy for 3 to 6 months during the initial evaluation; this time is used to educate patients, obtain microbiologic information, adopt pulmonary hygiene measures, and assess for disease progression. However, periods of placebo exposure for greater time periods could be problematic for patient safety, but the allowance of rescue therapy should mitigate such concern. Another option is to use the investigational drug or placebo as an add-on or replacement of a drug in a multidrug regimen to show “incremental benefit” of the drug. This approach requires a much greater number of patients and much longer study duration to have sufficient statistical power to show a benefit over the comparator regimen (assuming it is an active and efficacious comparator). Lastly, patients with treatment-refractory disease could have the study drug or placebo as an add-on to a failing standard regimen.
This issue raises questions regarding what defines acceptable companion therapy for NTM-PD. All medications have potential adverse effects that may be intolerable or toxic. They may interact with the subject’s other medications, preventing use of some antibiotics. It therefore cannot be presumed that all subjects would be treated with the same medications. Combinations would need to be justified by evidence that supports efficacy, safety, or prevention of resistance.
Study Outcome Measures
As noted earlier, there is a need for a clinical outcome measure that satisfies regulatory requirements and patient expectations as well. Currently there is no validated instrument for the specific purposes of NTM treatment trials. To assess how a patient “feels,” the preferred instrument is one that assesses PROs. A major challenge is the heterogeneity of symptoms reported by patients. For some patients, cough is the primary symptom, whereas for others it may be fatigue; to include both types of patients in a study, the instrument must be sensitive to changes in both. Instruments that have been used in studies include the St. George’s Respiratory Questionnaire and the Quality of Life-Bronchiectasis questionnaire, and each has demonstrated improvement while on treatment,18,19 although neither has shown obvious differences associated with treatment in controlled clinical trials.9,14 Perhaps they could be refined to be more sensitive to change with respect to NTM-PD, although neither of these instruments was designed for this purpose; it may be necessary to develop new instruments. A recent publication evaluating the Quality of Life-Bronchiectasis questionnaire with an NTM module in an observational cohort found improvement to correlate with culture conversion in MAC-PD patients.19 The data suggest potential utility of these PROs, and they should be evaluated in prospective fashion. The FDA provides guidance on the development of PROs for use in drug development [http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM205269.pdf].
These instruments must also be sensitive to identifying when symptoms are attributed to the underlying condition or the treatment itself. For example, systemic antibiotics could cause fatigue, and inhaled antibiotics are known to provoke cough.14 It is difficult to assess when the symptom is both an adverse event and a treatment outcome. This observation raises the necessity for careful consideration regarding the timing of these measurements, whether while on therapy or at some time point following their discontinuation. A limitation of quality of life measures is that they are usually performed at two fixed time points (eg, baseline and a defined time point during treatment). In the context of NTM-PD, some symptoms may increase while on treatment due to the impact of drugs, but earlier sputum culture conversion could result in a shorter treatment period and, therefore, shorter duration of treatment-related symptoms. Treatment-related symptoms may be mitigated, and the therapy better tolerated, if patients are apprised of what to expect. Patients typically understand and welcome the concept of “short-term pain for long-term gain”; our current methods of assessment of PROs will need to address this concept as well.
Although PROs are preferred, there are clinician-reported outcomes and performance outcomes that may also be relevant. Radiographic changes have been reported in the literature, but there is no validated scoring method that has been tested in NTM-PD treatment trials. Also, radiographic changes do not meet the definition of efficacy in terms of “feels, functions, and survives.” The 6MWT has been used in studies showing improvement with active treatment in a smaller trial but not in the larger trial.9,14 Interestingly, however, the measure was significantly correlated with culture conversion in both studies. The 6MWT measures physical functioning, but it may not capture the totality of treatment response in NTM-PD; many patients do not experience breathlessness or functional decline. Because the antibiotics would not be expected to directly improve cardiopulmonary performance, the 6MWT might be relevant only for subjects who have shown a significant reduction in infection (eg, bacterial burden, culture conversion). Finally, it may prove useful to consider composite end points, based on a combination of individual end points, for drugs that may benefit patients in several ways, as has been used in other chronic inflammatory conditions (eg, rheumatoid arthritis); this approach may provide reflections of disease activity that are sensitive to change.20
Because this is treatment of an infectious disease, there will be continued interest in microbiologic end points. Successful treatment of NTM-PD by any definition cannot be accomplished without control of the organism in the lung. If microbiologic measures could be shown to serve as a surrogate measure, this might allow for shorter studies. The onus is on investigators to produce evidence that supports or refutes the clinical importance of culture conversion or other microbiologic end points on relevant clinical outcomes. Studies have primarily used culture conversion as the main interpretation of the antibiotic effect, but other measures may reflect bacterial burden. Semi-quantitative culture results have correlated with symptomatic and radiographic improvement, as well as culture conversion.8 Time to positivity in broth cultures can predict microbiologic response to treatment of TB,21 but this topic has not been studied in NTM infections. Molecular techniques are increasingly available and may provide alternatives to culture-based assessment of bacterial burden in the future.
A novel concept would be to show reduction in bacterial burden that associates with clinical benefits but does not eradicate the pathogen. Because eradication is infrequent given our current therapeutic armamentarium, the notion of suppressive therapy is attractive. Designing trials with suppression of pathogens as a goal may still achieve the desired clinical outcomes with long periods of life without disease activity (ie, remission or low disease activity), as is currently done with inhaled antibiotics for the treatment of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis.22 Because many patients with refractory disease remain on antibiotics for years, it would seem that clinicians and patients have already adopted this treatment paradigm as acceptable.
Monitoring During the Study
A key challenge to monitoring during a study is the considerable discomfort expressed by clinicians with blinding to microbiologic data during a prolonged study. Blinding to sputum culture results is done to avoid the impact the results may have on clinician decision-making and possible influences on patient-reported health-related quality of life. To maintain equipoise, it is critical for the clinicians to remain blinded, which is another reason why studies cannot be of long duration. If persistence of NTM in cultures drives treatment decisions, then eventually clinicians will need to know the data if they perceive that patients are not improving.
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 treatment trials. We are in agreement that long duration trials (ie, longer than 3-6 months) are not acceptable, and clinicians expressed a willingness to tolerate trials up to 6 months with placebo and blinding to microbiologic data; after this point, they would want to be able to amend the treatment regimen if there is no clear evidence of improvement.
The next step is to validate novel or existing PROs to be used in NTM-PD treatment trials. Such instruments must identify patients whose symptoms could respond to antibiotic therapy and how those symptoms correlate with microbiologic changes. Refinement of PROs will have to occur in prospective observational trials and eventual testing of the PROs in clinical trials. Finally, there could be development of novel functional measures (eg, wearable devices/steps) that might prove fruitful.
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. J. D. C. reports grants and personal fees from GlaxoSmithKline, Boehringer Ingelheim, Bayer HealthCare, Grifols, and Insmed; personal fees from Napp and Aradigm Corporation; and grants from AstraZeneca and Gilead Sciences, outside of the submitted work. C. L. D. reports grants from Insmed; personal fees from Insmed, Paratek, Johnson & Johnson, Meiji, Matinas BioPharma, Cipla, and Beyond Air; and grants and personal fees from Spero, outside of the submitted work. K. O. reports grants and nonfinancial support from Beyond Air, as well as grants from Matinas BioPharma, outside of the submitted work; and has also served in an (unpaid) advisory capacity for Merck & Co, Qrumpharma, Spero Therapeutics, AN2 Therapeutics, and Oricula Therapeutics. A. O. reports grants from Insmed and the COPD Foundation; and personal fees from Insmed, Merck, Electromed, and Xellia, outside of the submitted work. S. K. reports personal fees from Insmed, outside of the submitted work. K. L. W. reports grants and personal fees from Insmed; and personal fees from Johnson & Johnson, Paratek, RedHill Biopharma, Horizon, and Spero, outside of the submitted work. None declared (T. A., A. L.).
Invited Panelists: External–Timothy Aksamit (Mayo Clinic), Erica Brittain (National Institutes of Health [NIH]/ National Institute of Allergy and Infectious Diseases), James D. Chalmers (University of Dundee), Charles L. Daley (National Jewish Health), Sonya Eremenco (Critical Path Institute), Patrick A. Flume (Medical University of South Carolina), David E. Griffith (UT Health East Texas), Ira Kalfus (RedHill Bio), Shannon Kasperbauer (National Jewish Health), Amy Leitman (NTM Info & Research), Anne O’Donnell (Georgetown University), Kenneth Olivier (NIH/National Heart, Lung, and Blood Institute), Mike Proschan (NIH/National Institute of Allergy and Infectious Diseases), Ashley Slagle (Aspen Consulting), Eugene Sullivan (Insmed), Angela Talley (Spero Therapeutics), Bruce Trapnell (Savara Pharmaceuticals), and Kevin L. Winthrop (Oregon Health Science University). US Food and Drug Administration—Wen-Hung Chen, Ed Cox, Cheryl Dixon, Karen Higgins, Hiwot Hiruy, Peter Kim, Robert Lim, and Sumathi Nambiar.
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Footnotes
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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