Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies

VanDevanter, Donald R.; Mayer-Hamblett, Nicole

doi:10.1097/mcp.0000000000000418

Cited by 10 publications

(8 citation statements)

References 26 publications

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“…Validated surrogate endpoints may be used if they are strongly associated with direct clinical endpoints. Growth has been used in the past as a validated surrogate endpoint, though not in any recent drug trials 35,37 . As CFTR modulator studies expand to younger populations, linear growth may be affected and may again become an outcome of interest 34,38 .…”

Section: Clinical Developmentmentioning

confidence: 99%

Drug development for cystic fibrosis

Sanders

Chmiel

2021

Pediatric Pulmonology

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The first regulatory approval for a drug developed specifically for cystic fibrosis (CF) occurred in 1993, and since then, several other drugs have been approved. Median predicted survival in people with CF in the United States has increased from approximately 30 years to 44.4 years over that same period. Highly effective modulators of the cystic fibrosis transmembrane conductance regulator became available to approximately 90% of people with CF ages 12 years and older in the United States in 2019 and in Europe in 2020. These transformative therapies will surely reduce morbidity and further extend longevity. The drug development pipeline is filled with therapies that address most aspects of CF disease. As survival and CF therapies advance, and the complexity of CF care increases, the process of drug development has become more sophisticated. In addition, detecting meaningful changes in outcome measures has become more difficult as the health status of people with CF improves. Innovative approaches are required to continue to advance drug development in CF. This review provides a general overview of drug development from the preclinical phase through Phase IV. Special considerations with respect to CF are integrated into the discussion of each phase of drug development. As CF care evolves, drug development must continue to evolve as well, until a one-time cure is available to all people with CF.

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Section: Clinical Developmentmentioning

confidence: 99%

Drug development for cystic fibrosis

Sanders

Chmiel

2021

Pediatric Pulmonology

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“…An additional challenge is the design of CF gene therapy trials in the age of highly effective modulator therapies, when discontinuation of those therapies may not be possible, and simple placebo controls are unlikely to be acceptable. 50 Finally, for the first trials using integrating vectors or gene-editing agents that can target the airway stem cells, the patient population requires additional thought, as it is possible that only patients with advanced disease will be eligible, due to the unknown long-term effects of the therapy.…”

Section: Lung Genetic Therapies Require New Outcome Assessment Technimentioning

confidence: 99%

Will Airway Gene Therapy for Cystic Fibrosis Improve Lung Function? New Imaging Technologies Can Help Us Find Out

Parsons

Donnelley

2020

Human Gene Therapy

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The promise of genetic therapies has turned into reality in recent years, with new first-line treatments for fatal diseases now available to patients. The development and testing of genetic therapies for respiratory diseases such as cystic fibrosis (CF) has also progressed. The addition of gene editing to the genetic agent toolbox, and its early success in other organ systems, suggests we will see rapid expansion of gene correction options for CF in the future. Although substantial progress has been made in creating techniques and genetic agents that can be highly effective for CF correction in vitro, physiologically relevant functional in vivo changes have been largely prevented by poor delivery efficiency within the lungs. Somewhat hidden from view, however, is the absence of reliable, accurate, detailed, and noninvasive outcome measures that can detect subtle disease and treatment effects in the lungs of humans or animal models. The ability to measure the fundamental function of the lung-ventilation, the effective transport of air throughout the lung-has been constrained by the available measurement technologies. Without sensitive measurement methods, it is difficult to quantify the effectiveness of genetic therapies for CF. The mainstays of lung health assessment are spirometry, which cannot provide adequate disease localization and is not sensitive enough to detect small early changes in disease; and computed tomography, which provides structural rather than functional information. Magnetic resonance imaging using hyperpolarized gases is increasingly useful for lung ventilation assessment, and it removes the radiation risk that accompanies X-ray methods. A new lung imaging technique, X-ray velocimetry, can now offer highly detailed regional lung ventilation information well suited to the diagnosis, treatment, and monitoring needs of CF lung disease, particularly after the application of genetic therapies. In this review, we discuss the options now available for imaging-based lung function measurement in the generation and use of genetic and other therapies for treating CF lung disease.

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“…An example would be a non-inferiority study, which is designed to show that a new therapy is not unacceptably worse than current standard therapy. This situation may arise in CF when comparing a new drug within the same therapeutic class (e.g., CFTR modulator or new inhaled antibiotic) to an established drug when comparison with a placebo would not be acceptable (42). Clinician surveys have indicated that many are uncomfortable withdrawing efficacious medications (43).…”

Section: Clinical Trial Endpointsmentioning

confidence: 99%

Drug Development for Cystic Fibrosis

Sanders

Chmiel

2020

Preprint

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The first drug specific for cystic fibrosis (CF) was approved in 1993, and since then several other drugs have been approved. Median predicted survival in people with CF has improved from approximately 30 years to 44.4 years over that same period. In 2020, highly-effective modulators of the cystic fibrosis transmembrane conductance regulator became available to approximately 90% of people with CF ages 12 years and older. These transformative therapies will surely reduce morbidity and further extend longevity. The drug development pipeline is filled with therapies that address most aspects of CF disease. As survival and CF therapies have advanced, and the complexity of CF care increases, the process of drug development has become more sophisticated. In addition, detecting meaningful changes in clinical outcomes has become more difficult as the health status of people with CF improves. Design of clinical trials in CF has become more complex, and innovative approaches are required to continue to advance drug development. This review provides a general overview of drug development from the pre-clinical phase through Phase IV. Special considerations with respect to CF are integrated into the discussion of each phase of drug development. The dawn of a new era has arrived for people with CF. As CF care evolves, drug development must continue to evolve as well, until a one-time cure is available to all people with CF.

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Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies

Cited by 10 publications

References 26 publications

Drug development for cystic fibrosis

Drug development for cystic fibrosis

Will Airway Gene Therapy for Cystic Fibrosis Improve Lung Function? New Imaging Technologies Can Help Us Find Out

Drug Development for Cystic Fibrosis

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