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Use of Lung Imaging Studies as Outcome Measures for Development of New Therapies in Cystic Fibrosis

¹ Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington

Correspondence and requests for reprints should be addressed to Bonnie W. Ramsey, M.D., Children's Hospital and Regional Medical Center, 4800 Sand Point Way NE, Mailstop MPW5-4, Seattle, WA 98105. E-mail: bonnie.ramsey{at}seattlechildrens.org

ABSTRACT

Most cystic fibrosis (CF) drug development has been based upon functional outcomes (e.g., FEV₁) rather than structural changes. This functional approach has the limitation of being insensitive of early changes in lung disease. Computer tomography (CT) scanning affords the opportunity to establish a new paradigm to stage the illness (and target populations) based upon morphology. Using this concept, treatment regimens would be tested to prevent progression, reverse early changes, or stabilize established structural damage. In this setting, imaging biomarkers could play a key role. This article reviews the potential uses of CT scanning in the different phases of drug development (phase 1 to 4 studies). In early-phase studies (i.e., human pharmacology and therapeutic exploratory trials), CT could be used to provide preliminary data on mechanisms of action and efficacy. For large phase 3, therapeutic, confirmatory trials, CT scans are less likely to be the primary endpoint, but may play a supportive role in clinical efficacy measures and subset analyses (e.g., infants). For postmarketing therapeutic use trials, CT scans could play an important role in defining long-term efficacy in subpopulations, such as infants and children. Further steps need to be taken to optimize imaging biomarkers. These steps include establishing standard procedures across multiple research sites, centralized reading centers, and a common scoring system. To validate optimal CT parameter(s), the CF community must continue to collect CT data in phase 1 and 2 trials documenting response to therapeutic intervention. In addition, there is a need for additional longitudinal epidemiology studies to establish the association of CT changes with other outcome measures, such as pulmonary function tests, quality of life measures, and mortality.

Key Words: cystic fibrosis • lung imaging • clinical trials