Use of lung imaging studies as outcome measures for development of new therapies in cystic fibrosis

Abstract

Most cystic fibrosis (CF) drug development has been based upon functional outcomes (e.g., FEV(1)) 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.

Figure 1.

Correlation between development phases and types of study. This matrix graph illustrates the relationship between the phases of development and types of study by objective that may be conducted during each clinical development of a new medicinal product. The shaded circles show the types of study usually conducted in a certain phase of development; the open circles show certain types of study that may be conducted in that phase of development but are less usual. Each circle represents an individual study. To illustrate the development of a single study, one circle is joined by a dotted line to an inset column that depicts the elements and sequence of an individual study. Reprinted from Reference 18.

Figure 2.

Stages of morphologic damage. This diagram illustrates the usual progression of structural and pathologic changes that occur in the airways of patients with cystic fibrosis (CF) as they age. The time frame is highly variable among individuals with CF, but usually commences during the first decade of life. The stages are arbitrarily chosen to link with possible treatment approaches shown at the bottom of the figure and discussed in more detail in the text.