Aspergillus Galactomannan Index: A Surrogate End Point to Assess Outcome of Therapy?

In this issue of Clinical Infectious Diseases, Miceli et al. [1] have investigated the correlation between circulating Aspergillus galactomannan values and clinical outcomes (survival) using data derived from the published literature on the use of the galactomannan assay. As such, the authors have touched on an important and challenging aspect of clinical trial design: can resolution of galactomannan antigenemia be used as a reliable surrogate end point of antifungal drug efficacy in clinical trials? There is little doubt that there are opportunities to improve our current and historical antifungal clinical trial designs, and because future drug development is being threatened by the negative calculated yields of pharmaceutical cost-benefit analyses, clinicians can argue that improved design leading to both more-definitive and more-efficient clinical trials has never been so important. Because the Infectious Diseases Society of America Antimicrobial Availability Task Force recently identified Aspergillus species as 1 of the 6 particularly problematic pathogens for which current outcomes and drug availability necessitate a "high priority" status [2], improving end points in studies of aspergillosis is a very timely goal. Clinical trials are performed to provide definitive evidence of the safety and efficacy of drugs or therapeutic approaches (e.g., drug combinations). Without a definitive study design, it is arguable whether enrollment of patients and exposure to potentially harmful therapies is even ethical. Defining end points to appropriately measure both efficacy and safety is one of the largest challenges in trial design. To measure the benefit-to-risk ratio, primary clinical end points should be clinical efficacy measures that both are significant (e.g., death, quality of life, and organ function) and adequately reflect the disease process that is impacted by the drug; one working group defined a clinical end point as "a characteristic or variable that reflects how a patient feels or functions, or how long a patient survives" [3, p. 568]. To facilitate performance of clinical trials, some researchers have advocated for the use of biomarkers or "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention" [3, p. 568] . A surrogate end point is a biomarker that is used to substitute for a clinical end point; it may be reliable when the marker both correlates with clinical outcome and fully captures the treatment effect [4] . A surrogate end point may be most useful when the outcome of a chronic disease process can take a long time to measure. Studies in oncology and cardiology have relied heavily on the use of surrogate markers [3]. Tumor markers (e.g., prostate-specific antigen and carcinoembryonic antigen) and tumor imaging (e.g., positron emission tomography and CT) are commonly employed in oncology trials. Cardiology trials have used surrogate end points to gain drug approval; for instance, blood pressure monitoring and cholesterol reduction have been accepted because of their correlation with the risks of heart disease and stroke [3]. Although the use of biomarkers may indicate efficacy in 1 biologic process, their use as substitute clinical end points (surrogate end points) has been associated with some controversy. Fleming and DeMets [5, 6] have reminded us that correlates do not necessarily make surrogates, largely because clinical outcomes are affected by multiple causative pathways, some of which are not measured by biomarkers that are even closely correlated with drug activity. This scenario comes into play when considering possible toxicities of a drug and in situations in which the natural history of the process is not well defined (or impacted by multiple variables). Therefore, it has been suggested that biomarkers are useful for phase 2 Received 10 December 2007; accepted 11 December 2007; electronically published 20 March 2008. Reprints or correspondence: Dr. Kieren A. Marr, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239 (marrki@ohsu.edu).