|
In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis.Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts.The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. Itroduction Outcome measures fall into three classes: clinical end-points, surrogate end-points and biomarkers.Clinical end-points reflect how a patient feels, functions or survives [1, 2] and detect a tangible benefit for the patient. The improved life expectancy in cystic fibrosis has rendered survival, the gold standard clinical efficacy measure, an impossible end-point to use in clinical trials. Therefore, intermediate clinical efficacy measures, such as the frequency of respiratory exacerbation were introduced. The latter has been used in registration trials for rhDNase [3], tobramycin solution for inhalation [4] and aztreonam lysinate [5]. Clinical end-points particularly useful for young children include anthropometric measures. Quality of life as measured by the Cystic Fibrosis Questionnaire-Revised is also accepted as a measure of treatment benefit in cystic fibrosis [6, 7]; however, it is considered only an optional end-point by the European Medicines Agency [6, 8]. A surrogate end-point is a laboratory measurement used as a substitute for clinical end-points and predicts the efficacy or toxicity of therapy [1, 2]. It is an indirect measurement of effect and is used when direct measurement of clinical effect is not feasible or practical. Surrogate end-points can be used complementary to measures of treatment benefit and may shorten the period of follow-up required. The link between the surrogate end-point and survival, long-term prognosis or accepted measures of treatment effect (both improvement and deterioration) must be proven. Forced expiratory volume in 1 s (FEV1) has been widely used as a surrogate end-point due to the established link with survival [9]. However, in many patients with cystic fibrosis, the rate of decline in FEV1 has slowed [10], limiting the current sensitivity of the measure, particularly in children or in patients with mild lung disease [10, 11]. A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or pharmacologic response to a therapeutic intervention” (e.g. nasal potential difference (NPD), mucociliary clearance, inflammatory markers and sputum bacterial density) [1, 2]. These measures are mainly used in phase-I or -II clinical trials when proof-of-concept for a specific compound is explored. Biomarkers are useful for gaining information about the mechanism of action of potential drugs, for identifying treatment responders and for dose selection. Some biomarkers are currently being considered for “promotion” to the status of surrogate end-point. They are often used as secondary outcome measures in phase-III trials which provide data on responsiveness, confirm mechanism of action and compile information for promotion of biomarkers to surrogate outcome measure. During phase-III trials with ivacaftor, cystic fibrosis transmembrane conductance regulator (CFTR) correctors (Vertex Pharmaceuticals Ltd, Cambridge, MA, USA) and ataluren (PTC Therapeutics Inc., South Plainfield, NJ, USA) in patients with cystic fibrosis, CFTR biomarkers are being used as end-points. These new therapies address the basic defect in cystic fibrosis and may be particularly well suited for people with early or mild lung disease. To gain acceptance by researchers and licensing bodies, an outcome measure must be assessed for clinimetric properties, such as reliability, validity and responsiveness to treatment (table 1). Reliability (e.g. an assessment of the consistency of a given measurement), is important, both in terms of inherent biological variation (repeatability) and also in relation to differences across different assessors and centres (reproducibility). To optimise reliability in multiple centre trials, standardised operating procedures (SOPs) and training are needed [12]. Validity refers to clinical and biological relevance; in other words, there must be a direct link with the disease process and the mechanism of action of the intervention [13]. The outcome measure should correlate with established measures of treatment benefit or a gold standard (i.e. concurrent validity and predictive validity) and reflect clinical severity (i.e. discriminate validity) [14]. When a gold standard is not available, evaluation of convergent validity can be performed (i.e. an outcome measure can be compared with another which measures the same attribute). Prediction of prognosis is also important, for example, the ability to predict survival (predictive validity). Responsiveness refers to the ability of the measurement to detect change due to an intervention known to alter the attribute of interest. CONCLUSION This document provides a systematic review of the clinimetric properties of CFTR biomarkers and provides supporting evidence for promoting these biomarkers to surrogate end-points. Data collected demonstrate the reliability, validity and responsiveness of NPD. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness are demonstrated. Validity is demonstrated for ICM, but further information is required on reliability and responsiveness. Normal values are collected for all three end-points. Further research requirements are proposed for each end-point. In particular, sweat test and ICM require further supporting data. There is great interest in biomarkers and surrogate end-points in cystic fibrosis. It is already more than a decade ago that participants in a National Institutes of Health (NIH) workshop challenged statisticians to develop robust metrics to study relationships between surrogate end-points, clinical end-points and interventions [1]. That NIH workshop also highlighted the need to assess data from both epidemiological studies and randomised clinical trials as a source of information on biomarkers when considering promotion to surrogacy [1]. In a small population such as cystic fibrosis, it is all the more important that valuable information is shared and that centres work together to improve clinical research. Acknowledgments Author affiliations are as follows. K. De Boeck, F. Vermeulen and M. Proesmans: University Hospital of Leuven, Leuven, Belgium; L. Kent: University of Ulster, and Belfast Health and Social Care Trust, Belfast, UK; J. Davies: Dept of Gene Therapy, National Heart and Lung Institute, Imperial College, London, UK; N. Derichs: CFTR Biomarker Centre and Cystic Fibrosis Centre, Dept of Paediatric Pulmonology and Immunology, Charité University Berlin, Germany; M. Amaral: Centre for Human Genetics, National Institute of Health Dr Ricardo Jorge, and Dept of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal; S.M. Rowe: Dept of Medicine, University of Alabama, Birmingham, AL, USA; P. Middleton: Ludwig Engel Centre for Respiratory Research, Westmead Millennium Institute, Westmead, Australia; H. de Jonge: Depts of Paediatric Gastroenterology and Biochemistry, Erasmus University Medical Centre, Rotterdam, the herlands; I. Bronsveld and R.A. de Nooijer: University Medical Centre, Utrecht, the herlands; M. Wilschanski: Pediatric Gastroenterology Unit, Hadassah University Hospitals, Hebrew University Medical School, Jerusalem, Israel; P. Melotti: Centro Fibrosi Cistica, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; I. Danner-Boucher: Laboratoire des Explorations Fonctionnelles and Service de Pneumologie, Hôpital G and R Laënnec, Nantes, France; S. Boerner: CF Center Cologne, University of Cologne, Cologne, Germany; I. Fajac: Service d'Explorations Fonctionnelles, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; K. Southern: Dept of Women's and Children's Health, University of Liverpool, Liverpool, UK; A. Bot: Dept of Biochemistry, Sophia Children's Hospital, Erasmus MC, Rotterdam, the herlands; Y. de Rijke: Dept of Internal Medicine, Erasmus University Medical Centre, Rotterdam, the herlands; E. de Wachter: Dept of Pediatric Pulmonology and CF-Clinic, Universitair Ziekenhuis Brussel, Brussels, Belgium; T. Leal: Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium; M.J. Hug: University Medical Centre, Freiburg, Germany; G. Rault: Centre de Référence et de Compétence de la Mucoviscidose, Centre de Perharidy, Roscoff, France; T. Nguyen-Khoa: Depts of Biochemistry A and Paediatric Pulmonology, CRCM, Hôpital Necker-Enfants Malades AP-PH, Paris, France; C. Barreto: Dept of Paediatrics, Hospital de Santa Maria, Lisbon, Portugal; and I. Sermet-Gaudelus: Hôpital Necker-Enfants Malades, Université Paris Descartes, INSERM U 845, Paris, France.()
|
