A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators.

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

Steps forward in regulatory pathways for acute and chronic heart failure.

A workshop was organized by the Agenzia Italiana del Farmaco (AIFA) to discuss unmet needs and ways forward in the development of medicines in heart failure, their rationale, and cost-effective use. An integrated, multidisciplinary approach, including patients' needs and perspectives, was advocated by all the participants as the way to the most effective treatment regimens. More work is needed for reaching consensus on clinical and functional endpoints, for validating patient reported outcomes and measurements of well-being. Similarly, the integration into the clinical programmes of the health technology assessment/payers perspective, in particular, the evaluation of 'real-life' treatment effectiveness and of health as a value, would help in shifting the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole health care regimen. Through this kind of workshop, AIFA is trying to build a template for meetings devoted to debate unmet needs with all stakeholders towards tentative road maps for the future.

Steps forward in regulatory pathways for acute and chronic heart failure.

A workshop was organized by the Agenzia Italiana del Farmaco (AIFA) to discuss unmet needs and ways forward in the development of medicines in heart failure, their rationale, and cost-effective use. An integrated, multidisciplinary approach, including patients' needs and perspectives, was advocated by all the participants as the way to the most effective treatment regimens. More work is needed for reaching consensus on clinical and functional endpoints, for validating patient reported outcomes and measurements of well-being. Similarly, the integration into the clinical programmes of the health technology assessment/payers perspective, in particular, the evaluation of 'real-life' treatment effectiveness and of health as a value, would help in shifting the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole health care regimen. Through this kind of workshop, AIFA is trying to build a template for meetings devoted to debate unmet needs with all stakeholders towards tentative road maps for the future.

A syringe simulation of biological controls for quality assessment of prospective lung volume measurements.

BACKGROUND: At present a syringe is being used for calibration of lung function devices, but biological controls are used to detect prospectively the variability and reproducibility of lung volumes measured by spirometers. Laboratory personnel is often used as biological control and therefore the cost for these measurements is substantial and may be reduced by replacement of a syringe procedure to increase the capacity of the laboratory to measure more patients. OBJECTIVES: To develop a mechanical syringe procedure for identification of instrument problems. METHODS: A commercial 3-liter precision syringe is used to simulate breathing maneuvers (inspiratory vital capacity, functional residual capacity, residual volume and total lung capacity) on a spirometer. Three healthy males representing biological controls performed spirometry, maximum expiratory flow volume and helium dilution forced residual capacity at bimonthly intervals for 3 years. Confidence intervals and interval widths are calculated for each parameter. Levene's test for equality of variances was used to test for significance between standard deviations. RESULTS: The interval width of inspiratory vital capacity, functional residual capacity, total lung capacity and residual volume of repeated measurements obtained from the syringe was significantly narrower than those of biological controls. In addition, almost all standard deviations from lung volumes obtained from the syringe were smaller and significantly different from those of the biological control. CONCLUSION: Our syringe procedure may replace biological controls for detection of variability of lung volumes. This will result in cost reduction and improve quality assessment of lung function devices.