European Respiratory Society
Outcomes in Clinical Trials

The traditional end-points for clinical studies of lung diseases were based on functional parameters. Their value as surrogate markers for disease activity and progression has been increasingly questioned by scientists, carers, regulatory agencies and funding bodies. Novel tools and methods with regard to biomarkers and patient-reported outcomes have made these parameters emerge from their status as interesting secondary end-points and become potential primary outcomes for clinical trials. Nevertheless, their relevance and validity still needs to be proven. This issue of the European Respiratory Monograph describes the current status regarding end-points in all relevant areas of pulmonary medicine.

  • European Respiratory Society Monographs
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      Correspondence: E.F.M. Wouters, Dept of Respiratory Medicine, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. Email:

      Definitions of chronic obstructive pulmonary disease (COPD), put forward in consensus reports and guidelines, reflect the dominance of physiological outcome parameters in clinical COPD trials. The focus on lung function changes and airflow limitation in particular seems paradoxical since, in many definitions, irreversibility of airflow limitation is part of the pathophysiological characteristics of COPD. This chapter reviews a wide variety of markers and outcomes applied in COPD intervention studies.

    2. Page 19
      Correspondence: C. Taube, Dept of Pulmonology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Email:

      Asthma is a heterogeneous syndrome with different phenotypes. This makes it necessary to measure different outcome parameters in clinical trials to adequately assess the response of a patient to a therapy. One issue was the heterogeneous assessment of different outcome parameters, which sometimes made it impossible to compare the results from different studies. Therefore, initiatives by the American Thoracic Society and the European Respiratory Society, as well as by the National Institutes of Health, resulted in recommendations on the assessment of different outcome parameters in asthma. These include symptoms, lung function, exacerbations, health-related quality of life and biomarkers. These outcome parameters describe different dimensions of the disease and a certain panel of parameters has been recommended as a basic outcome parameter for clinical trials in patients with asthma.

    3. Page 37
      Correspondence: T.M. Maher, Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. Email:

      Following publication of the first true multicentre randomised controlled trial in 2004, there has been an exponential growth in clinical trial activity in idiopathic pulmonary fibrosis (IPF). Whilst the majority of trials published to date have been negative, each has generated information on the strengths and limitations of a range of clinical trial outcome measures. Furthermore, analysis of clinical trial data has improved understanding of disease behaviour as well as the utility of many routinely collected clinical measures. However, despite this, there remains considerable debate about the optimal choice of primary end-point for registration studies in IPF with all-cause mortality, progression-free survival and forced vital capacity all having their advocates. For early-phase studies in IPF there is a lot less clarity around optimal outcome measures with few if any able to detect meaningful disease change in a sufficiently small sample size.

    4. Page 54
      Correspondence: R. Amin, Dept of Respiratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. Email:

      The most commonly used outcome measures in clinical trials in cystic fibrosis (CF) patients include forced expiratory volume in 1 s (FEV1), pulmonary exacerbations and, more recently, health-related quality of life. These three outcomes are considered surrogate end-points by the CF research community and regulatory agencies, as improvements in these parameters are likely to predict clinical benefit. However, with improved patient clinical status, pulmonary function tests such as FEV1 are often within the normal range and pulmonary exacerbations requiring hospitalisation have become a less frequent event. Hence, there is a need for new, more sensitive outcome measures. Novel end-points undergo a rigorous validation process before they can be used as primary outcomes in pivotal clinical trials. Here, we review the established surrogate end-points used in clinical trials in CF and provide an overview of other promising end-points, such as multiple-breath washout technology, imaging technology, measures of airway infection and inflammation focusing on bronchoalveolar lavage and sputum, as well as intestinal current measurements.

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      Correspondence: H. Olschewski, Ludwig Boltzmann Institute for Lung Vascular Research, Stiftingtalstrasse 24, 8010, Graz, Austria. Email:

      The number of clinical studies on pulmonary arterial hypertension (PAH) and, as a result, the number of available drugs for the disease has grown rapidly over the past two decades. Epoprostenol was the first targeted therapy that was registered for PAH. It was followed by further prostanoids (treprostinil and iloprost), endothelin receptor antagonists (bosentan and ambrisentan) and phosphodiesterase-5 inhibitors (sildenafil and tadalafil). Two additional drugs have also currently been submitted for approval. Further clinical trials have evaluated combination therapy in PAH and PAH drugs in non-PAH pulmonary hypertension. Recently, pilot studies have addressed the effects of PAH drugs in patients with very early pulmonary vascular changes who do not fulfil the criteria of manifest PAH. The aim of this chapter is to provide a guide to the most important previous and current PAH trials in order to give an overview of the current therapeutic approaches in PAH.

    6. Page 85
      Correspondence: D.J. Cook, Room D176 St Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, ON, Canada. Email:

      In this chapter, we discuss some pros and cons of different selected outcome measures for randomised clinical trials in the intensive care unit. The most important principle is that the outcome measure selected should reflect the objective of the trial. Choosing the best outcome for a randomised controlled trial is one of the most important elements of study design for those running the trial. Interpreting that outcome in the light of other study outcomes is one of the most important skills of readers. Pilot trials are useful tools to ensure mechanistic plausibility and feasibility of larger trials, along with other objectives. While mortality may be the most robust patient-important outcome, other outcomes may be suitable, such as ventilator-free days and quality-adjusted life-years, and could reduce the sample size requirements. Adjudication is a useful tool to ensure validity of outcomes prone to bias in judgement. Ultimately, the choices of primary, secondary and tertiary outcomes need to be informed by the research question and selected in the context of research resources.

    1. Page 90
      Correspondence: A. Prasse, Dept of Pneumology, University Medical Clinic Freiburg, Kilianstrasse 5, 79106 Freiburg, Germany. Email:

      In the last decade, major advances have been made in the field of biomarker research in various lung diseases, including asthma, chronic obstructive pulmonary disease, lower respiratory tract infections, lung cancer and interstitial lung diseases. Multiple biomarkers have been implemented in the clinical practice of respiratory physicians. In parallel with the evolving field of personalised medicine, the number of clinical trials that utilise biomarkers is increasing every year. The concepts of biomarker-stratified patient selection and targeted therapy have been established and their efficiency successfully proven. In lung cancer research, which takes a pioneering role, biomarker-driven research has become an integral part of nearly every clinical trial. Moreover, biomarkers are used to predict and monitor treatment responses. This chapter summarises current achievements of clinical trials in biomarker research related to lung diseases.

    2. Page 96
      Correspondence: P.W. Jones, Division of Clinical Science, St George’s, University of London, London, SW17 0RE, UK. Email:

      Health status measurements are used as a marker of impaired quality of life and now form an integral part of clinical trials. They complement markers of pathophysiological processes and can provide an overall measure of the impact of symptoms and the level of benefit due to treatment. In this chapter, chronic obstructive pulmonary disease is taken as an example. A number of disease-specific measures are available, which differ in method of development, size and structure. They can provide important clinical insights and generate questions about mechanisms of benefit. The older instruments are now being recognised by regulatory authorities as valid outcome measures in clinical trials, but some of the new shorter instruments may eventually replace them. Methods of analysing health status data in the context of clinical trials are still evolving and have to deal with issues of clinical trial effects and the effect of early drop-out. There are particular challenges associated with comparison of the magnitude of difference in effect between active drugs.

    3. Page 105
      Correspondence: S.L. Eremenco, Evidera, Inc., 7101 Wisconsin Avenue, Suite 600, Bethesda, MD, 20814, USA. Email:

      This chapter provides an overview of the use of electronic patient-reported outcomes (ePRO) in clinical trials focusing on respiratory and pulmonary contexts. Benefits of ePRO data collection include less subject burden, avoidance of secondary data entry errors, easier implementation of skip patterns, date and time stamping, more accurate and complete data, and less missing data. Patient-reported outcome end-points collected in clinical trials include end-points used across therapeutic areas, such as symptoms and impact, as well as those specific to the respiratory/pulmonary context, such as rescue medication use, healthcare resource utilisation, and physiological end-points. Common modes of data collection used in clinical trials and considerations for mode selection and migration from paper to electronic modes are discussed. Finally, study design considerations when implementing ePRO in clinical trials include the frequency and timing of assessments, compliance strategies for clinical trials, and compliance monitoring. Appropriate mode selection, migration, and clinical trial implementation are key steps to realise the benefits of ePRO in clinical trials.

    4. Page 117
      Correspondence: H. Watz, Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research, Woehrendamm 80, D-22927 Grosshansdorf, Germany. Email:

      Many health benefits related to primary and secondary prevention of chronic diseases can be ascribed to regular physical activity. Respiratory diseases often lead to physical inactivity, which is an indicator of poor prognosis in chronic obstructive pulmonary disease. Sustained improvement of physical inactivity is a key component in the treatment of respiratory diseases and is believed to be a clinically relevant end-point. However, more research is needed to accurately measure levels of physical activity and to define clinically meaningful changes for patients. The greatest impact of regular physical activity on mortality reduction can be achieved by mild-to-moderate physical activity making physical inactivity a modifiable risk factor for non-communicable diseases, with an impact or mortality rate comparable to that of smoking.

    5. Page 127
      Correspondence: D.E. O'Donnell, Dept of Medicine, Queen's University, 102 Stuart Street, Kingston, ON, K7L 2V6, Canada. Email:

      Pulmonary function tests are paramount for diagnosis, follow-up and prognosis in patients with suspected or established lung disease. Accordingly, they remain widely used in assessing the efficacy of medical and surgical treatments in respiratory medicine. Chronic obstructive pulmonary disease (COPD) epitomises a complex, multi-component disease in which pulmonary function tests have played a major role in establishing the current standards of treatment. However, it has become clear that assessment of the underlying physiological impairment in COPD requires an abundance of information, which exceeds that provided by simple spirometry. Based on the large accumulated experience from pulmonary function tests in clinical trials involving patients with COPD, this chapter provides an overview of the physiological rationale, strengths and limitations of a range of established and emerging physiological markers for potential use in future investigations of pharmacological therapy in mild-to-severe chronic respiratory disease.

    6. Page 146
      Correspondence: D.G. Parr, Cardio-Respiratory Division, University Hospital Coventry, Clifford Bridge Road, Coventry, CV2 2DX, UK. Email:

      Contemporary imaging modalities have been employed as biomarkers in a wide range of respiratory diseases. Quantitative assessment of morphology, function and molecular pathogenetic processes using imaging potentially offers significant advantages over traditional outcome measures, particularly in clinical studies of slowly progressive disorders and rare diseases. The variety and complexity of techniques have developed greatly over the last few decades but translation from “bench to bedside” into accepted outcomes for use in clinical studies has lagged behind. Consequently, the extensive literature on methodological detail is not yet appropriately reflected in tangible clinical productivity. Computed tomography densitometry and morphometry are the most validated imaging biomarkers and, consequently, clinical experience is greatest in these modalities, particularly in the field of obstructive airway disease. Progress in the clinical arena will require consensus on appropriate validation strategies and procedural standardisation, and the involvement of industry, and regulatory and reimbursement agencies should be sought at an early stage of development in order to deliver benefit effectively to patients.

    7. Page 170
      Correspondence: T. Troosters, University Hospitals Leuven, Respiratory Division, Pulmonary Rehabilitation, Herestraat 49, B3000 Leuven, Belgium. Email:

      Exercise tests are increasingly used to assess the effects of pharmacological and nonpharmacological interventions. They are also used to study symptoms and the reduction thereof, as well as the mechanisms of action of interventions.

      Laboratory tests are particularly useful to study the physiology of exercise, operational lung volumes, gas exchange and symptoms. Field tests are less complex and less controlled, but can be deployed in settings where an exercise laboratory is not available. Functional exercise tests are designed to assess the capacity of patients to cope with exercise relevant to daily function, such as walking, stair climbing or combined tasks. Cycle tests may be more sensitive to change in studies where besides lung function also peripheral muscle improves. Walking tests may be more sensitive to change when an intervention improves lung function only. A last choice in terms of determining the optimal test for a clinical trial is to use either endurance or incremental tests. In chronic obstructive pulmonary disease, endurance tests have shown to be much more responsive than incremental tests, particularly in patients who are ventilatory limited. Other factors that influence the response of interventions are the exercise intensity and the duration for which the intervention is applied.

    8. Page 179
      Correspondence: D.J. Kass, University of Pittsburgh, 3459 Fifth Ave, MUH 628NW, Pittsburgh, PA 15213, USA. Email:

      The promise of personalised medicine is to employ the most basic molecular make-up of a patient to drive individualised, efficacious and cost-effective treatments. Omics, technologies that measure biological function on a global basis, is the key to opening the door to personalised medicine. However, advances in omics technologies have not been incorporated into current clinical trial design in pulmonary medicine. We suggest that the next generation of treatments will be driven by the collection of omics data in patients participating in pulmonary clinical trials. This is critically important because patient populations presenting with chronic advanced lung diseases such as asthma, chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis are heterogeneous and complex, and thus to prove outcomes, studies need to be large and costly. Integrating omics in our clinical trial designs will allow trialists to focus treatments on patients likely to respond and to identify clinically relevant surrogate outcome and drug effect biomarkers. Omics will also lead to unprecedented opportunities for biological discovery in the pathogenesis of lung disease. In this chapter, we focus on how omics technologies will address the shortcomings of current clinical trial designs and what the challenges of incorporating omics into clinical trials are.