Integrating real-life studies in the global therapeutic research framework

Therapeutic guidelines draw heavily on evidence from randomised controlled trials (RCTs) undertaken in well-characterised, highly-selective populations and managed in tightly-controlled settings. Respiratory RCTs have high internal validity, but often represent fewer than 5% of patients treated in routine care.1Herland K Akselsen J-P Skjønsberg OH et al.How representative are clinical study patients with asthma or COPD for a larger 'real life' population of patients with obstructive lung disease?.Respir Med. 2005; 99: 11-19Summary Full Text Full Text PDF PubMed Scopus (275) Google Scholar As such, the extent to which RCT efficacy can be extrapolated to indicate outcomes achievable in real-life respiratory populations and routine care settings is often unclear. So-called real-life research typically refers to pragmatic trials and observational studies designed to better reflect aspects of routine care than most RCTs.2Price D Chisholm A van der Molen T Roche N Hillyer EV Bousquet J Reassessing the evidence hierarchy in asthma: evaluating comparative effectiveness.Curr Allergy Asthma Rep. 2011; 11: 526-538Crossref PubMed Scopus (40) Google Scholar They generally investigate the effectiveness of an intervention, whereas RCTs typically assess its efficacy. Therefore, a real-life study often includes wide patient populations or has follow-up intensity mimicking clinical practice.2Price D Chisholm A van der Molen T Roche N Hillyer EV Bousquet J Reassessing the evidence hierarchy in asthma: evaluating comparative effectiveness.Curr Allergy Asthma Rep. 2011; 11: 526-538Crossref PubMed Scopus (40) Google Scholar Whether or not a study realistically represents real-life conditions can be unclear. A trial might involve intensive patient follow-up, yet include a broad population fairly representative of the true treated population. Conversely, an observational study can focus on outcomes in a highly-selected patient population, yet involve no clinical intervention beyond usual care. The challenge is to recognise and describe which elements of a study represent real-life, and to find a unified way of presenting them. We proposed a framework to classify different studies by design to assist those involved in the use, conduct, review, and quality appraisal of therapeutic research, including patients, clinicians, policy-makers, and guideline developers. It distills the discussions of the Respiratory Effectiveness Group collaborators held in February and May, 2013. The framework (figure 1)3Pavord ID Korn S Howarth P et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.Lancet. 2012; 380: 651-659Summary Full Text Full Text PDF PubMed Scopus (1721) Google Scholar, 4Pauwels RA Busse WW O'Byrne PM et al.The inhaled Steroid Treatment as Regular Therapy in early asthma (START) study: rationale and design.Control Clin Trials. 2001; 22: 405-419Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 5Sheikh A Hurwitz B Sibbald B Barnes G Howe M Durham S House dust mite barrier bedding for childhood asthma: randomised placebo controlled trial in primary care [ISRCTN63308372].BMC Fam Pract. 2002; 3: 12Crossref PubMed Scopus (24) Google Scholar, 6Price D Musgrave SD Shepstone L et al.Leukotriene antagonists as first-line or add-on asthma-controller therapy.N Engl J Med. 2011; 364: 1695-1707Crossref PubMed Scopus (222) Google Scholar, 7Allegra L Cremonesi G Girbino G et al.for the PRISMA (PRospectIve Study on asthMA control) Study GroupReal-life prospective study on asthma control in Italy: cross-sectional phase results.Respir Med. 2012; 106: 205-214Summary Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 8Colice G Martin RJ Israel E et al.Asthma outcomes and costs of therapy with extrafine beclomethasone and fluticasone.J Allergy Clin Immunol. 2013; 132: 45-54.e10Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 9Williams B Noonan G Reiss TF et al.Long-term asthma control with oral montelukast and inhaled beclomethasone for adults and children 6 years and older.Clin Exp Allergy. 2001; 31: 845-854Crossref PubMed Scopus (73) Google Scholar classifies studies within a two-dimensional real-life space bound by the study population (y-axis) and ecology of care (x-axis). The ecology of care axis categorises study interventions along a continuous scale (from highly-controlled efficacy RCT management and follow-up, at one end, to usual care at the other). The label between the two—pragmatically controlled—refers to controlled trials that are designed to resemble usual care in terms of intensity of follow-up and in terms of reference, studied, and concomitant treatments. The population axis categorises study populations along a continuum from those with a confirmed, pure diagnosis (denoting a highly-selected population with no interfering comorbidities, modifying treatments or risk factors) through to a so-called managed-as population (ie, managed as having a condition with or without a confirmed diagnosis). Neither of these characteristics on its own is sufficient to describe the validity or utility of clinical study results to real life. Figure 1 illustrates typical positions of the most common study designs, but studies can be located anywhere within the framework depending on the specifics of their design. The origin of the two axes corresponds to trials with the highest internal and lowest external validity. The further a trial is positioned from the origin, the greater are its real-life attributes, conditioning its generalisability. Figure 2 shows how several published asthma studies can be positioned relative to each other within this integrated space on the basis of their study design and patient selection criteria. The position of a study within the space is not a marker of its quality; it is a descriptive classification, similar to the more comprehensive ten-domain PRECIS (pragmatic-explanatory continuum indicator summary) wheel.10Thorpe KE Zwarenstein M Oxman AD et al.A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers.J Clin Epidemiol. 2009; 62: 464-475Summary Full Text Full Text PDF PubMed Scopus (837) Google Scholar The proposed framework does not replace the PRECIS wheel, but offers an initial description that can be further developed by application of the PRECIS domains, if required. Once the nature of a study and its position within the proposed framework have been established, appropriate quality assessment tools can be selected and applied to the design of the study and its reporting. Comprehensive assessment of therapeutic strategies requires evaluation of both their efficacy under optimum conditions (high internal validity) and effectiveness in real-life populations and situations (high external validity). To ascertain the relevance of study findings to target populations and clinical decision making, studies must first be well described in terms of patient selection and ecology of care. Only then can appropriate quality assessments be selected and undertaken. The proposed framework will need systematic assessment to ascertain its applicability (panel).PanelApplication of the frameworkThe proposed framework must be tested to assess its practical use to help: •Inform literature reviews and evidence assessments on the efficacy and effectiveness of clinical management options•Develop guidelines that base recommendations on an integrated efficacy–effectiveness evidence baseA step-by-step approach to application: •Specify the type of patients and the healthcare settings in which a therapeutic option is to be targeted•Undertake a literature review of the published studies in this area•Position all the studies covered by the literature review within the integrated patient-ecology of care framework. If necessary, the PRECIS wheel10Thorpe KE Zwarenstein M Oxman AD et al.A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers.J Clin Epidemiol. 2009; 62: 464-475Summary Full Text Full Text PDF PubMed Scopus (837) Google Scholar can be used for further classification•On the basis of their position within the framework: •determine which studies apply (or not) to the target population•identify quality assessment methods relating to relevant studies•Assess the quality of studies specific to the target population to identify those that warrant: •journal publication•consideration when making prescribing decisions•integration into decision making and recommendations The proposed framework must be tested to assess its practical use to help: •Inform literature reviews and evidence assessments on the efficacy and effectiveness of clinical management options•Develop guidelines that base recommendations on an integrated efficacy–effectiveness evidence base A step-by-step approach to application: •Specify the type of patients and the healthcare settings in which a therapeutic option is to be targeted•Undertake a literature review of the published studies in this area•Position all the studies covered by the literature review within the integrated patient-ecology of care framework. If necessary, the PRECIS wheel10Thorpe KE Zwarenstein M Oxman AD et al.A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers.J Clin Epidemiol. 2009; 62: 464-475Summary Full Text Full Text PDF PubMed Scopus (837) Google Scholar can be used for further classification•On the basis of their position within the framework: •determine which studies apply (or not) to the target population•identify quality assessment methods relating to relevant studies•Assess the quality of studies specific to the target population to identify those that warrant: •journal publication•consideration when making prescribing decisions•integration into decision making and recommendations We declare that we have no conflicts of interest.