Real-Life Asthma Care in Canada

1McMaster University, Hamilton, Ontario; 2McGill University, Montreal, Quebec Correspondence: Dr Andrew McIvor, McMaster University, St Joseph’s Healthcare, Firestone Institute for Respiratory Health, T2127, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6. Telephone 905-522-1155 ext 34330, fax 905-521-6183, e-mail amcivor@stjosham.on.ca The double-blind, randomized, controlled trial (DBRCT) continues to be considered the most valid design for assessment of efficacy. Results of DBRCTs provide the evidence that is used as the basis to approve, or not, a medical intervention for use in the general target population. With a highly selected patient sample that is treated under a rigorous protocol, the DBRCT provides data on the benefits produced by a treatment under ideal conditions. Therefore, issues of adherence and compliance, accessibility to care, presence of comorbid conditions and use of concomitant medications have a minimal impact on the results of DBRCTs. For several highly prevalent chronic conditions, there is a discrepancy between the efficacy results observed in DBRCTs and the effectiveness observed in a real-life setting under routine clinical practice and patient management. The discrepancy is predominantly in the negative direction, in which the benefits observed in real life are inferior to those anticipated by extrapolating the results of DBRCTs. The main reason for this treatment gap is related to the fact that DBRCTs enroll highly selected patients that are treated and followed up according to a strict regimen, as defined in the study protocol. In addition, medication is provided free of charge and compliance to the required regimen is maximized with protocol-driven manoeuvres. As a result, access to care and compliance have no impact on the study outcomes. Participation of patients in the study is determined by predetermined criteria; thus, the physician’s judgment and clinical decision does not affect patient management. Physicians participating in phase II and III DBRCTs are predominantly academics and specialists with strong interest in research and the field. Conversely, in the real-life setting, access to care and compliance with treatment play a major role in achieving therapeutic goals. The decision regarding which treatment to use and overall management of the patient is made by the treating physician and does not always follow a regimen; nor does it always adhere to treatment guidelines. As a result, there is significant diversity in the type of patients treated with a specific medication. Variability with respect to demographics, comorbidity, concomitant medication use and even socioeconomic status could affect not only compliance with treatment, but also the efficacy of the drug. The discrepancy between the evidence generated in DBRCTs results observed in the real-life setting presents a significant problem in the assessment of the population based benefit-risk ratio of approved medications. Continued support for the use of the medication requires valid demonstration of real-life benefit and assessment of safety. DBRCTs are typically powered to assess efficacy but do not have sufficient sample size to detect rare, but potentially serious, adverse events. Therefore, there is a need for several welldesigned postmarketing studies that could generate data assessing real-life effectiveness and providing valid evaluation of safety. Postmarketing studies using either the phase IV or Post Marketing Observational Study (PMOS) design are the essential and the only possible source of data for assessment of real-life effectiveness and safety that could be used to determine population based benefit-risk ratios. Phase IV studies are conducted in the practices of community physicians according to a pre-specified protocol that defines treatment and follow-up procedures. In addition, in phase IV studies, the medication under study is provided by the sponsor at no cost to the patient. As such, the phase IV study may not be considered to be a complete representation of the real-life setting, given that accessibility to care and adherence to treatment guidelines may not be relevant. However, contrary to controlled clinical trials that are conducted by research-oriented clinicians and academics, phase IV studies are conducted by community physicians in their routine clinical practice setting. In addition, while patients enrolled in controlled clinical trials are highly selected to maximize response to treatment and minimize confounding by comorbidity and concomitant medication use, the phase IV patients are those who would be treated with the study medication. Therefore, between-patient variability with respect to medical history profile, predisposing confounders and compliance are more representative of the target population of patients that will receive the medication under investigation in real life. Given these considerations, phase IV studies emulate the real-life setting and their results could be used in the assessment of effectiveness and safety in the real-life setting. The PMOS, the next step in the assessment of the real-life effectiveness and safety, is also conducted in the practices of community physicians with patients who would be treated with the study medication independently of the study. In the pure PMOS, patients are not treated according to a prespecified protocol but are managed according to the routine practice of the treating physicians. In addition, in the PMOS, the medication is acquired through the regular sources, including health care plans or out of pocket by the patient. Therefore, factors such as accessibility to care, adherence to treatment guidelines and compliance may affect the outcome, and the real-life setting is better represented when compared with the phase IV study. Based on the above discussion, we can conclude that postmarketing research comprised of phase IV and PMOS closes the loop for drug evaluation and are as important in the overall assessment of benefit-risk as the first phase I and final pivotal phase III studies. Both phase IV and PMOS are necessary, each one providing answers to different questions and incremental value in the assessment of drug therapy. While the PMOS better simulates the reallife study, the phase IV study provides an assessment of effectiveness when accessibility to care is not an issue. Both are necessary asthma CaRe in Canada