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New Concepts in Clinical Research – an Expansion of the Possibilities
Paediatric Respiratory Reviews 14 (2013) 139–140
Contents lists available at SciVerse ScienceDirect
Paediatric Respiratory Reviews
Editorial
New Concepts in Clinical Research – an Expansion of the Possibilities Consumers of literature regarding evidence-based medicine are accustomed to the assertion that the most reliable guidance regarding treatment recommendations comes from randomized double-blinded clinical trials that compare physiological responses to treatment vs placebo control in a restricted, homogeneous population to evaluate efficacy of an intervention1. However, we have tried to apply this high standard across the healthcare spectrum a number of difficulties have arisen, particularly in pediatrics and most especially in rare diseases of childhood. Well executed clinical trials are extremely expensive and their feasibility may be limited by barriers to enrollment (especially when dealing with a rare or unusual condition) and impracticalities of blinding (especially when the intervention is not a simple pill). There are a number of potential ethical concerns around safety and informed consent in pediatrics and also about the use of a placebo when an established therapy is already available. Outcomes of interest to patients may not be objectively measurable, and the results obtained in a narrowly defined population in a controlled environment may not be the same as those obtained in day-to-day clinical practice2. From a practical standpoint, clinicians and researchers must therefore often turn to clinical research tools that are less methodologically ‘‘pure’’ and more susceptible to threats to validity but can nonetheless be applied in a rigorous manner sufficient to provide adequately reliable evidence upon which to base treatment decisions. This issue of PRR features a brief minisymposium on New Concepts in Clinical Research that focuses attention on newly evolving approaches to creating new clinical knowledge. The U.S. Cystic Fibrosis (CF) Foundation Patient Registry and other CF registries such as the Epidemiologic Study of CF and European, Canadian, and Australian national registries have been of immeasurable benefit in advancing our understanding of the natural history of cystic fibrosis and risk factors for different trajectories in disease progression3. Data registries are particularly helpful for understanding rare diseases, and as knowledge of how to develop them and use them has spread4, we are seeing a blossoming of interest and emulation of the CF registry model adopted for use in other pediatric conditions5,6. Nonetheless, their analysis needs to be approached with some caution3. The article in this issue by Psoter and Rosenfeld (Opportunities and pitfalls of registry data for clinical research) reviews the opportunities and pitfalls of registry-based studies. Following an extensive discussion of the sources of bias, including information and selection bas and confounding, the authors provide a practical approach to determining whether a registry analysis would be an appropriate undertaking to address a particular type of research question. When addressing a research question, whether by using a randomized clinical trial or observational study, the choice of 1526-0542/$ – see front matter ß 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.prrv.2013.07.001
dependent variable or outcome measure is of critical importance. We are relatively fortunate in pulmonary medicine to have a collection of easily quantifiable disease outcomes of interest such as spirometry, but as clinical researchers (and regulatory agencies) have become more sophisticated in their desire to measure important disease outcomes it has become clear that simple measures such as FEV1 have inadequate association with the patient’s experience of disease severity or other measures, whether in asthma7 or in CF8. There is a clear escalation of interest in the use of patient-reported outcomes (PROs) but lingering skepticism as well as misunderstanding over their usefulness. The article in this issue by Blackwell, Marciel, and Quittner (Utilization of PatientReported Outcomes as a Step towards Collaborative Medicine) provides guidance on interpretation of these measures, examines current guidelines for their development and application in clinical research, describes methods for selecting appropriate measures for pediatric populations, and even presents a model for incorporating PROs into clinical practice. In the face of a new abundance of therapeutic options in pediatric pulmonary medicine, choices increasingly need to be made, not just between several ‘‘me-too’’ products but among different classes of therapeutics as well. This is recently coming to a head in CF, where treatment complexity is beginning to weigh more and more heavily9, but in asthma as well10. Researchers and healthcare providers will need to learn a new vocabulary and new skill set in order to make appropriate comparisons and subsequent decisions in standardizing (as well as personalizing) treatment regimens.11 The performance (and interpretation) of Comparative Effectiveness Research (CER) requires an understanding of the distinction between efficacy and effectiveness, and between explanatory and pragmatic trials; furthermore one cannot really understand CER, in my opinion, without an understanding of cost-effectiveness analysis. These concepts are all nicely explained and expanded upon in a very practical paper by Goss and Tefft entitled Comparative effectiveness research – what is it and how does one do it? In summary, the world of clinical research is expanding, with greater options and greater capabilities than appeared to be available a decade ago. The articles in this month’s minisymposium on New Concepts in Clinical Research offer a useful introduction to some of these. References 1. Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20:21–35. 2. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624–32.
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Editorial / Paediatric Respiratory Reviews 14 (2013) 139–140
3. Schechter MS. Patient registry analyses: seize the data, but caveat lector. J Pediatr 2008;153:733–5. 4. Gliklich R, Dreyer N, eds. Registries for Evaluating Patient Outcomes: A User’s Guide. AHRQ Publication No. 07-EHC001-1. Rockville, MD: Agency for Healthcare Research and Quality. April 2007. Available at http://effectivehealthcare. ahrq.gov/repFiles/PatOutcomes.pdf. 5. Eng CM, Fletcher J, Wilcox WR, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007;30:184–92. 6. Thibadeau JK, Ward EA, Soe MM, et al. Testing the feasibility of a National Spina Bifida Patient Registry. Birth defects research Part A. Clinical and molecular teratology 2013;97:36–41. 7. Gandhi RK, Blaiss MS. What are the best estimates of pediatric asthma control? Current opinion in allergy and clinical immunology 2006;6:106–12.
8. Zemanick ET, Harris JK, Conway S, et al. Measuring and improving respiratory outcomes in cystic fibrosis lung disease: opportunities and challenges to therapy. J Cyst Fibros 2010;9:1–16. 9. Sawicki GS, Ren CL, Konstan MW, Millar SJ, Pasta DJ, Quittner AL. Treatment complexity in cystic fibrosis: Trends over time and associations with sitespecific outcomes. J Cyst Fibros 2013. 10. Ducharme FM, Noya FJ, Allen-Ramey FC, Maiese EM, Gingras J, Blais L. Clinical effectiveness of inhaled corticosteroids versus montelukast in children with asthma: prescription patterns and patient adherence as key factors. Current medical research and opinion 2012;28:111–9. 11. Price D, Chisholm A, van der Molen T, Roche N, Hillyer EV, Bousquet J. Reassessing the evidence hierarchy in asthma: evaluating comparative effectiveness. Current allergy and asthma reports 2011;11:526–38.
Contents lists available at SciVerse ScienceDirect
Paediatric Respiratory Reviews
Editorial
New Concepts in Clinical Research – an Expansion of the Possibilities Consumers of literature regarding evidence-based medicine are accustomed to the assertion that the most reliable guidance regarding treatment recommendations comes from randomized double-blinded clinical trials that compare physiological responses to treatment vs placebo control in a restricted, homogeneous population to evaluate efficacy of an intervention1. However, we have tried to apply this high standard across the healthcare spectrum a number of difficulties have arisen, particularly in pediatrics and most especially in rare diseases of childhood. Well executed clinical trials are extremely expensive and their feasibility may be limited by barriers to enrollment (especially when dealing with a rare or unusual condition) and impracticalities of blinding (especially when the intervention is not a simple pill). There are a number of potential ethical concerns around safety and informed consent in pediatrics and also about the use of a placebo when an established therapy is already available. Outcomes of interest to patients may not be objectively measurable, and the results obtained in a narrowly defined population in a controlled environment may not be the same as those obtained in day-to-day clinical practice2. From a practical standpoint, clinicians and researchers must therefore often turn to clinical research tools that are less methodologically ‘‘pure’’ and more susceptible to threats to validity but can nonetheless be applied in a rigorous manner sufficient to provide adequately reliable evidence upon which to base treatment decisions. This issue of PRR features a brief minisymposium on New Concepts in Clinical Research that focuses attention on newly evolving approaches to creating new clinical knowledge. The U.S. Cystic Fibrosis (CF) Foundation Patient Registry and other CF registries such as the Epidemiologic Study of CF and European, Canadian, and Australian national registries have been of immeasurable benefit in advancing our understanding of the natural history of cystic fibrosis and risk factors for different trajectories in disease progression3. Data registries are particularly helpful for understanding rare diseases, and as knowledge of how to develop them and use them has spread4, we are seeing a blossoming of interest and emulation of the CF registry model adopted for use in other pediatric conditions5,6. Nonetheless, their analysis needs to be approached with some caution3. The article in this issue by Psoter and Rosenfeld (Opportunities and pitfalls of registry data for clinical research) reviews the opportunities and pitfalls of registry-based studies. Following an extensive discussion of the sources of bias, including information and selection bas and confounding, the authors provide a practical approach to determining whether a registry analysis would be an appropriate undertaking to address a particular type of research question. When addressing a research question, whether by using a randomized clinical trial or observational study, the choice of 1526-0542/$ – see front matter ß 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.prrv.2013.07.001
dependent variable or outcome measure is of critical importance. We are relatively fortunate in pulmonary medicine to have a collection of easily quantifiable disease outcomes of interest such as spirometry, but as clinical researchers (and regulatory agencies) have become more sophisticated in their desire to measure important disease outcomes it has become clear that simple measures such as FEV1 have inadequate association with the patient’s experience of disease severity or other measures, whether in asthma7 or in CF8. There is a clear escalation of interest in the use of patient-reported outcomes (PROs) but lingering skepticism as well as misunderstanding over their usefulness. The article in this issue by Blackwell, Marciel, and Quittner (Utilization of PatientReported Outcomes as a Step towards Collaborative Medicine) provides guidance on interpretation of these measures, examines current guidelines for their development and application in clinical research, describes methods for selecting appropriate measures for pediatric populations, and even presents a model for incorporating PROs into clinical practice. In the face of a new abundance of therapeutic options in pediatric pulmonary medicine, choices increasingly need to be made, not just between several ‘‘me-too’’ products but among different classes of therapeutics as well. This is recently coming to a head in CF, where treatment complexity is beginning to weigh more and more heavily9, but in asthma as well10. Researchers and healthcare providers will need to learn a new vocabulary and new skill set in order to make appropriate comparisons and subsequent decisions in standardizing (as well as personalizing) treatment regimens.11 The performance (and interpretation) of Comparative Effectiveness Research (CER) requires an understanding of the distinction between efficacy and effectiveness, and between explanatory and pragmatic trials; furthermore one cannot really understand CER, in my opinion, without an understanding of cost-effectiveness analysis. These concepts are all nicely explained and expanded upon in a very practical paper by Goss and Tefft entitled Comparative effectiveness research – what is it and how does one do it? In summary, the world of clinical research is expanding, with greater options and greater capabilities than appeared to be available a decade ago. The articles in this month’s minisymposium on New Concepts in Clinical Research offer a useful introduction to some of these. References 1. Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20:21–35. 2. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624–32.
140
Editorial / Paediatric Respiratory Reviews 14 (2013) 139–140
3. Schechter MS. Patient registry analyses: seize the data, but caveat lector. J Pediatr 2008;153:733–5. 4. Gliklich R, Dreyer N, eds. Registries for Evaluating Patient Outcomes: A User’s Guide. AHRQ Publication No. 07-EHC001-1. Rockville, MD: Agency for Healthcare Research and Quality. April 2007. Available at http://effectivehealthcare. ahrq.gov/repFiles/PatOutcomes.pdf. 5. Eng CM, Fletcher J, Wilcox WR, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007;30:184–92. 6. Thibadeau JK, Ward EA, Soe MM, et al. Testing the feasibility of a National Spina Bifida Patient Registry. Birth defects research Part A. Clinical and molecular teratology 2013;97:36–41. 7. Gandhi RK, Blaiss MS. What are the best estimates of pediatric asthma control? Current opinion in allergy and clinical immunology 2006;6:106–12.
8. Zemanick ET, Harris JK, Conway S, et al. Measuring and improving respiratory outcomes in cystic fibrosis lung disease: opportunities and challenges to therapy. J Cyst Fibros 2010;9:1–16. 9. Sawicki GS, Ren CL, Konstan MW, Millar SJ, Pasta DJ, Quittner AL. Treatment complexity in cystic fibrosis: Trends over time and associations with sitespecific outcomes. J Cyst Fibros 2013. 10. Ducharme FM, Noya FJ, Allen-Ramey FC, Maiese EM, Gingras J, Blais L. Clinical effectiveness of inhaled corticosteroids versus montelukast in children with asthma: prescription patterns and patient adherence as key factors. Current medical research and opinion 2012;28:111–9. 11. Price D, Chisholm A, van der Molen T, Roche N, Hillyer EV, Bousquet J. Reassessing the evidence hierarchy in asthma: evaluating comparative effectiveness. Current allergy and asthma reports 2011;11:526–38.