Pragmatic Clinical Trials in CKD: Opportunities and Challenges
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BRIEF REVIEW www.jasn.org Pragmatic Clinical Trials in CKD: Opportunities and Challenges † ‡ | †† Ian H. de Boer,* Csaba P. Kovesdy, § Sankar D. Navaneethan, ¶ Carmen A. Peralta,** †† ‡‡ || Delphine S. Tuot, Miguel A. Vazquez, and Deidra C. Crews,§§ for the American Society of Nephrology Chronic Kidney Disease Advisory Group *Division of Nephrology and †Department of Medicine, Kidney Research Institute, University of Washington, Seattle, WA; ‡Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN; §Nephrology Section, Memphis VA Medical center, Memphis, TN; |Section of Nephrology, Department of Medicine, Selzman Institute for Kidney Health, Baylor College of Medicine; ¶Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX; **Kidney Health Research Collaborative and ††Division of Nephrology, University of California San Francisco, San Francisco, CA; ‡‡Division of Nephrology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX; §§Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine; and ||Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD ABSTRACT Randomized controlled trials in CKD lag in number behind those of other chronic demonstration of treatment efficacy and diseases, despite the high morbidity and mortality experienced by patients with kidney implementation of proven therapies in disease and the exorbitant costs of their health care. Observational studies of CKD clinical care, and high-quality RCT evi- frequently yield seemingly paradoxic associations of traditional risk factors with dence has remained scarce for many im- outcomes, making it difficult to extrapolate the results of trials conducted in people portant and practical clinical questions. with normal kidney function to patients with CKD. However, many completed trials in Upon this general background, con- CKD have been limited by intermediate outcomes of unclear clinical significance or ducting investigations in CKD has faced narrow eligibility criteria that limit external validity, and implementation of proven additional challenges. The number of RCTs therapies remains a challenge. It is therefore imperative that the nephrology com- conducted in patients with CKD or ESRD munity capitalize on recent interest in novel approaches to trial design, such as prag- is one of the smallest compared with other matic clinical trials. These trials are meant to promote research within real world medical subspecialties,7 in spite of the ris- settings to yield clinically relevant results with greater applicability than those of ing prevalence of CKD, the enormously traditional trials, while maintaining many advantages, such as controlling for potential high morbidity and mortality experienced sources of bias. We provide a description of pragmatic clinical trials and a discussion by patients with kidney disease, and the of advantages, disadvantages, and practical challenges inherent to this study design, high costs of CKD and ESRD care.8,9 Pub- in the context of specific scientific questions relevant to patients with CKD. lished nephrology RCTs have often exam- ined intermediate outcomes that are of J Am Soc Nephrol 27: ccc–ccc, 2016. doi: 10.1681/ASN.2015111264 unclear significance to patients, providers, and families, with important exceptions. The complex and heterogeneous nature THE NEED FOR CLINICAL TRIALS After their ubiquitous acceptance as the of CKD has often led to restrictive enroll- IN CKD sine qua non of causal assessment, RCTs ment criteria that limit external validity.7 evolved from small single-center studies Inthesecondhalfofthepastcentury,sig- to large, multicenter trials. With this shift, nificant progress has been made in under- the cost of conducting RCTs increased dra- Published online ahead of print. Publication date standing principles of causal inference and matically, common disease states amena- available at www.jasn.org. in statistical techniques underlying the ble to drug intervention (such as hyper- Correspondence: Dr. Ian de Boer, Division of Ne- proper planning and analysis of interven- cholesterolemia and hypertension) phrology and Kidney Research Institute, University of Washington Medicine/Nephrology, Box 359606, 1 4 tional trials. As a result, the randomized became a dominant focus of inquiry, 325 9th Ave, Seattle, WA 98104. Email: deboer@u. controlled trial (RCT) has become the and commercial entities took on enlarging washington.edu fi 5,6 gold standard tool for proving the ef cacy roles in trial design and conduct. At the Copyright © 2016 by the American Society of and safety of therapeutic interventions.2,3 same time, gaps emerged between Nephrology J Am Soc Nephrol 27: ccc–ccc, 2016 ISSN : 1046-6673/2710-ccc 1 BRIEF REVIEW www.jasn.org Insufficient implementation of the few In reality, any single trial is neither fully intervention implementation, safety mon- proven therapies has contributed to in- pragmatic nor fully explanatory.15 The itoring, and outcome ascertainment.18,21 creasedriskofCKDanditscomplications PRagmatic Explanatory Continuum Indi- Interest in PCTs has grown quickly in economically and socially disadvan- cator Summary-2 tool identifies nine do- over the last decade,15 and the nephrol- taged populations.10,11 Moreover, observa- mains to quantitate the extent to which a ogy community has been an early leader tional studies of people with CKD and clinical trial is pragmatic.20 The most prag- in this surge, as demonstrated by the ex- ESRD have frequently observed seemingly matic trials apply broad eligibility criteria, amples below. PCTs that involve popu- paradoxic associations of traditional risk recruit from clinical settings, conduct pro- lations with kidney disease have been factors with clinical outcomes,12 making cedures in the context of usual care using facilitated and encouraged through spe- it difficult to extrapolate the results of available clinical infrastructure, apply in- cific funding mechanisms from sponsors RCTs conducted in patients with normal terventions with flexible protocols using critical to nephrology research, including kidney function to patients with CKD. usual encouragement, assess outcomes rel- the National Institutes of Health, Depart- It is therefore imperative that the evant to patients using readily obtainable ment of Veterans Affairs, and the Patient nephrology community capitalize on the metrics, and apply intention-to-treat anal- Centered Outcomes Research Institute. Of recent wave of interest in novel approaches ysis (Figure 1). Rarely is a clinical trial note, interest in PCTs has grown along to clinical trial design, such as pragmatic pragmatic in all aspects of its design. Of- with interest in another movement that clinical trials (PCTs). This review article ten, some design elements are made less may appear conflicting – the Precision will provide a description of the concept of pragmatic in order to maintain internal Medicine Initiative.22 Indeed, whereas PCTs, a discussion of the advantages, dis- validity or to accommodate practical needs PCTs focus on applicability to popula- advantages, and practical challenges of for implementation. Ultimately, the choice tions, precision medicine focuses on ap- PCTs, and examples of PCTs conducted of design for any clinical trial depends on plicability to individuals. However, there among patients with CKD. the underlying scientific question and the is no reason that trials advancing preci- context in which it is addressed. sion medicine cannot incorporate prag- PCTs are suited for the evaluation of a matic design elements, and PCTs can in- WHAT ARE PCTS? wide variety of medical interventions in- form precision medicine by building in cluding individual medical treatments and personalized components (e.g., inter- PCTs have been recognized as important strategies to deliver those treatments to vention flexibility) or the evaluation of tools for evaluating medical interventions patient populations. Depending on the between-participant heterogeneity in since at least 1967.13 Over time, the term intervention and setting, PCTs may em- response. “pragmatic” has been used to refer to a va- ploy cluster randomization, active com- riety of interrelated elements of trial de- parator groups, and quasi-experimental sign.14–16 Central to all definitions is an designs. The electronic health record POTENTIAL BENEFITS OF PCT emphasis on external validity. PCTs are de- (EHR) plays a central role in most PCTs. DESIGNS IN CKD signed so that their results can be quickly EHR data can efficiently facilitate every and directly applied to relevant clinical step of a clinical trial, from screening to There are several potential benefits to populations. Toward this goal, common enrollment, collection of baseline data, PCTs in CKD (Table 1). First, PCTs may features of PCTs include broad eligibility criteria, comparisons of clinically relevant alternatives, integration of research into clinical practice, and evaluation of a broad range of relevant health outcomes.17,18 The Gruppo Italiano per lo Studio della Strep- tochinasi nell’Infarto Miocardico trial of thrombolysis for acute myocardial infarc- tion is often cited as an example of an early and successful PCT.19 PCTs have been con- trasted with explanatory trials, which strive to determine whether an intervention has beneficial effects in humans, often using conditions that maximize the likelihood of demonstrating a treatment effect while