Journal of clinical epidemiology
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Next generation genomic sequencing (NGS) technologies-whole genome and whole exome sequencing-are now cheap enough to be within the grasp of many health care organizations. To many, NGS is symbolic of cutting edge health care, offering the promise of "precision" and "personalized" medicine. Historically, research and clinical application has been a two-way street in clinical genetics: research often driven directly by the desire to understand and try to solve immediate clinical problems affecting real, identifiable patients and families, accompanied by a low threshold of willingness to apply research-driven interventions without resort to formal empirical evaluations. ⋯ We argue that clinical uses of genomic sequencing should remain limited to specialist and research settings, that screening for secondary findings in clinical testing should be limited to the maximum extent possible, and that the benefits, harms, and economic implications of their routine use be systematically evaluated. All stakeholders have a responsibility to ensure that patients receive effective, safe health care, in an economically sustainable health care system. There should be no exception for genome-based interventions.
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Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory, and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials. ⋯ A first step should be to determine to what extent existing health care databases provide the necessary study data and can accommodate data collection and management. When more elaborate or detailed data collection or more structured follow-up is required, data collection in a pragmatic trial will have to be tailor-made, often using a hybrid approach using a dedicated electronic case report form (eCRF). In this case, the eCRF should be kept as simple as possible to reduce the burden for practitioners and minimize influence on routine clinical practice.
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Pragmatic trials offer the opportunity to obtain real-life data on the relative effectiveness and safety of a treatment before or after market authorization. This is the penultimate paper in a series of eight, describing the impact of design choices on the practical implementation of pragmatic trials. ⋯ Current ICH guidance recommends that all serious adverse events and all drug-related events must be reported in an interventional trial. In line with current guidance, we propose a risk-based approach to the collection of non-drug-related non-serious adverse events and even serious events not related to treatment based on the risk profile of the medicine/class in the patient population of interest. Different options available to support the collection and reporting of safety data while minimizing study-related follow-up visits are discussed. A risk-based approach to monitoring trial conduct is also discussed, highlighting the difference in the balance of risks likely to occur in a pragmatic trial compared to traditional clinical trials and the careful consideration that must be given to the mitigation and management of these risks to maintain routine care.
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Pragmatic trials may deliver real-world evidence on the added value of new medications compared with usual care and inform decision making earlier in development. This fifth paper in a series on pragmatic trials in the Journal discusses usual care as a comparator and the allocation of treatment strategies. The allocation and implementation of treatment strategies should resemble clinical practice as closely as possible. ⋯ Using clinical guidelines to define usual care can be helpful in standardizing comparator treatments; however, this may decrease the applicability of the results to real-life settings. Conversely, using multiple usual-care treatment arms will increase the complexity of the study. The specific objectives of the trial and design choices should be discussed with all stakeholders to realize the full potential of the pragmatic trial.
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Results from pragmatic trials should reflect the comparative treatment effects encountered in patients in real-life clinical practice to guide treatment decisions. Therefore, pragmatic trials should focus on outcomes that are relevant to patients, clinical practice, and treatment choices. This sixth article in the series (see Box) discusses different types of outcomes and their suitability for pragmatic trials, design choices for measuring these outcomes, and their implications and challenges. ⋯ Methods that decrease bias or enhance precision of the results, such as standardization and blinding of outcome assessment, should be considered when a high risk of bias or high variability is expected. The selection of outcomes in pragmatic trials should be relevant for decision making and feasible in terms of executing the trial in the context of interest. Therefore, this should be discussed with all stakeholders as early as feasible to ensure the relevance of study results for decision making in clinical practice and the ability to perform the study.