This paper addresses challenges of identifying, enrolling, and retaining participants in a trial conducted within a routine care setting. All patients who are potential candidates for the treatments in routine clinical practice should be considered eligible for a pragmatic trial. To ensure generalizability, the recruited sample should have a similar distribution of the treatment effect modifiers as the target population. In practice, this can be best achieved by including-within the selected sites-all patients without further selection. If relevant heterogeneity between subgroups is expected, increasing the relative proportion of the subgroup of patients in the heterogeneous trial could be considered (oversampling) or a separate trial in this subgroup can be planned. Selection will nevertheless occur. Low enrollment and loss to follow-up can introduce selection and can jeopardize validity as well as generalizability. Pragmatic trials are conducted in clinical practice rather than in a dedicated research setting, which could reduce recruitment rates. However, if a trial poses a minimal burden to the physician and the patient and routine clinical practice is maximally adhered to, the participation rate may be high and loss to follow-up will not be a specific problem for pragmatic trials.

BackgroundThe inclusion of patient preferences (PP) in the medical product life cycle is a topic of growing interest to stakeholders such as academics, Health Technology Assessment (HTA) bodies, reimbursement agencies, industry, patients, physicians and regulators. This review aimed to understand the potential roles, reasons for using PP and the expectations, concerns and requirements associated with PP in industry processes, regulatory benefit-risk assessment (BRA) and marketing authorization (MA), and HTA and reimbursement decision-making.MethodsA systematic review of peer-reviewed and grey literature published between January 2011 and March 2018 was performed. Consulted databases were EconLit, Embase, Guidelines International Network, PsycINFO and PubMed. A two-step strategy was used to select literature. Literature was analyzed using NVivo (QSR international).ResultsFrom 1015 initially identified documents, 72 were included. Most were written from an academic perspective (61%) and focused on PP in BRA/MA and/or HTA/reimbursement (73%). Using PP to improve understanding of patients’ valuations of treatment outcomes, patients’ benefit-risk trade-offs and preference heterogeneity were roles identified in all three decision-making contexts. Reasons for using PP relate to the unique insights and position of patients and the positive effect of including PP on the quality of the decision-making process. Concerns shared across decision-making contexts included methodological questions concerning the validity, reliability and cognitive burden of preference methods. In order to use PP, general, operational and quality requirements were identified, including recognition of the importance of PP and ensuring patient understanding in PP studies.ConclusionsDespite the array of opportunities and added value of using PP throughout the different steps of the MPLC identified in this review, their inclusion in decision-making is hampered by methodological challenges and lack of specific guidance on how to tackle these challenges when undertaking PP studies. To support the development of such guidance, more best practice PP studies and PP studies investigating the methodological issues identified in this review are critically needed.Electronic supplementary materialThe online version of this article (10.1186/s12911-019-0875-z) contains supplementary material, which is available to authorized users.

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. Randomization at the level of the site, as opposed to at the individual level, may be preferred. Data analysis according to the intention-to-treat principle is recommended, and crossover between treatment arms and strong treatment preferences may be accounted for in the study design in specific situations. Although usual care is the comparator of choice, this may differ substantially between centers and countries complicating comparator choice. 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.

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. Measuring outcomes in pragmatic trials should not interfere with real-world clinical practice to ensure generalizability of trial results, and routinely collected outcomes should be prioritized. Typical outcomes include mortality, morbidity, functional status, well-being, and resource use. Surrogate endpoints are typically avoided as primary outcome. It is important to measure outcomes over a relevant time horizon and obtain valid and precise results. As pragmatic trials are often open label, a less subjective outcome can reduce bias. 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.

In light of increasing attention towards the use of real-world evidence (RWE) in decision making in recent years, this commentary aims to reflect on the experiences gained in accessing and using RWE for comparative effectiveness research as a part of the Innovative Medicines Initiative GetReal Consortium and discuss their implications for RWE use in decision-making.