RCTs are considered the gold standard for demonstrating the efficacy of medicinal products and for obtaining an initial estimate of the risk of adverse outcomes. However, they are not necessarily indicative of the benefits, risks or comparative effectiveness of an intervention when used in clinical practice. The IMI GetReal Glossary defines a pragmatic clinical trial as ‘a study comparing several health interventions among a randomised, diverse population representing clinical practice, and measuring a broad range of health outcomes’. Pragmatic clinical trials are focused on evaluating benefits and risks of treatments in patient populations and settings that are more representative of routine clinical practice. To ensure generalisability, pragmatic trials should represent the patients to whom the treatment will be applied, for instance, inclusion criteria may be broader (e.g. allowing co-morbidity, co-medication, wider age range), and the follow-up may be minimised and allow for treatment switching. Monitoring safety in a phase III real-world effectiveness trial: use of novel methodology in the Salford Lung Study (Pharmacoepidemiol Drug Saf 2017;26(3):344-352) describes the model of a phase III pragmatic clinical trial where patients were enrolled through primary care practices using minimal exclusion criteria and without extensive diagnostic testing, and where potential safety events were captured through patients’ electronic health records and triggered review by the specialist safety team.
Pragmatic explanatory continuum summary (PRECIS): a tool to help trial designers (CMAJ 2009; 180(10): E45-E57) is a tool to support pragmatic trial designs and help define and evaluate the degree of pragmatism. The PRECIS tool has been further refined and now comprises nine domains each scored on a 5 point Likert scale ranging from very explanatory to very pragmatic with an exclusive focus on the issue of applicability (The PRECIS-2 tool: designing trials that are fit for purpose. BMJ 2015;350: h2147). A checklist and additional guidance is also provided in Improving the reporting of pragmatic trials: an extension of the CONSORT statement (BMJ 2008; 337 (a2390): 1-8).
Based on the evidence that the current costs and complexity of conducting randomised trials lead to more restrictive eligibility criteria and short durations of trials, and therefore reduce the generalisability and reliability of the evidence about the efficacy and safety of new and existing interventions, the article The Magic of Randomization versus the Myth of Real-World Evidence (N Engl J Med. 2020;382(7):674-678) proposes measures to remove practical obstacles to the conduct of randomised trials of appropriate size.
Large simple trials are pragmatic clinical trials with minimal data collection narrowly focused on clearly defined outcomes important to patients as well as clinicians. Their large sample size provides adequate statistical power to detect even small differences in effects. Additionally, large simple trials include a follow-up time that mimics routine clinical practice.
Large simple trials are particularly suited when an adverse event is very rare or has a delayed latency (with a large expected attrition rate), when the population exposed to the risk is heterogeneous (e.g. different indications and age groups), when several risks need to be assessed in the same trial or when many confounding factors need to be balanced between treatment groups. In these circumstances, the cost and complexity of a traditional RCT may outweigh its advantages and large simple trials can help keep the volume and complexity of data collection to a minimum.
Outcomes that are simple and objective can also be measured from the routine process of care using epidemiological follow-up methods, for example by using questionnaires or hospital discharge records. Examples of published large simple trials are An assessment of the safety of paediatric ibuprofen: a practitioner based randomised clinical trial (JAMA 1995;279:929-33) and Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Zodiac Observational Study of Cardiac Outcomes (ZODIAC) (Am J Psychiatry 2011;168(2):193-201).
Note that the use of the term ‘simple’ in the expression ‘Large simple trials’ refers to data structure and not to data collection. It is used in relation to situations in which a small number of outcomes are measured. The term may therefore not adequately reflect the complexity of the studies undertaken.
Randomised database studies can be considered a special form of a large simple trial where patients included in the trial are enrolled in a healthcare system with electronic records. Eligible patients may be identified and flagged automatically by the software, with the advantage of allowing comparison of included and non-included patients. Database screening or record linkage can be used to detect and measure outcomes of interest otherwise assessed through the normal process of care. Patient recruitment, informed consent and proper documentation of patient information are hurdles that still need to be addressed in accordance with the applicable legislation for RCTs. Randomised database studies attempt to combine the advantages of randomisation and observational database studies. These and other aspects of randomised database studies are discussed in The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials (Health Technol Assess. 2014;18(43):1-146) which illustrates the practical implementation of randomised studies in general practice databases.
There are few published examples of randomised database studies, but this design could become more common in the near future with the increasing computerisation of medical records. Pragmatic randomised trials using routine electronic health records: putting them to the test (BMJ 2012;344:e55) describes a project to implement randomised trials in the everyday clinical work of general practitioners, comparing treatments that are already in common use, and using routinely collected electronic healthcare records both to identify participants and to gather results.
A particular form of randomised databases studies is the registry-based randomised trial, which uses an existing registry as a platform for the identification of cases, their randomisation and their follow-up. The editorial The randomized registry trial - the next disruptive technology in clinical research? (N Engl J Med 2013; 369(17):1579-1581) introduces the concept. This hybrid design tries to achieve both internal and external validity by using a robust design (a RCT) in a data source with higher generalisability (registries). Other examples are the TASTE trial that followed patients in the long-term using data from a Scandinavian registry (Thrombus aspiration during ST-segment elevation myocardial infarction. N. Engl J Med.
2013;369(17):1587-97) and A registry-based randomized trial comparing radial and femoral approaches in women undergoing percutaneous coronary intervention: the SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) trial (JACC Cardiovasc Interv. 2014;7(8):857-67).