“…Unlike the Nuremberg code, this declaration has been updated and revised many times, most recently in 2013. It encompasses international research ethics and outlines rules for research combined with medical care and non-therapeutic research (Nellhaus & Davies, 2017). While the Nuremberg code focuses on research participants' rights, the DoH focuses on clinicians' obligations to research participants.…”
Clinical trials are conducted to find better ways to prevent, screen for, diagnose or treat human disease. The development of clinical trials throughout history has built the foundation for ethically and scientifically robust research. As our healthcare needs have evolved, so have clinical trials and the standards by which they are run. Vanessa Raymont and colleagues explore the past, present and future of the clinical trial.
“…Unlike the Nuremberg code, this declaration has been updated and revised many times, most recently in 2013. It encompasses international research ethics and outlines rules for research combined with medical care and non-therapeutic research (Nellhaus & Davies, 2017). While the Nuremberg code focuses on research participants' rights, the DoH focuses on clinicians' obligations to research participants.…”
Clinical trials are conducted to find better ways to prevent, screen for, diagnose or treat human disease. The development of clinical trials throughout history has built the foundation for ethically and scientifically robust research. As our healthcare needs have evolved, so have clinical trials and the standards by which they are run. Vanessa Raymont and colleagues explore the past, present and future of the clinical trial.
“…Clinical trials have evolved, substantially, from the first described systematic comparison of dietary regimens 2500 years ago in Babylon, to the 1747 scurvy trial, the first double-blinded trial of patulin for the common cold conducted in the 1940’s, and the establishment of modern ethical standards and regulatory frameworks following World War II (Fig. 1 ) [ 2 , 3 ]. Fig.…”
Section: Introductionmentioning
confidence: 99%
“… Fig. 1 Timeline of important milestones in the general history of clinical trials based on references [ 2 , 3 ]. A historical timeline of key critical care studies and RCTs is available elsewhere [ 6 ] …”
Randomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance.
“…One was the significant scientific developments of the 19th and 20th centuries that produced a multitude of new medicinal products that needed to be tested, particularly after WWII [ [1] , [2] , [3] ]. A second was the emergence in the 1940s and 1950s of clinical trials incorporating all the essential elements, common today, like control groups, randomization, and blinding [ [3] , [4] , [5] , [6] ]. A third was the development of a drug regulatory environment [ 2 , 3 , 6 ].…”
Section: Introductionmentioning
confidence: 99%
“…In the United States, starting with the basic regulations of 1906 and evolving into the much stricter 1962 Kefauver-Harris Amendment that required not only proof of safety for new drugs, but substantial evidence of efficacy based on adequate and well-controlled studies [ 2 , 3 ]. A fourth was the development of strict regulations for the ethical conduct of clinical research and the protection of study participants [ 2 , 4 , 5 ].…”
Background
The demand for clinical trial participants is today one of the highest it has ever been and continues to increase. At the same time, subject recruitment continues to be problematic and the major reason for clinical trial premature terminations. The literature on clinical trial recruitment, which spans several decades and includes hundreds of studies, has an abundance of findings that can be synthesized by way of an overview to provide a well-informed and complete picture of the factors that determine subject participation.
Objectives
An overview of the systematic reviews that report barriers and facilitators to clinical trial participation was conducted. The extracted data were synthesized, and a thematic framework of the factors that affect subject participation in clinical trials was developed. The overview extended across medical subjects and demographics.
Methods
Thirty reviews that complied with the inclusion criteria were included. These reviews covered 753 relevant primary studies and reported 881 barriers and facilitators. The barriers and facilitators were thematically synthesized and a thematic framework of 20 themes was developed. The quality of the included reviews was assessed and reported.
Main results
Several opportunities to increase clinical trial participation, by developing interventions and changing the trial design, derived from an analysis of the thematic framework. That analysis also showed that most of the 20 themes operate mainly as a barrier or as a facilitator, and that most have an effect across medical subjects. As to the quality elements assessed, some reviews complied almost fully but most only partially.
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