Explore the vast range of titles available.

Randomized, controlled trials date back much farther than is usually recognized, and their history offers insights into the intellectual and social forces shaping what would become a medical research standard and a mechanism for taming the therapeutic marketplace. The birth of the randomized, controlled trial (RCT) is typically dated to a 1948 evaluation by the British Medical Research Council (MRC) of streptomycin for the treatment of tuberculosis. But controlled clinical trials and discussions of their designs were increasingly being published in medical journals for at least half a century before the MRC’s report, which was part of a much longer history of efforts to empirically assess experimental therapies. An exploration of this deeper history offers insights into the intellectual and social forces shaping both the advent of and resistance to the controlled clinical trial as a medical research . . .

Over the past 70 years, randomized, controlled trials (RCTs) have reshaped medical knowledge and practice. Popularized by mid-20th-century clinical researchers and statisticians aiming to reduce bias and enhance the accuracy of clinical experimentation, RCTs have often functioned well in that role. Yet the past seven decades also bear witness to many limitations of this new “gold standard.” The scientific and political history of RCTs offers lessons regarding the complexity of medicine and disease and the economic and political forces that shape the production and circulation of medical knowledge. The Rise of RCTs Physicians and medical researchers have attempted for millennia . . .

The introduction of randomised controlled trials (RCTs) by the UK Medical Research Council (MRC) in the 1940s constitutes one of the most important experimental advances in modern medicine.1 Through the examination of the efficacy-or otherwise-of drugs and other interventions, RCTs have become the essential scientific arbiter through which treatments are translated from the laboratory to the clinic.

Objective To examine the traditional diet-heart hypothesis through recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE) and to put findings in the context of existing diet-heart randomized controlled trials through a systematic review and meta-analysis.Design The MCE (1968-73) is a double blind randomized controlled trial designed to test whether replacement of saturated fat with vegetable oil rich in linoleic acid reduces coronary heart disease and death by lowering serum cholesterol. Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators. Further, a systematic review and meta-analyses of randomized controlled trials that lowered serum cholesterol by providing vegetable oil rich in linoleic acid in place of saturated fat without confounding by concomitant interventions was conducted.Setting One nursing home and six state mental hospitals in Minnesota, United States.Participants Unpublished documents with completed analyses for the randomized cohort of 9423 women and men aged 20-97; longitudinal data on serum cholesterol for the 2355 participants exposed to the study diets for a year or more; 149 completed autopsy files.Interventions Serum cholesterol lowering diet that replaced saturated fat with linoleic acid (from corn oil and corn oil polyunsaturated margarine). Control diet was high in saturated fat from animal fats, common margarines, and shortenings.Main outcome measures Death from all causes; association between changes in serum cholesterol and death; and coronary atherosclerosis and myocardial infarcts detected at autopsy.Results The intervention group had significant reduction in serum cholesterol compared with controls (mean change from baseline −13.8% v −1.0%; P<0.001). Kaplan Meier graphs showed no mortality benefit for the intervention group in the full randomized cohort or for any prespecified subgroup. There was a 22% higher risk of death for each 30 mg/dL (0.78 mmol/L) reduction in serum cholesterol in covariate adjusted Cox regression models (hazard ratio 1.22, 95% confidence interval 1.14 to 1.32; P<0.001). There was no evidence of benefit in the intervention group for coronary atherosclerosis or myocardial infarcts. Systematic review identified five randomized controlled trials for inclusion (n=10 808). In meta-analyses, these cholesterol lowering interventions showed no evidence of benefit on mortality from coronary heart disease (1.13, 0.83 to 1.54) or all cause mortality (1.07, 0.90 to 1.27).Conclusions Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes. Findings from the Minnesota Coronary Experiment add to growing evidence that incomplete publication has contributed to overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid.

The objective of this study was to contrast the historical development of experiments and quasi-experiments and provide the motivation for a journal series on quasi-experimental designs in health research. A short historical narrative, with concrete examples, and arguments based on an understanding of the practice of health research and evidence synthesis. Health research has played a key role in developing today's gold standard for causal inference—the randomized controlled multiply blinded trial. Historically, allocation approaches developed from convenience and purposive allocation to alternate and, finally, to random allocation. This development was motivated both by concerns for manipulation in allocation as well as statistical and theoretical developments demonstrating the power of randomization in creating counterfactuals for causal inference. In contrast to the sequential development of experiments, quasi-experiments originated at very different points in time, from very different scientific perspectives, and with frequent and long interruptions in their methodological development. Health researchers have only recently started to recognize the value of quasi-experiments for generating novel insights on causal relationships. While quasi-experiments are unlikely to replace experiments in generating the efficacy and safety evidence required for clinical guidelines and regulatory approval of medical technologies, quasi-experiments can play an important role in establishing the effectiveness of health care practice, programs, and policies. The papers in this series describe and discuss a range of important issues in utilizing quasi-experimental designs for primary research and quasi-experimental results for evidence synthesis.

As we enter a new era of treatment for heart failure with reduced ejection fraction, historical perspective is provided in a timeline (at NEJM.org) of 26 randomized, controlled trials in heart-failure treatment that have been published in the Journal since 1986. With the publication of the PARADIGM-HF trial in the Journal (pages 993–1004) we may be entering a new era of treatment for heart failure with reduced ejection fraction. To provide a historical perspective on the beginning of this new epoch, we constructed an interactive timeline (available with the full text of this article at NEJM.org) of 26 randomized, controlled trials in heart-failure treatment that have been published in the Journal since 1986. Each of these articles — some demonstrating successes and others documenting disappointments — represents a critical step in the effort to reduce mortality from heart failure with reduced . . .

eHealth interventions appear and change so quickly that they challenge the way we conduct research. By the time a randomized trial of a new intervention is published, technological improvements and clinical discoveries may make the intervention dated and unappealing. This and the spate of health-related apps and websites may lead consumers, patients, and caregivers to use interventions that lack evidence of efficacy. This paper aims to offer strategies for increasing the speed and usefulness of eHealth research. The paper describes two types of strategies based on the authors' own research and the research literature: those that improve the efficiency of eHealth research, and those that improve its quality. Efficiency strategies include: (1) think small: conduct small studies that can target discrete but significant questions and thereby speed knowledge acquisition; (2) use efficient designs: use such methods as fractional-factorial and quasi-experimental designs and surrogate endpoints, and experimentally modify and evaluate interventions and delivery systems already in use; (3) study universals: focus on timeless behavioral, psychological, and cognitive principles and systems; (4) anticipate the next big thing: listen to voices outside normal practice and connect different perspectives for new insights; (5) improve information delivery systems: researchers should apply their communications expertise to enhance inter-researcher communication, which could synergistically accelerate progress and capitalize upon the availability of \"big data\"; and (6) develop models, including mediators and moderators: valid models are remarkably generative, and tests of moderation and mediation should elucidate boundary conditions of effects and treatment mechanisms. Quality strategies include: (1) continuous quality improvement: researchers need to borrow engineering practices such as the continuous enhancement of interventions to incorporate clinical and technological progress; (2) help consumers identify quality: consumers, clinicians, and others all need to easily identify quality, suggesting the need to efficiently and publicly index intervention quality; (3) reduce the costs of care: concern with health care costs can drive intervention adoption and use and lead to novel intervention effects (eg, reduced falls in the elderly); and (4) deeply understand users: a rigorous evaluation of the consumer's needs is a key starting point for intervention development. The challenges of distinguishing and distributing scientifically validated interventions are formidable. The strategies described are meant to spur discussion and further thinking, which are important, given the potential of eHealth interventions to help patients and families.