Randomized controlled trial
A randomized controlled trial (or randomized control trial;[2] RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical techniques, medical devices, diagnostic procedures, diets or other medical treatments.[3][4]
Participants who enroll in RCTs differ from one another in known and unknown ways that can influence study outcomes, and yet cannot be directly controlled. By randomly allocating participants among compared treatments, an RCT enables statistical control over these influences. Provided it is designed well, conducted properly, and enrolls enough participants, an RCT may achieve sufficient control over these confounding factors to deliver a useful comparison of the treatments studied.
Definition and examples[edit]
An RCT in clinical research typically compares a proposed new treatment against an existing standard of care; these are then termed the 'experimental' and 'control' treatments, respectively. When no such generally accepted treatment is available, a placebo may be used in the control group so that participants are blinded to their treatment allocations. This blinding principle is ideally also extended as much as possible to other parties including researchers, technicians, data analysts, and evaluators. Effective blinding experimentally isolates the physiological effects of treatments from various psychological sources of bias.
The randomness in the assignment of participants to treatments reduces selection bias and allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments.[5] Blinding reduces other forms of experimenter and subject biases.
A well-blinded RCT is considered the gold standard for clinical trials. Blinded RCTs are commonly used to test the efficacy of medical interventions and may additionally provide information about adverse effects, such as drug reactions. A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.[6]
The terms "RCT" and "randomized trial" are sometimes used synonymously, but the latter term omits mention of controls and can therefore describe studies that compare multiple treatment groups with each other in the absence of a control group.[7] Similarly, the initialism is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", leading to ambiguity in the scientific literature.[8][9] Not all RCTs are randomized controlled trials (and some of them could never be, as in cases where controls would be impractical or unethical to use). The term randomized controlled clinical trial is an alternative term used in clinical research;[10] however, RCTs are also employed in other research areas, including many of the social sciences.
History[edit]
The first reported clinical trial was conducted by James Lind in 1747 to identify treatment for scurvy.[11] The first blind experiment was conducted by the French Royal Commission on Animal Magnetism in 1784 to investigate the claims of mesmerism. An early essay advocating the blinding of researchers came from Claude Bernard in the latter half of the 19th century. Bernard recommended that the observer of an experiment should not have knowledge of the hypothesis being tested. This suggestion contrasted starkly with the prevalent Enlightenment-era attitude that scientific observation can only be objectively valid when undertaken by a well-educated, informed scientist.[12] The first study recorded to have a blinded researcher was conducted in 1907 by W. H. R. Rivers and H. N. Webber to investigate the effects of caffeine.[13]
Randomized experiments first appeared in psychology, where they were introduced by Charles Sanders Peirce and Joseph Jastrow in the 1880s,[14] and in education.[15][16][17]
In the early 20th century, randomized experiments appeared in agriculture, due to Jerzy Neyman[18] and Ronald A. Fisher. Fisher's experimental research and his writings popularized randomized experiments.[19]
The first published Randomized Controlled Trial in medicine appeared in the 1948 paper entitled "Streptomycin treatment of pulmonary tuberculosis", which described a Medical Research Council investigation.[20][21][22] One of the authors of that paper was Austin Bradford Hill, who is credited as having conceived the modern RCT.[23]
Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s.[24]
By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine.[25] As of 2004, more than 150,000 RCTs were in the Cochrane Library.[23] To improve the reporting of RCTs in the medical literature, an international group of scientists and editors published Consolidated Standards of Reporting Trials (CONSORT) Statements in 1996, 2001 and 2010, and these have become widely accepted.[1][5] Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce the bias.
Classifications[edit]
By study design[edit]
One way to classify RCTs is by study design. From most to least common in the healthcare literature, the major categories of RCT study designs are:[38]
The types of statistical methods used in RCTs depend on the characteristics of the data and include:
Regardless of the statistical methods used, important considerations in the analysis of RCT data include:
RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice because RCTs reduce spurious causality and bias. Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct of evidence-based practice. Some examples of scientific organizations' considering RCTs or systematic reviews of RCTs to be the highest-quality evidence available are:
Notable RCTs with unexpected results that contributed to changes in clinical practice include:
Criticism[edit]
A 2018 review of the 10 most cited randomised controlled trials noted poor distribution of background traits, difficulties with blinding, and discussed other assumptions and biases inherent in randomised controlled trials. These include the "unique time period assessment bias", the "background traits remain constant assumption", the "average treatment effects limitation", the "simple treatment at the individual level limitation", the "all preconditions are fully met assumption", the "quantitative variable limitation" and the "placebo only or conventional treatment only limitation".[116]