Randomized controlled trial
A randomized controlled trial is a type of scientific experiment designed to evaluate the efficacy or safety of an intervention by minimizing bias through the random allocation of participants to one or more comparison groups.
In this design, at least one group receives the intervention under study, while another group receives an alternative treatment, a placebo, or standard care.
RCTs are a fundamental methodology in modern clinical trials and are considered one of the highest-quality sources of evidence in evidence-based medicine, due to their ability to reduce selection bias and the influence of confounding factors.
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
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, or not given information, about 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. 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.
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. Similarly, the initialism is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", leading to ambiguity in the scientific literature. Not all RCTs are randomized controlled trials. The term randomized controlled clinical trial is an alternative term used in clinical research; however, RCTs are also employed in other research areas, including [|many of the social sciences].
History
In the posthumously published Ortus Medicinae, Jan Baptist van Helmont made the first proposal of a RCT, to test two treatment regimes of fever. One treatment would be conducted by practitioners of Galenic medicine involving bloodletting and purging, and the other would be conducted by van Helmont. It is likely that he never conducted the trial, and merely proposed it as an experiment that could be conducted.The first reported clinical trial was conducted by James Lind in 1747 to identify a treatment for scurvy, and principles for conducting controlled trials were further elaborated by the Irish physician James Henry in 1843. 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. The first study recorded to have a blinded researcher was published in 1907 by W. H. R. Rivers and H. N. Webber to investigate the effects of caffeine.
Randomized experiments first appeared in psychology, where they were introduced by Charles Sanders Peirce and Joseph Jastrow in the 1880s, and in education. The earliest experiments comparing treatment and control groups were published by Robert Woodworth and Edward Thorndike in 1901, and by John E. Coover and Frank Angell in 1907.
In the early 20th century, randomized experiments appeared in agriculture, due to Jerzy Neyman and Ronald A. Fisher. Fisher's experimental research and his writings popularized randomized experiments.
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. One of the authors of that paper was Austin Bradford Hill, who is credited as having conceived the modern RCT.
Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s.
By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine. As of 2004, more than 150,000 RCTs were in the Cochrane Library. To improve the reporting of RCTs in the medical literature, an international group of scientists and editors published Consolidated Standards of Reporting Trials Statements in 1996, 2001 and 2010, and these have become widely accepted.
Ethics
Although subjects almost always provide informed consent for their participation in an RCT, studies since 1982 have documented that RCT subjects may believe that they are certain to receive treatment that is best for them personally; that is, they do not understand the difference between research and treatment. Determining the amount of information required to ensure informed consent can be difficult, and further research is necessary to determine the prevalence of and ways to address therapeutic misconception.Placebo-controlled trials have been deemed unethical in instances where not receiving treatment may lead to harm for the patient, such as an aggravation of symptoms or risk of death. Crossover trials, active-controlled trials, and other approaches have been used to mitigate this issue, though these options may not always be suitable for study, and have received their own criticism.
Active-controlled trials in particular may raise ethical considerations regarding clinical equipoise. Although the principle of equipoise is common to clinical trials and has been applied to RCTs, equipoise may be difficult to ascertain, and the ethics of RCTs have special considerations. It has been argued that equipoise itself is insufficient to justify RCTs. "Collective equipoise" may also conflict with a lack of personal equipoise, including that of the patient. Zelen's design, which has been used for some RCTs, randomizes subjects before they provide informed consent, which may be ethical for RCTs of screening and selected therapies, but is likely unethical "for most therapeutic trials." While some randomisation approaches have been used to minimize the risk that patients are exposed to less effective treatment, such as randomising patients with unequal rates, or adapting the rates during the trial's duration based on outcomes, these solutions have been criticized for raising more ethical problems than they resolve.
Whilst the above issues have resulted in robust practice guidelines around the conduct of RCTs, formulating balanced regulations tends to be difficult. Strict protections may act in favor of indigenous populations, but could fail on a globalised setting, as their imposition urges the outsourcing of trials to countries with poorer standards and more economically vulnerable populations. Frameworks which place great emphasis on patient well-being have also been criticized by some as paternalistic.
The RCT method variations may also create cultural effects that have not been well understood. For example, patients with terminal illness may join trials in the hope of being cured, even when treatments are unlikely to be successful.
Trial registration
In 2004, the announced that all trials starting enrolment after July 1, 2005, must be registered prior to consideration for publication in one of the 12 member journals of the committee. However, trial registration may still occur late or not at all.Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication.
Classifications
By study design
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:- Parallel-group – each participant is randomly assigned to a group, and all the participants in the group receive an intervention.
- Crossover – over time, each participant receives an intervention in a random sequence.
- Stepped-wedge trial - " involves random and sequential crossover of clusters from control to intervention until all clusters are exposed." In the past, this design has been called a "waiting list designs" or "phased implementations."
- Cluster – pre-existing groups of participants are randomly selected to receive an intervention.
- Factorial – each participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions.