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 such as a drug, surgical procedure, medical device, diet, or diagnostic test. 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. Participants who enroll in RCTs differ from one another in known and unknown ways that can influence study outcomes 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. 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. 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.
In the posthumously published Ortus Medicinae (1648), Jan Baptist van Helmont made the first proposal of a randomized controlled trial 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. 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. In education, the earliest experiments comparing treatment and control groups were published by Robert Woodworth and Edward Thorndike in 1901. 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. 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.
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. 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. 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. It has been argued that equipoise itself is insufficient to justify RCTs. Zelen's design which has been used for some RCTs randomizes subjects before they provide informed consent. This may be ethical for RCTs of screening and selected therapies but is likely unethical for most therapeutic trials. While strict protections may act in favor of indigenous populations, they could fail on a globalised setting as their imposition urges the outsourcing of trials to countries with poorer standards and more economically vulnerable populations. 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.
The advantages of proper randomization in RCTs include eliminating bias in treatment assignment specifically selection bias and confounding. It facilitates blinding of the identity of treatments from investigators participants and assessors. It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance. There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate an unpredictable sequence of allocations. A second and more practical issue is allocation concealment which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed prior to definitively allocating them to their respective groups. Non-random systematic methods of group assignment such as alternating subjects between one group and the other can cause limitless contamination possibilities. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient. Such practices introduce selection bias and confounders possibly distorting the results of the study. Some standard methods of ensuring allocation concealment include sequentially numbered opaque sealed envelopes SNOSE, sequentially numbered containers, pharmacy controlled randomization, and central randomization. A 2005 study determined that most RCTs have unclear allocation concealment in their protocols, in their publications, or both. On the other hand, a 2008 study of 146 meta-analyses concluded that the results of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective.
Due to the recent emergence of RCTs in social science, their application in these fields remain a contested issue among academics. In economics, RCTs have become a staple of identifying causal inference among microeconomic studies particularly in development economics. In 1994, Paul Glewwe, eventual Nobel Prize winner, Michael Kremer, and Sylvie Moulin started one of the earliest RCTs in an economic setting by conducting a long run intervention in a school in Kenya. They published the results fifteen years later. Three years later in 1997, the largest field experiment in a developing context, the PROGRESA program in Mexico, was studied by a multitude of economic researchers. The American Economic Association maintains a registry of all active and completed RCTs within the discipline. Since its founding in 2013, the AEA has tracked over 7,400 field experiments across 100 countries. Researchers in transport science argue that public spending on programmes such as school travel plans could not be justified unless their efficacy is demonstrated by randomized controlled trials. Graham-Rowe and colleagues reviewed 77 evaluations of transport interventions found in the literature. They concluded that most of the studies were of low quality and advocated the use of randomized controlled trials wherever possible in future transport research. A 2005 review found 83 randomized experiments in criminology published in 1982, 2004 compared with only 35 published in 1957, 1981. Between 1980 and 2016, over 1,000 reports of RCTs have been published in education. For example, a 2009 study randomized 260 elementary school teachers' classrooms to receive or not receive a program of behavioral screening.
RCTs can be expensive; one study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke prior to 2000 with a total cost of US$335 million for a mean cost of US$12 million per RCT. Nevertheless, the return on investment of RCTs may be high as the same study projected that the 28 RCTs produced a net benefit to society at 10-years of 46 times the cost of the trials program. The conduct of an RCT takes several years until being published thus data is restricted from the medical community for long years and may be of less relevance at time of publication. It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions. Interventions to prevent events that occur only infrequently such as sudden infant death syndrome and uncommon adverse outcomes like a rare side effect of a drug would require RCTs with extremely large sample sizes. Due to the costs of running RCTs these usually only inspect one variable or very few variables rarely reflecting the full picture of a complicated medical situation. Historically it has been difficult to effectively utilize RCTs for the study of surgical procedures. Unlike with the study of medication where blinding tends to be relatively easy through placebos, blinding of the investigator-surgeon may be impossible within a surgical trial. RCTs may also be considered infeasible or unethical for studying the mental health impacts of interventions with obvious physical effects especially when those are highly sought out by patients.
A 2011 study done to disclose possible conflicts of interests in underlying research studies used for medical meta-analyses reviewed 29 meta-analyses and found that conflicts of interests in the studies underlying the meta-analyses were rarely disclosed. The 29 meta-analyses included 11 from general medicine journals, 15 from specialty medicine journals, and 3 from the Cochrane Database of Systematic Reviews. Of these, 318 RCTs reported funding sources with 219 (69%) industry funded. A systematic review published in 2003 found four 1986, 2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs. In all the articles there was a correlation of industry sponsorship and positive study outcome. A 2004 study of 1999, 2001 RCTs published in leading medical and surgical journals determined that industry-funded RCTs are more likely to be associated with statistically significant pro-industry findings. These results have been mirrored in trials in surgery where although industry funding did not affect the rate of trial discontinuation it was however associated with a lower odds of publication for completed trials. One possible reason for the pro-industry results in industry-funded published RCTs is publication bias. Other authors have cited the differing goals of academic and industry sponsored research as contributing to the difference. Commercial sponsors may be more focused on performing trials of drugs that have already shown promise in early stage trials and on replicating previous positive results to fulfill regulatory requirements for drug approval.
Common questions
What is a 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 such as a drug, surgical procedure, medical device, diet, or diagnostic test.
When was the first reported clinical trial conducted for scurvy?
The first reported clinical trial was conducted by James Lind in 1747 to identify a treatment for scurvy. Principles for conducting controlled trials were further elaborated by the Irish physician James Henry in 1843.
Who conceived the modern randomized controlled trial in medicine?
Austin Bradford Hill is credited as having conceived the modern RCT during the 1948 paper entitled Streptomycin treatment of pulmonary tuberculosis which described a Medical Research Council investigation. This publication marked the first published Randomized Controlled Trial in medicine.
How much did 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke cost prior to 2000?
One study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke prior to 2000 with a total cost of US$335 million for a mean cost of US$12 million per RCT. The same study projected that these 28 RCTs produced a net benefit to society at 10-years of 46 times the cost of the trials program.