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.
By outcome of interest (efficacy vs. effectiveness)
RCTs can be classified as "explanatory" or "pragmatic." Explanatory RCTs test efficacy in a research setting with highly selected participants and under highly controlled conditions. In contrast, pragmatic RCTs test effectiveness in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice."By hypothesis (superiority vs. noninferiority vs. equivalence)
Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and "equivalence trials", which differ in methodology and reporting. Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way. Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment." Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other.Randomization
The advantages of proper randomization in RCTs include:- "It eliminates 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."
However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect.
Procedures
The treatment allocation is the desired proportion of patients in each treatment arm.An ideal randomization procedure would achieve the following goals:
- Maximize statistical power, especially in subgroup analyses. Generally, equal group sizes maximize statistical power, however, unequal groups sizes may be more powerful for some analyses, and are sometimes desired for non-analytic reasons.
- Minimize selection bias. This may occur if investigators can consciously or unconsciously preferentially enroll patients between treatment arms. A good randomization procedure will be unpredictable so that investigators cannot guess the next subject's group assignment based on prior treatment assignments. The risk of selection bias is highest when previous treatment assignments are known or can be guessed.
- Minimize allocation bias. This may occur when covariates that affect the outcome are not equally distributed between treatment groups, and the treatment effect is confounded with the effect of the covariates. If the randomization procedure causes an imbalance in covariates related to the outcome across groups, estimates of effect may be biased if not adjusted for the covariates.
Simple
This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing." Also known as "complete" or "unrestricted" randomization, it is robust against both selection and accidental biases. However, its main drawback is the possibility of imbalanced group sizes in small RCTs. It is therefore recommended only for RCTs with over 200 subjects.Restricted
To balance group sizes in smaller RCTs, some form of "restricted" randomization is recommended. The major types of restricted randomization used in RCTs are:- Permuted-block randomization or blocked randomization: a "block size" and "allocation ratio" are specified, and subjects are allocated randomly within each block. For example, a block size of 6 and an allocation ratio of 2:1 would lead to random assignment of 4 subjects to one group and 2 to the other. This type of randomization can be combined with "stratified randomization", for example by center in a multicenter trial, to "ensure good balance of participant characteristics in each group." A special case of permuted-block randomization is random allocation, in which the entire sample is treated as one block. The major disadvantage of permuted-block randomization is that even if the block sizes are large and randomly varied, the procedure can lead to selection bias. Another disadvantage is that "proper" analysis of data from permuted-block-randomized RCTs requires stratification by blocks.
- Adaptive biased-coin randomization methods : In these relatively uncommon methods, the probability of being assigned to a group decreases if the group is overrepresented and increases if the group is underrepresented. The methods are thought to be less affected by selection bias than permuted-block randomization.
Adaptive
- Covariate-adaptive randomization, of which one type is minimization: The probability of being assigned to a group varies in order to minimize "covariate imbalance." Minimization is reported to have "supporters and detractors" because only the first subject's group assignment is truly chosen at random, the method does not necessarily eliminate bias on unknown factors.
- Response-adaptive randomization, also known as outcome-adaptive randomization: The probability of being assigned to a group increases if the responses of the prior patients in the group were favorable. Although arguments have been made that this approach is more ethical than other types of randomization when the probability that a treatment is effective or ineffective increases during the course of an RCT, ethicists have not yet studied the approach in detail.
Allocation concealment
Some standard methods of ensuring allocation concealment include sequentially numbered, opaque, sealed envelopes ; sequentially numbered containers; pharmacy controlled randomization; and central randomization. It is recommended that allocation concealment methods be included in an RCT's protocol, and that the allocation concealment methods should be reported in detail in a publication of an RCT's results; however, 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.
Sample size
The number of treatment units assigned to control and treatment groups, affects an RCT's reliability. If the effect of the treatment is small, the number of treatment units in either group may be insufficient for rejecting the null hypothesis in the respective statistical test. The failure to reject the null hypothesis would imply that the treatment shows no statistically significant effect on the treated in a given test. But as the sample size increases, the same RCT may be able to demonstrate a significant effect of the treatment, even if this effect is small.Blinding
An RCT may be blinded, by "procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received." Unlike allocation concealment, blinding is sometimes inappropriate or impossible to perform in an RCT; for example, if an RCT involves a treatment in which active participation of the patient is necessary, participants cannot be blinded to the intervention.Traditionally, blinded RCTs have been classified as "single-blind", "double-blind", or "triple-blind"; however, in 2001 and 2006 two studies showed that these terms have different meanings for different people. The 2010 CONSORT Statement specifies that authors and editors should not use the terms "single-blind", "double-blind", and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after assignment to interventions and how."
RCTs without blinding are referred to as "unblinded", "open", or "open-label". In 2008 a study concluded that the results of unblinded RCTs tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective; for example, in an RCT of treatments for multiple sclerosis, unblinded neurologists felt that the treatments were beneficial. In pragmatic RCTs, although the participants and providers are often unblinded, it is "still desirable and often possible to blind the assessor or obtain an objective source of data for evaluation of outcomes."
Analysis of data
The types of statistical methods used in RCTs depend on the characteristics of the data and include:- For dichotomous outcome data, logistic regression and other methods can be used.
- For continuous outcome data, analysis of covariance tests the effects of predictor variables.
- For time-to-event outcome data that may be censored, survival analysis is appropriate.
- Whether an RCT should be stopped early due to interim results. For example, RCTs may be stopped early if an intervention produces "larger than expected benefit or harm", or if "investigators find evidence of no important difference between experimental and control interventions."
- The extent to which the groups can be analyzed exactly as they existed upon randomization. A "pure" intention-to-treat analysis is "possible only when complete outcome data are available" for all randomized subjects; when some outcome data are missing, options include analyzing only cases with known outcomes and using imputed data. Nevertheless, the more that analyses can include all participants in the groups to which they were randomized, the less bias that an RCT will be subject to.
- Whether subgroup analysis should be performed. These are "often discouraged" because multiple comparisons may produce false positive findings that cannot be confirmed by other studies.
Reporting of results
For other RCT study designs, "CONSORT extensions" have been published, some examples are:
- Consort 2010 Statement: Extension to Cluster Randomised Trials
- Consort 2010 Statement: Non-Pharmacologic Treatment Interventions
- "Reporting of surrogate endpoints in randomised controlled trial reports : extension checklist with explanation and elaboration"
Relative importance and observational studies
Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:
- If study designs are ranked by their potential for new discoveries, then anecdotal evidence would be at the top of the list, followed by observational studies, followed by RCTs.
- RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to the expected stable or progressively worse natural course of the condition treated. One example is combination chemotherapy including cisplatin for metastatic testicular cancer, which increased the cure rate from 5% to 60% in a 1977 non-randomized study.
Interpretation of statistical results
Peer review
of results is an important part of the scientific method. Reviewers examine the study results for potential problems with design that could lead to unreliable results, evaluate the study in the context of related studies and other evidence, and evaluate whether the study can be reasonably considered to have proven its conclusions. To underscore the need for peer review and the danger of overgeneralizing conclusions, two Boston-area medical researchers performed a randomized controlled trial in which they randomly assigned either a parachute or an empty backpack to 23 volunteers who jumped from either a biplane or a helicopter. The study was able to accurately report that parachutes fail to reduce injury compared to empty backpacks. The key context that limited the general applicability of this conclusion was that the aircraft were parked on the ground, and participants had only jumped about two feet.Advantages
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:- As of 1998, the National Health and Medical Research Council of Australia designated "Level I" evidence as that "obtained from a systematic review of all relevant randomised controlled trials" and "Level II" evidence as that "obtained from at least one properly designed randomised controlled trial."
- Since at least 2001, in making clinical practice guideline recommendations the United States Preventive Services Task Force has considered both a study's design and its internal validity as indicators of its quality. It has recognized "evidence obtained from at least one properly randomized controlled trial" with good internal validity as the highest quality evidence available to it.
- The GRADE Working Group concluded in 2008 that "randomised trials without important limitations constitute high quality evidence."
- For issues involving "Therapy/Prevention, Aetiology/Harm", the Oxford Centre for Evidence-based Medicine as of 2011 defined "Level 1a" evidence as a systematic review of RCTs that are consistent with each other, and "Level 1b" evidence as an "individual RCT."
- After Food and Drug Administration approval, the antiarrhythmic agents flecainide and encainide came to market in 1986 and 1987 respectively. The non-randomized studies concerning the drugs were characterized as "glowing", and their sales increased to a combined total of approximately 165,000 prescriptions per month in early 1989. In that year, however, a preliminary report of an RCT concluded that the two drugs increased mortality. Sales of the drugs then decreased.
- Prior to 2002, based on observational studies, it was routine for physicians to prescribe hormone replacement therapy for post-menopausal women to prevent myocardial infarction. In 2002 and 2004, however, published RCTs from the Women's Health Initiative claimed that women taking hormone replacement therapy with estrogen plus progestin had a higher rate of myocardial infarctions than women on a placebo, and that estrogen-only hormone replacement therapy caused no reduction in the incidence of coronary heart disease. Possible explanations for the discrepancy between the observational studies and the RCTs involved differences in methodology, in the hormone regimens used, and in the populations studied. The use of hormone replacement therapy decreased after publication of the RCTs.
Disadvantages
Time and costs
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, in that 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, based on evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product.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 and uncommon adverse outcomes would require RCTs with extremely large sample sizes and may, therefore, best be assessed by observational studies.
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; whereas the case report, for example, can detail many aspects of the patient's medical situation.
Conflict of interest dangers
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. The 29 meta-analyses reviewed an aggregate of 509 randomized controlled trials. Of these, 318 RCTs reported funding sources with 219 industry funded. 132 of the 509 RCTs reported author conflict of interest disclosures, with 91 studies disclosing industry financial ties with one or more authors. The information was, however, seldom reflected in the meta-analyses. Only two reported RCT funding sources and none reported RCT author-industry ties. The authors concluded "without acknowledgment of COI due to industry funding or author industry financial ties from RCTs included in meta-analyses, readers' understanding and appraisal of the evidence from the meta-analysis may be compromised."Some RCTs are fully or partly funded by the health care industry as opposed to government, nonprofit, or other sources. A systematic review published in 2003 found four 1986–2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and 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.
Ethics and feasibility
Whilst RCTs are considered the golden standard of research in evidence-based medicine, they may be inappropriate for study in certain contexts. For instance, RCTs may be improper for studying medical interventions with "obvious" benefits to patients, as such practice would unethically deny the control group of effective treatment. Challenges may also arise in instances where a treatment requires the active participation of participants, such as psychotherapy or approaches based on community development.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, and the evident physiological impacts of surgery may compromise blinding on the part of the subjects without the use of sham controls, which are only considered possible for a narrow range of surgical interventions.
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, such as with abortion and adolescent transgender healthcare. Other than compromising masking, it is likely that RCT study designs for some of these interventions would also result in high likelihood of withdrawal, non-adherence, and response bias in the control groups, making RCTs potentially unreliable.
In social science
Due to the recent emergence of RCTs in social science, their application in these fields remain a contested issue among academics. Some writers from a medical or health background have argued that existing research in a range of social science disciplines lacks rigour, and should be improved by greater use of randomized control trials. Similarly, many economists have found RCTs are the gold standard for ensuring outcomes represent causal inference and not just correlation. Overall, the adaptation of RCTs into social science has become significant in recent decades.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, publishing 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 impact of RCTs on the discipline has only grown, as economists have found this method as a first-best approach to causal inference identification. While not at the forefront, the use of RCTs has helped to bolster the credibility revolution in empirical microeconomics, as well as becoming popularized as a result of the need for more rigorous identification.Despite the shift towards using RCTs in research, there still remains division between economists on its use. John A. List, a proponent of field experiments, particularly RCTs, finds that this method differs significantly from lab experiments, and therefore provide more robust measures for identification. RCTs also offer the advantage of providing true observational data that can be used where the absence of data would make it difficult to build a causal model with.
The American Economic Association maintains a registry of all active and completed RCTs within the discipline. The registry is free to use and is designed to ensure researchers may share information with regard to on-going field work, as well as failures or limitations of study settings. Since its founding in 2013, the AEA has tracked over 7,400 field experiments across 100 countries, with annual RCT registries growing year over year.
Transport science
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, categorising them into 5 "quality levels". 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.Dr. Steve Melia took issue with these conclusions, arguing that claims about the advantages of RCTs, in establishing causality and avoiding bias, have been exaggerated. He proposed the following eight criteria for the use of RCTs in contexts where interventions must change human behaviour to be effective:
The intervention:
- Has not been applied to all members of a unique group of people
- Is applied in a context or setting similar to that which applies to the control group
- Can be isolated from other activities—and the purpose of the study is to assess this isolated effect
- Has a short timescale between its implementation and maturity of its effects
- Are either known to the researchers, or else all possible alternatives can be tested
- Do not involve significant feedback mechanisms between the intervention group and external environments
- Have a stable and predictable relationship to exogenous factors
- Would act in the same way if the control group and intervention group were reversed
Criminology