Randomized controlled trial

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Flowchart of four phases (enrollment, intervention allocation, follow-up, and data analysis) of a parallel randomized trial of two groups, modified from the CONSORT (Consolidated Standards of Reporting Trials) 2010 Statement Flowchart of Phases of Parallel Randomized Trial - Modified from CONSORT 2010.png
Flowchart of four phases (enrollment, intervention allocation, follow-up, and data analysis) of a parallel randomized trial of two groups, modified from the CONSORT (Consolidated Standards of Reporting Trials) 2010 Statement

A randomized controlled trial (or randomized control trial; [2] RCT) is a type of scientific (often medical) experiment which aims to reduce bias when testing a new treatment. The people participating in the trial are randomly allocated to either the group receiving the treatment under investigation or to a group receiving standard treatment (or placebo treatment) as the control. Randomization minimises selection bias and the different comparison groups allow the researchers to determine any effects of the treatment when compared with the no treatment (control) group, while other variables are kept constant. The RCT is often considered the gold standard for a clinical trial. RCTs are often used to test the efficacy or effectiveness of various types of medical intervention and may provide information about adverse effects, such as drug reactions. Random assignment of intervention is done after subjects have been assessed for eligibility and recruited, but before the intervention to be studied begins.

Randomized experiment

In science, randomized experiments are the experiments that allow the greatest reliability and validity of statistical estimates of treatment effects. Randomization-based inference is especially important in experimental design and in survey sampling.

Selection bias is the bias introduced by the selection of individuals, groups or data for analysis in such a way that proper randomization is not achieved, thereby ensuring that the sample obtained is not representative of the population intended to be analyzed. It is sometimes referred to as the selection effect. The phrase "selection bias" most often refers to the distortion of a statistical analysis, resulting from the method of collecting samples. If the selection bias is not taken into account, then some conclusions of the study may not be accurate.

Scientific control subject or observation selected to minimize the effects of variables other than the independent variable of an experiment

A scientific control is an experiment or observation designed to minimize the effects of variables other than the independent variable. This increases the reliability of the results, often through a comparison between control measurements and the other measurements. Scientific controls are a part of the scientific method.

Contents

Random allocation in real trials is complex, but conceptually the process is like tossing a coin. After randomization, the two (or more) groups of subjects are followed in exactly the same way and the only differences between them is the care they receive. For example, in terms of procedures, tests, outpatient visits, and follow-up calls, should be those intrinsic to the treatments being compared. The most important advantage of proper randomization is that it minimizes allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments. [3]

The terms "RCT" and randomized trial are sometimes used synonymously, but the methodologically sound practice is to reserve the "RCT" name only for trials that contain control groups, in which groups receiving the experimental treatment are compared with control groups receiving no treatment (a placebo-controlled study) or a previously tested treatment (a positive-control study). The term "randomized trials" omits mention of controls and can describe studies that compare multiple treatment groups with each other (in the absence of a control group). [4] Similarly, although the "RCT" name is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", the methodologically sound practice, to avoid ambiguity in the scientific literature, is to retain "control" in the definition of "RCT" and thus reserve that name only for trials that contain controls. Not all randomized clinical trials are randomized controlled trials (and some of them could never be, in cases where controls would be impractical or unethical to institute). The term randomized controlled clinical trials is a methodologically sound alternate expansion for "RCT" in RCTs that concern clinical research; [5] [6] [7] however, RCTs are also employed in other research areas, including many of the social sciences.

Placebo-controlled study

Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect. Placebos are most commonly used in blinded trials, where subjects do not know whether they are receiving real or placebo treatment. Often, there is also a further "natural history" group that does not receive any treatment at all.

Scientific literature comprises scholarly publications that report original empirical and theoretical work in the natural and social sciences, and within an academic field, often abbreviated as the literature. Academic publishing is the process of contributing the results of one's research into the literature, which often requires a peer-review process. Original scientific research published for the first time in scientific journals is called the primary literature. Patents and technical reports, for minor research results and engineering and design work, can also be considered primary literature. Secondary sources include review articles and books. Tertiary sources might include encyclopedias and similar works intended for broad public consumption.

Clinical trials are experiments or observations done in clinical research. Such prospective biomedical or behavioral research studies on human participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments and known interventions that warrant further study and comparison. Clinical trials generate data on safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial – their approval does not mean that the therapy is 'safe' or effective, only that the trial may be conducted.

History

The first reported clinical trial was conducted by James Lind in 1747 to identify treatment for scurvy. [8] Randomized experiments appeared in psychology, where they were introduced by Charles Sanders Peirce, [9] and in education. [10] [11] [12] Later, randomized experiments appeared in agriculture, due to Jerzy Neyman [13] and Ronald A. Fisher. Fisher's experimental research and his writings popularized randomized experiments. [14]

James Lind Scottish physician and pioneer of naval hygiene

James Lind was a Scottish doctor. He was a pioneer of naval hygiene in the Royal Navy. By conducting one of the first ever clinical trials, he developed the theory that citrus fruits cured scurvy. He argued for the health benefits of better ventilation aboard naval ships, the improved cleanliness of sailors' bodies, clothing and bedding, and below-deck fumigation with sulphur and arsenic. He also proposed that fresh water could be obtained by distilling sea water. His work advanced the practice of preventive medicine and improved nutrition.

Scurvy human disease

Scurvy is a disease resulting from a lack of vitamin C. Early symptoms include weakness, feeling tired, and sore arms and legs. Without treatment, decreased red blood cells, gum disease, changes to hair, and bleeding from the skin may occur. As scurvy worsens there can be poor wound healing, personality changes, and finally death from infection or bleeding.

Experimental psychology refers to work done by those who apply experimental methods to psychological study and the processes that underlie it. Experimental psychologists employ human participants and animal subjects to study a great many topics, including sensation & perception, memory, cognition, learning, motivation, emotion; developmental processes, social psychology, and the neural substrates of all of these.

The first published RCT in medicine appeared in the 1948 paper entitled "Streptomycin treatment of pulmonary tuberculosis", which described a Medical Research Council investigation. [15] [16] [17] One of the authors of that paper was Austin Bradford Hill, who is credited as having conceived the modern RCT. [18]

Streptomycin An antibiotic effective against various gram-positive and gram-negative bacteria

Streptomycin is an antibiotic used to treat a number of bacterial infections. This includes tuberculosis, Mycobacterium avium complex, endocarditis, brucellosis, Burkholderia infection, plague, tularemia, and rat bite fever. For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide. It is given by injection into a vein or muscle.

Tuberculosis infectious disease caused by the bacterium Mycobacterium tuberculosis

Tuberculosis (TB) is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but can also affect other parts of the body. Most infections do not have symptoms, in which case it is known as latent tuberculosis. About 10% of latent infections progress to active disease which, if left untreated, kills about half of those affected. The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night sweats, and weight loss. It was historically called "consumption" due to the weight loss. Infection of other organs can cause a wide range of symptoms.

Austin Bradford Hill English epidemiologist and statistician

Sir Austin Bradford Hill FRS, English epidemiologist and statistician, pioneered the randomized clinical trial and, together with Richard Doll, demonstrated the connection between cigarette smoking and lung cancer. Hill is widely known for pioneering the "Bradford Hill" criteria for determining a causal association.

By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine. [19] As of 2004, more than 150,000 RCTs were in the Cochrane Library. [18] 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] [3] 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.

Cochrane Library

The Cochrane Library is a collection of databases in medicine and other healthcare specialties provided by Cochrane and other organizations. At its core is the collection of Cochrane Reviews, a database of systematic reviews and meta-analyses which summarize and interpret the results of medical research. The Cochrane Library aims to make the results of well-conducted controlled trials readily available and is a key resource in evidence-based medicine.

CONSORT encompasses various initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomized controlled trials.

Ethics

Although the principle of clinical equipoise ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials [20] has been applied to RCTs, the ethics of RCTs have special considerations. For one, it has been argued that equipoise itself is insufficient to justify RCTs. [21] For another, "collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention is effective). [22] Finally, 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." [23] [24]

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. [25] [26] Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception". [26]

The RCT method variations may also create cultural effects that have not been well understood. [27] 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 International Committee of Medical Journal Editors (ICMJE) 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. [28] However, trial registration may still occur late or not at all. [29] [30] Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication. [31]

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: [32]

An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial. [32]

By outcome of interest (efficacy vs. effectiveness)

RCTs can be classified as "explanatory" or "pragmatic." [35] Explanatory RCTs test efficacy in a research setting with highly selected participants and under highly controlled conditions. [35] In contrast, pragmatic RCTs (pRCTs) test effectiveness in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice." [35]

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. [36] Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way. [36] Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment." [36] Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other. [36]

Randomization

The advantages of proper randomization in RCTs include: [37]

There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate an unpredictable sequence of allocations; this may be a simple random assignment of patients to any of the groups at equal probabilities, may be "restricted", or may be "adaptive." 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" and can cause a breach of allocation concealment. [38]

However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect. [39]

Procedures

The treatment allocation is the desired proportion of patients in each treatment arm.

An ideal randomization procedure would achieve the following goals: [40]

However, no single randomization procedure meets those goals in every circumstance, so researchers must select a procedure for a given study based on its advantages and disadvantages.

Simple

This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing." [37] 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. [44]

Restricted

To balance group sizes in smaller RCTs, some form of "restricted" randomization is recommended. [44] The major types of restricted randomization used in RCTs are:

  • Permuted-block randomization or blocked randomization: a "block size" and "allocation ratio" (number of subjects in one group versus the other group) are specified, and subjects are allocated randomly within each block. [38] 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." [3] A special case of permuted-block randomization is random allocation, in which the entire sample is treated as one block. [38] 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. [40] Another disadvantage is that "proper" analysis of data from permuted-block-randomized RCTs requires stratification by blocks. [44]
  • Adaptive biased-coin randomization methods (of which urn randomization is the most widely known type): 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. [38] The methods are thought to be less affected by selection bias than permuted-block randomization. [44]

Adaptive

At least two types of "adaptive" randomization procedures have been used in RCTs, but much less frequently than simple or restricted randomization:

  • Covariate-adaptive randomization, of which one type is minimization : The probability of being assigned to a group varies in order to minimize "covariate imbalance." [44] Minimization is reported to have "supporters and detractors" [38] because only the first subject's group assignment is truly chosen at random, the method does not necessarily eliminate bias on unknown factors. [3]
  • 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. [44] 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. [45]

Allocation concealment

"Allocation concealment" (defined as "the procedure for protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the study") is important in RCTs. [46] In practice, clinical investigators in RCTs often find it difficult to maintain impartiality. 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. [38] Such practices introduce selection bias and confounders (both of which should be minimized by randomization), possibly distorting the results of the study. [38] Adequate allocation concealment should defeat patients and investigators from discovering treatment allocation once a study is underway and after the study has concluded. Treatment related side-effects or adverse events may be specific enough to reveal allocation to investigators or patients thereby introducing bias or influencing any subjective parameters collected by investigators or requested from subjects.

Some standard methods of ensuring allocation concealment include sequentially numbered, opaque, sealed envelopes (SNOSE); sequentially numbered containers; pharmacy controlled randomization; and central randomization. [38] 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. [47] 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. [48]

Sample size

The number of treatment units (subjects or groups of subjects) 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. [49]

Blinding

An RCT may be blinded, (also called "masked") by "procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received." [48] 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 (e.g., physical therapy), 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. [50] [51] 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 (for example, participants, care providers, those assessing outcomes) and how." [3]

RCTs without blinding are referred to as "unblinded", [52] "open", [53] or (if the intervention is a medication) "open-label". [54] 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; [48] for example, in an RCT of treatments for multiple sclerosis, unblinded neurologists (but not the blinded neurologists) felt that the treatments were beneficial. [55] 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." [35]

Analysis of data

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:

Reporting of results

The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for reporting RCTs." [60] The CONSORT 2010 checklist contains 25 items (many with sub-items) focusing on "individually randomised, two group, parallel trials" which are the most common type of RCT. [1]

For other RCT study designs, "CONSORT extensions" have been published, some examples are:

Relative importance and observational studies

Two studies published in The New England Journal of Medicine in 2000 found that observational studies and RCTs overall produced similar results. [64] [65] The authors of the 2000 findings questioned the belief that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of the highest grade." [64] [65] However, a 2001 study published in Journal of the American Medical Association concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common" between observational studies and RCTs. [66]

Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:

Interpretation of statistical results

Like all statistical methods, RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors. Regarding Type I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different. [71] Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the negative results, [72] by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely reported sample size calculations. [73]

Peer review

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 (for example by creating a systematic bias), 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 over-generalizing 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. [74]

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:

Notable RCTs with unexpected results that contributed to changes in clinical practice include:

Disadvantages

Many papers discuss the disadvantages of RCTs. [68] [86] [87] Among the most frequently cited drawbacks are:

Time and costs

RCTs can be expensive; [87] 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, [88] 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. [88]

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. [89]

It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions. [68] [87]

Interventions to prevent events that occur only infrequently (e.g., sudden infant death syndrome) and uncommon adverse outcomes (e.g., a rare side effect of a drug) would require RCTs with extremely large sample sizes and may therefore best be assessed by observational studies. [68]

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 (e.g. patient history, physical examination, diagnosis, psychosocial aspects, follow up). [89]

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 (RCTs). Of these, 318 RCTs reported funding sources with 219 (69%) industry funded. 132 of the 509 RCTs reported author conflict of interest disclosures, with 91 studies (69%) disclosing industry financial ties with one or more authors. The information was, however, seldom reflected in the meta-analyses. Only two (7%) 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." [90]

Some RCTs are fully or partly funded by the health care industry (e.g., the pharmaceutical 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. [91] 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." [92] 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. [93] One possible reason for the pro-industry results in industry-funded published RCTs is publication bias. [92] 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. [94]

Ethics

If a disruptive innovation in medical technology is developed, it may be difficult to test this ethically in an RCT if it becomes "obvious" that the control subjects have poorer outcomes—either due to other foregoing testing, or within the initial phase of the RCT itself. Ethically it may be necessary to abort the RCT prematurely, and getting ethics approval (and patient agreement) to withhold the innovation from the control group in future RCT's may not be feasible.

Historical control trials (HCT) exploit the data of previous RCTs to reduce the sample size; however, these approaches are controversial in the scientific community and must be handled with care. [95]

In social science

Due to the recent emergence of RCTs in social science, the use of RCTs in social sciences is a contested issue. 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.

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. [96] Graham-Rowe and colleagues [97] 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 [98] 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 8 criteria for the use of RCTs in contexts where interventions must change human behaviour to be effective:

The intervention:

  1. Has not been applied to all members of a unique group of people (e.g. the population of a whole country, all employees of a unique organisation etc.)
  2. Is applied in a context or setting similar to that which applies to the control group
  3. Can be isolated from other activities – and the purpose of the study is to assess this isolated effect
  4. Has a short timescale between its implementation and maturity of its effects

And the causal mechanisms:

  1. Are either known to the researchers, or else all possible alternatives can be tested
  2. Do not involve significant feedback mechanisms between the intervention group and external environments
  3. Have a stable and predictable relationship to exogenous factors
  4. Would act in the same way if the control group and intervention group were reversed

International development

RCTs are currently being used by a number of international development experts to measure the impact of development interventions worldwide. Development economists at research organizations including Abdul Latif Jameel Poverty Action Lab (J-PAL) [99] [100] [101] and Innovations for Poverty Action [102] have used RCTs to measure the effectiveness of poverty, health, and education programs in the developing world. While RCTs can be useful in policy evaluation, it is necessary to exercise care in interpreting the results in social science settings. For example, interventions can inadvertently induce socioeconomic and behavioral changes that can confound the relationships (Bhargava, 2008).

For some development economists, the main benefit to using RCTs compared to other research methods is that randomization guards against selection bias, a problem present in many current studies of development policy. In one notable example of a cluster RCT in the field of development economics, Olken (2007) randomized 608 villages in Indonesia in which roads were about to be built into six groups (no audit vs. audit, and no invitations to accountability meetings vs. invitations to accountability meetings vs. invitations to accountability meetings along with anonymous comment forms). [103] After estimating "missing expenditures" (a measure of corruption), Olken concluded that government audits were more effective than "increasing grassroots participation in monitoring" in reducing corruption. [103] Overall, it is important in social sciences to account for the intended as well as the unintended consequences of interventions for policy evaluations.

Criminology

A 2005 review found 83 randomized experiments in criminology published in 1982-2004, compared with only 35 published in 1957-1981. [104] The authors classified the studies they found into five categories: "policing", "prevention", "corrections", "court", and "community". [104] Focusing only on offending behavior programs, Hollin (2008) argued that RCTs may be difficult to implement (e.g., if an RCT required "passing sentences that would randomly assign offenders to programmes") and therefore that experiments with quasi-experimental design are still necessary. [105]

Education

RCTs have been used in evaluating a number of educational interventions. Between 1980 and 2016, over 1,000 reports of RCTs have been published. [106] For example, a 2009 study randomized 260 elementary school teachers' classrooms to receive or not receive a program of behavioral screening, classroom intervention, and parent training, and then measured the behavioral and academic performance of their students. [107] Another 2009 study randomized classrooms for 678 first-grade children to receive a classroom-centered intervention, a parent-centered intervention, or no intervention, and then followed their academic outcomes through age 19. [108]

Mock randomised controlled trials, or simulations using confectionery, can conducted in the classroom to teach students and health professionals the principles of RCT design and critical appraisal. [109]

See also

Related Research Articles

Evidence-based medicine (EBM) is an approach to medical practice intended to optimize decision-making by emphasizing the use of evidence from well-designed and well-conducted research. Although all medicine based on science has some degree of empirical support, EBM goes further, classifying evidence by its epistemologic strength and requiring that only the strongest types can yield strong recommendations; weaker types can yield only weak recommendations. The term was originally used to describe an approach to teaching the practice of medicine and improving decisions by individual physicians about individual patients. Use of the term rapidly expanded to include a previously described approach that emphasized the use of evidence in the design of guidelines and policies that apply to groups of patients and populations. It has subsequently spread to describe an approach to decision-making that is used at virtually every level of health care as well as other fields.

Meta-analysis statistical method that summarizes data from multiple sources

A meta-analysis is a statistical analysis that combines the results of multiple scientific studies.

Cochrane (organisation) British nonprofit for reviews of medical research

Cochrane is a British charity formed to organise medical research findings so as to facilitate evidence-based choices about health interventions faced by health professionals, patients, and policy makers. Cochrane includes 53 review groups that are based at research institutions worldwide. Cochrane has approximately 30,000 volunteer experts from around the world.

Publication bias is a type of bias that occurs in published academic research. It occurs when the outcome of an experiment or research study influences the decision whether to publish or otherwise distribute it. Publication bias matters because literature reviews regarding support for a hypothesis can be biased if the original literature is contaminated by publication bias. Publishing only results that show a significant finding disturbs the balance of findings.

Evidence hierarchies reflect the relative authority of various types of biomedical research, which create levels of evidence, or at least levels of methodologies that produce evidence. There is broad agreement on the relative strength of the principal types of epidemiological studies but no single, universally-accepted hierarchy of evidence. More than 80 different hierarchies have been proposed for assessing medical evidence. Typically, randomized controlled trials (RCTs) rank above observational studies, while expert opinion and anecdotal experience are ranked at the bottom. Some evidence hierarchies place systematic review and meta analysis above RCTs.

An intention-to-treat (ITT) analysis of the results of an experiment is based on the initial treatment assignment and not on the treatment eventually received. ITT analysis is intended to avoid various misleading artifacts that can arise in intervention research such as non-random attrition of participants from the study or crossover. ITT is also simpler than other forms of study design and analysis because it does not require observation of compliance status for units assigned to different treatments or incorporation of compliance into the analysis. Although ITT analysis is widely employed in published clinical trials, it can be incorrectly described and there are some issues with its application. Furthermore, there is no consensus on how to carry out an ITT analysis in the presence of missing outcome data.

Zelen's design is an experimental design for randomized clinical trials proposed by Harvard School of Public Health statistician Marvin Zelen (1927-2014). In this design, patients are randomized to either the treatment or control group before giving informed consent. Because the group to which a given patient is assigned is known, consent can be sought conditionally.

In epidemiology, reporting bias is defined as "selective revealing or suppression of information" by subjects. In artificial intelligence research, the term reporting bias is used to refer to people's tendency to under-report all the information available.

In medicine, levels of evidence (LoE) are arranged in a ranking system used in evidence-based practices to describe the strength of the results measured in a clinical trial or research study. The design of the study and the endpoints measured affect the strength of the evidence.

Treatment of chronic fatigue syndrome (CFS) is variable and uncertain, and the condition is primarily managed rather than cured.

The analysis of clinical trials involves a large number of related topics including:

The Jadad scale, sometimes known as Jadad scoring or the Oxford quality scoring system, is a procedure to independently assess the methodological quality of a clinical trial. It is named after Colombian physician Alex Jadad who in 1996 described a system for allocating the trial a score of between zero and five (rigorous). It is the most widely used such assessment in the world, and as of 2017, its seminal paper has been cited in over 13000 scientific works.

Sham surgery is a faked surgical intervention that omits the step thought to be therapeutically necessary.

Critical appraisal is the use of explicit, transparent methods to assess the data in published research, applying the rules of evidence to factors such as internal validity, adherence to reporting standards, conclusions and generalizability. Critical appraisal methods form a central part of the systematic review process. They are used in evidence-based healthcare training to assist clinical decision-making, and are increasingly used in evidence-based social care and education provision.

A cluster randomised controlled trial is a type of randomised controlled trial in which groups of subjects are randomised. Cluster randomised controlled trials are also known as cluster randomised trials, group-randomised trials, and place-randomized trials.

Renal sympathetic denervation (RSDN), or renal denervation (RDN), is a minimally invasive, endovascular catheter based procedure using radiofrequency ablation or ultrasound ablation aimed at treating resistant hypertension. Nerves in the wall of the renal artery are ablated by applying radiofrequency pulses or ultrasound to the renal arteries. This causes reduction of sympathetic afferent and efferent activity to the kidney and blood pressure can be decreased. Early data from international clinical trials without sham controls was promising - demonstrating large blood pressure reductions in patients with treatment-resistant hypertension. However, in 2014 a prospective, single-blind, randomized, sham-controlled clinical trial failed to confirm a beneficial effect on blood pressure. A 2014 consensus statement from The Joint UK Societies did not recommend the use of renal denervation for treatment of resistant hypertension on current evidence.

A stepped-wedge trial is a type of randomised controlled trial, a scientific experiment which is structured to reduce bias when testing new medical treatments, social interventions, or other testable hypotheses. In a traditional RCT, a part of the participants in the experiment are simultaneously and randomly assigned to a group that receives the treatment and another part to a group that does not. In an SWT, typically a logistical constraint prevents the simultaneous treatment of some participants, and instead, all or most participants receive the treatment in waves or "steps".

Allegiance bias in behavioral sciences, denote to the finding or conclusions being crafted in a manner that reconciles best with the investigator's or researcher's perspectives and preferences, instead of retaining its empirical, innate or native state.

Evidence-based research (EBR) is "the use of prior research in a systematic and transparent way to inform a new study so that it is answering questions that matter in a valid, efficient and accessible manner". According to EBR, any new study should be informed by systematically examining existing evidence to determine the study's need, design, and methods. In addition, results of a study should be placed in context by incorporating them in a systematic review of similar earlier studies.

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