Randomized controlled trial
A randomized controlled trial (RCT) is a type of scientific experiment
An experiment is a methodical procedure carried out with the goal of verifying, falsifying, or establishing the validity of a hypothesis. Experiments vary greatly in their goal and scale, but always rely on repeatable procedure and logical analysis of the results...

  - a form of clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

 - most commonly used in testing the safety (or more specifically, information about adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s and adverse effects of other treatments) and efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...

 or effectiveness
Effectiveness is the capability of producing a desired result. When something is deemed effective, it means it has an intended or expected outcome, or produces a deep, vivid impression.-Etymology:...

 of healthcare services (such as medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....

 or nursing
Nursing is a healthcare profession focused on the care of individuals, families, and communities so they may attain, maintain, or recover optimal health and quality of life from conception to death....

) or health
Health is the level of functional or metabolic efficiency of a living being. In humans, it is the general condition of a person's mind, body and spirit, usually meaning to be free from illness, injury or pain...

 technologies (such as pharmaceuticals, medical devices or surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...

). The key distinguishing feature of the usual RCT is that study subjects, after assessment of eligibility and recruitment, but before the intervention to be studied begins, are randomly allocated to receive one or other of the alternative treatments under study. 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 up in exactly the same way, and the only differences between the care they receive, for example, in terms of procedures, tests, outpatient visits, follow-up calls etc. should be those intrinsic to the treatments being compared. The most important advantage of proper randomization is that it minimises allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments."

The terms "RCT" and randomized trial are often used synonymously, but some authors distinguish between "RCTs" which compare treatment groups with control
Scientific control
Scientific control allows for comparisons of concepts. It is a part of the scientific method. Scientific control is often used in discussion of natural experiments. For instance, during drug testing, scientists will try to control two groups to keep them as identical and normal as possible, then...

 groups not receiving treatment (as in a placebo-controlled study), and "randomized trials" which can compare multiple treatment groups with each other. RCTs are sometimes known as randomized control trials. RCTs are also called randomized clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

or randomized controlled clinical trials when they concern clinical research
Clinical research
Clinical research is a branch of medical science that determines the safety and effectiveness of medications, devices, diagnostic products and treatment regimens intended for human use...

; however, RCTs are also employed in other research areas such as criminology
Criminology is the scientific study of the nature, extent, causes, and control of criminal behavior in both the individual and in society...

, education
Education in its broadest, general sense is the means through which the aims and habits of a group of people lives on from one generation to the next. Generally, it occurs through any experience that has a formative effect on the way one thinks, feels, or acts...

, social work
Social work
Social Work is a professional and academic discipline that seeks to improve the quality of life and wellbeing of an individual, group, or community by intervening through research, policy, community organizing, direct practice, and teaching on behalf of those afflicted with poverty or any real or...

 and international development
International development
International development or global development is a concept that lacks a universally accepted definition, but it is most used in a holistic and multi-disciplinary context of human development — the development of greater quality of life for humans...



Randomized experiment
Randomized experiment
In science, randomized experiments are the experiments that allow the greatest reliability and validity of statistical estimates of treatment effects...

s first appeared in psychology
Experimental psychology
Experimental psychology is a methodological approach, rather than a subject, and encompasses varied fields within psychology. Experimental psychologists have traditionally conducted research, published articles, and taught classes on neuroscience, developmental psychology, sensation, perception,...

, where they were introduced by Charles Sanders Peirce, and in education
School of education
In the United States and Canada, a school of education is a division within a university that is devoted to scholarship in the field of education, which is an interdisciplinary branch of the social sciences encompassing sociology, psychology, linguistics, economics, political science, public...

. Later, randomized experiments appeared in agriculture, due to Jerzy Neyman
Jerzy Neyman
Jerzy Neyman , born Jerzy Spława-Neyman, was a Polish American mathematician and statistician who spent most of his professional career at the University of California, Berkeley.-Life and career:...

 and Ronald A. Fisher. Fisher's experimental research and his writings popularized randomized experiments.

The first published RCT appeared in the 1948 paper entitled "Streptomycin
Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...

 treatment of pulmonary tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

", which described a Medical Research Council
Medical Research Council (UK)
The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills...

 investigation. One of the authors of that paper was Austin Bradford Hill
Austin Bradford Hill
Sir Austin Bradford Hill FRS , English epidemiologist and statistician, pioneered the randomized clinical trial and, together with Richard Doll, was the first to demonstrate the connection between cigarette smoking and lung cancer...

, 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
Cochrane Library
The Cochrane Library is a collection of databases in medicine and other healthcare specialties provided by the Cochrane Collaboration and other organisations. At its core is the collection of Cochrane Reviews, a database of systematic reviews and meta-analyses which summarize and interpret the...

. To improve the reporting of RCTs in the medical literature, an international group of scientists and editors published Consolidated Standards of Reporting Trials
Consolidated Standards of Reporting Trials
CONSORT encompasses various initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomized controlled trials.-The CONSORT Statement:...

 (CONSORT) Statements in 1996, 2001, and 2010 which have become widely accepted.


Although the principle of clinical equipoise
Clinical equipoise
Clinical equipoise, also known as the principle of equipoise, provides the ethical basis for medical research involving patients assigned to different treatment arms of a clinical trial...

 ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials has been applied to RCTs, the ethics
Ethics, also known as moral philosophy, is a branch of philosophy that addresses questions about morality—that is, concepts such as good and evil, right and wrong, virtue and vice, justice and crime, etc.Major branches of ethics include:...

 of RCTs have special considerations. For one, it has been argued that equipoise itself is insufficient to justify RCTs. For another, "collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention is effective). 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
Screening (medicine)
Screening, in medicine, is a strategy used in a population to detect a disease in individuals without signs or symptoms of that disease. Unlike what generally happens in medicine, screening tests are performed on persons without any clinical sign of disease....

 and selected therapies, but is likely unethical "for most therapeutic trials."

By study design

One way to classify RCTs is by study design
Study design
Clinical study design is the formulation of trials and experiments in medical and epidemiological research, sometimes known as clinical trials. Many of the considerations here are shared under the more general topic of design of experiments but there can be others, in particular related to patient...

. From most to least common in the medical literature, the major categories of RCT study designs are:
  • Parallel-group
    Parallel study
    A Parallel study is a type of clinical study where two groups of treatments, A and B, are given so that one group receives only A while another group receives only B...

     – each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.
  • Crossover
    Crossover study
    A crossover study is a longitudinal study in which subjects receive a sequence of different treatments . While crossover studies can be observational studies, many important crossover studies are controlled experiments, which are discussed in this article...

     – over time, each participant receives (or does not receive) an intervention in a random sequence.
  • Split-body – separate parts of the body of each participant (e.g., the left and right sides of the face) are randomized to receive (or not receive) an intervention.
  • Cluster
    Cluster randomised controlled trial
    A cluster randomised controlled trial is a type of randomised controlled trial in which groups of subjects are randomised...

     – pre-existing groups of participants (e.g., villages, schools) are randomly selected to receive (or not receive) an intervention.
  • Factorial
    Factorial experiment
    In statistics, a full factorial experiment is an experiment whose design consists of two or more factors, each with discrete possible values or "levels", and whose experimental units take on all possible combinations of these levels across all such factors. A full factorial design may also be...

     – each participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions (e.g., group 1 receives vitamin X and vitamin Y, group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group 4 receives placebo X and placebo Y).

An analysis of the 616 RCTs indexed in PubMed
PubMed is a free database accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez information retrieval system...

 during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial.

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
Effectiveness is the capability of producing a desired result. When something is deemed effective, it means it has an intended or expected outcome, or produces a deep, vivid impression.-Etymology:...

 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
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....

 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.


The advantages of proper randomization
Randomization is the process of making something random; this means:* Generating a random permutation of a sequence .* Selecting a random sample of a population ....

 in RCTs include:
  • "It eliminates bias in treatment assignment," specifically selection bias
    Selection bias
    Selection bias is a statistical bias in which there is an error in choosing the individuals or groups to take part in a scientific study. It is sometimes referred to as the selection effect. The term "selection bias" most often refers to the distortion of a statistical analysis, resulting from the...

     and confounding
    In statistics, a confounding variable is an extraneous variable in a statistical model that correlates with both the dependent variable and the independent variable...

  • "It facilitates blinding (masking) 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; 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.

Randomization procedures

An ideal randomization procedure would achieve the following goals:
  • Equal group sizes for adequate statistical power
    Statistical power
    The power of a statistical test is the probability that the test will reject the null hypothesis when the null hypothesis is actually false . The power is in general a function of the possible distributions, often determined by a parameter, under the alternative hypothesis...

    , especially in subgroup analyses
    Subgroup analysis
    Subgroup analysis, in the context of design and analysis of experiments, refers to looking for pattern in a subset of the subjects....

  • Low selection bias. That is, the procedure should not allow an investigator to predict the next subject's group assignment by examining which group has been assigned the fewest subjects up to that point.
  • Low probability of confounding (i.e., a low probability of "accidental bias"), which implies a balance in covariate
    In statistics, a covariate is a variable that is possibly predictive of the outcome under study. A covariate may be of direct interest or it may be a confounding or interacting variable....

    s across groups. If the randomization procedure causes an imbalance in covariates related to the outcome across groups, estimates of effect may be biased
    Bias of an estimator
    In statistics, bias of an estimator is the difference between this estimator's expected value and the true value of the parameter being estimated. An estimator or decision rule with zero bias is called unbiased. Otherwise the estimator is said to be biased.In ordinary English, the term bias is...

     if not adjusted for the covariates (which may be unmeasured and therefore impossible to adjust for).

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 randomization

This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing." Also known as "complete" or "unrestricted" randomization, it is robust
Robust statistics
Robust statistics provides an alternative approach to classical statistical methods. The motivation is to produce estimators that are not unduly affected by small departures from model assumptions.- Introduction :...

 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 randomization

To balance group sizes in smaller RCTs, some form of "restricted" randomization
Restricted randomization
Many processes have more than one source of variation in them. In order to reduce variation in processes, these multiple sources must be understood, and that often leads to the concept of nested or hierarchical data structures. For example, in the semiconductor industry, a batch process may operate...

 is recommended. The major types of restricted randomization used in RCTs are:
  • Permuted-block randomization
    Randomized block design
    In the statistical theory of the design of experiments, blocking is the arranging of experimental units in groups that are similar to one another. Typically, a blocking factor is a source of variability that is not of primary interest to the experimenter...

    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. 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
    Multicenter trial
    A multicenter research trial is a clinical trial conducted at more than one medical center or clinic. Most large clinical trials, particularly Phase III trials, are conducted at several clinical research centers...

    , 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 (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 over-represented and increases if the group is under-represented. The methods are thought to be less affected by selection bias than permuted-block randomization.


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." 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

"Allocation concealment" (defined as "the procedure for protecting the randomisation process so that the treatment to be allocated is not known before the patient is entered into the study") is considered desirable in RCTs. In practice, in taking care of individual patients, 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. Such practices introduce selection bias and confounders
Lurking variable
In statistics, a confounding variable is an extraneous variable in a statistical model that correlates with both the dependent variable and the independent variable...

 (both of which should be minimized by randomization), thereby possibly distorting the results of the study. 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. It is recommended that allocation concealment methods be included in an RCT's protocol
Clinical trial protocol
A clinical trial protocol is a document that describes the objective, design, methodology, statistical considerations, and organization of a clinical trial...

, and that the allocation concealment methods should be reported in detail in a publication of an RCT's results; however, 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
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...

 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
Subjectivity refers to the subject and his or her perspective, feelings, beliefs, and desires. In philosophy, the term is usually contrasted with objectivity.-Qualia:...

 as opposed to objective
Objectivity (philosophy)
Objectivity is a central philosophical concept which has been variously defined by sources. A proposition is generally considered to be objectively true when its truth conditions are met and are "mind-independent"—that is, not met by the judgment of a conscious entity or subject.- Objectivism...



An RCT may be Blinded, (also called "masked") 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 (e.g., physical therapy
Physical therapy
Physical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...

), 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
Consolidated Standards of Reporting Trials
CONSORT encompasses various initiatives developed by the CONSORT Group to alleviate the problems arising from inadequate reporting of randomized controlled trials.-The 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."

RCTs without blinding are referred to as "unblinded", "open", or (if the intervention is a medication) "open-label
Open-label trial
An open-label trial or open trial is a type of clinical trial in which both the researchers and participants know which treatment is being administered....

". 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
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...

, unblinded neurologists (but not blinded 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 from RCTs

The types of statistical methods used in RCTs depend on the characteristics of the data and include:
  • For dichotomous (binary) outcome data, logistic regression
    Logistic regression
    In statistics, logistic regression is used for prediction of the probability of occurrence of an event by fitting data to a logit function logistic curve. It is a generalized linear model used for binomial regression...

     (e.g., to predict sustained virological response after receipt of peginterferon alfa-2a for hepatitis C
    Hepatitis C
    Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...

    ) and other methods can be used.
  • For continuous outcome data, analysis of covariance (e.g., for changes in blood lipid levels after receipt of atorvastatin
    Atorvastatin , sold by Pfizer under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms...

     after acute coronary syndrome
    Acute coronary syndrome
    Acute coronary syndrome is usually one of three diseases involving the coronary arteries: ST elevation myocardial infarction , non ST elevation myocardial infarction , or unstable angina ....

    ) tests the effects of predictor variables.
  • For time-to-event outcome data that may be censored
    Censoring (statistics)
    In statistics, engineering, and medical research, censoring occurs when the value of a measurement or observation is only partially known.For example, suppose a study is conducted to measure the impact of a drug on mortality. In such a study, it may be known that an individual's age at death is at...

    , survival analysis
    Survival analysis
    Survival analysis is a branch of statistics which deals with death in biological organisms and failure in mechanical systems. This topic is called reliability theory or reliability analysis in engineering, and duration analysis or duration modeling in economics or sociology...

     (e.g., Kaplan–Meier estimators and Cox proportional hazards models for time to coronary heart disease
    Coronary heart disease
    Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...

     after receipt of hormone replacement therapy in menopause
    Hormone replacement therapy (menopause)
    Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...

    ) is appropriate.

Regardless of the statistical methods used, important considerations in the analysis of RCT data include:
  • Whether a 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 (i.e., whether a so-called "intention-to-treat analysis" is used). 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
    Imputation (statistics)
    In statistics, imputation is the substitution of some value for a missing data point or a missing component of a data point. Once all missing values have been imputed, the dataset can then be analysed using standard techniques for complete data...

     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
    Subgroup analysis
    Subgroup analysis, in the context of design and analysis of experiments, refers to looking for pattern in a subset of the subjects....

     should be performed. These are "often discouraged" because multiple comparisons
    Multiple comparisons
    In statistics, the multiple comparisons or multiple testing problem occurs when one considers a set of statistical inferences simultaneously. Errors in inference, including confidence intervals that fail to include their corresponding population parameters or hypothesis tests that incorrectly...

     may produce false positive findings that cannot be confirmed by other studies.

Reporting of RCT results

The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for reporting RCTs." 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. For other RCT study designs, "CONSORT extensions" have been published.


RCTs are considered by most to be the most reliable form of scientific evidence
Scientific method
Scientific method refers to a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge. To be termed scientific, a method of inquiry must be based on gathering empirical and measurable evidence subject to specific principles of...

 in the hierarchy of evidence
Hierarchy of evidence
Evidence hierarchies reflect the relative authority of various types of biomedical research. Although there is no single, universally-accepted hierarchy of evidence, there is broad agreement on the relative strength of the principal types of research...

 that influences healthcare policy and practice because RCTs reduce spurious causality and bias. Results of RCTs may be combined in systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...

s which are increasingly being used in the conduct of evidence-based medicine
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...

. 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
    National Health and Medical Research Council
    The National Health and Medical Research Council is Australia's peak funding body for medical research, with a budget of roughly 700 million dollars a year...

     of Australia designated "Level I" evidence as that "obtained from a systematic review
    Systematic review
    A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...

     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
    Internal validity
    Internal validity is the validity of inferences in scientific studies, usually based on experiments as experimental validity.- Details :...

     as indicators of its quality. It has recognized "evidence obtained from at least one properly randomized controlled trial" with good internal validity
    Internal validity
    Internal validity is the validity of inferences in scientific studies, usually based on experiments as experimental validity.- Details :...

     (i.e., a rating of "I-good") 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 2009 defined "Level 1a" evidence as a systematic review of RCTs that are consistent with each other, and "Level 1b" evidence as an "individual RCT (with narrow Confidence Interval
    Confidence interval
    In statistics, a confidence interval is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. It is an observed interval , in principle different from sample to sample, that frequently includes the parameter of interest, if the...


Notable RCTs with unexpected results that contributed to changes in clinical practice include:
  • After Food and Drug Administration
    Food and Drug Administration
    The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

     approval, the antiarrhythmic agents flecainide
    Flecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias . It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation , paroxysmal supraventricular tachycardia Flecainide acetate is a class Ic antiarrhythmic agent used to...

     and encainide
    Encainide is a class Ic antiarrhythmic agent. It is no longer used because its frequent proarrhythmic side effects....

     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 a 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
    Myocardial infarction
    Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

    . In 2002 and 2004, however, published RCTs from the Women's Health Initiative
    Women's Health Initiative
    The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...

     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.


Many papers discuss the disadvantages of RCTs. Among the most frequently-cited drawbacks are:

Limitations of external validity

The extent to which RCTs' results are applicable outside the RCTs varies; that is, RCTs' external validity
External validity
External validity is the validity of generalized inferences in scientific studies, usually based on experiments as experimental validity....

 may be limited. Factors that can affect RCTs' external validity include:
  • Where the RCT was performed (e.g., what works in one country may not work in another)
  • Characteristics of the patients (e.g., an RCT may include patients whose prognosis is better than average, or may exclude "women, children, the elderly, and those with common medical conditions")
  • Study procedures (e.g., in an RCT patients may receive intensive diagnostic procedures and follow-up care difficult to achieve in the "real world")
  • Outcome measures (e.g., RCTs may use composite measures infrequently used in clinical practice)
  • Incomplete reporting of adverse effects of interventions


RCTs can be expensive; one study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke
National Institute of Neurological Disorders and Stroke
The National Institute of Neurological Disorders and Stroke is a part of the U.S. National Institutes of Health . It conducts and funds research on brain and nervous system disorders and has a budget of just over US$1.5 billion...

 prior to 2000 with a total cost of US$335 million, for a mean
In statistics, mean has two related meanings:* the arithmetic mean .* the expected value of a random variable, which is also called the population mean....

 cost of US$12 million per RCT. Nevertheless, the return on investment
Return on investment
Return on investment is one way of considering profits in relation to capital invested. Return on assets , return on net assets , return on capital and return on invested capital are similar measures with variations on how “investment” is defined.Marketing not only influences net profits but also...

 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
Per capita
Per capita is a Latin prepositional phrase: per and capita . The phrase thus means "by heads" or "for each head", i.e. per individual or per person...

 gross domestic product
Gross domestic product
Gross domestic product refers to the market value of all final goods and services produced within a country in a given period. GDP per capita is often considered an indicator of a country's standard of living....



The conduction of a 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.

Relative importance of RCTs and observational studies

Two studies published in The New England Journal of Medicine in 2000 found that observational studies
Observational study
In epidemiology and statistics, an observational study draws inferences about the possible effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator...

 and RCTs overall produced similar results. The authors of the 2000 findings cast doubt on the ideas that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of the highest grade." However, a 2001 study published in Journal of the American Medical Association
Journal of the American Medical Association
The Journal of the American Medical Association is a weekly, peer-reviewed, medical journal, published by the American Medical Association. Beginning in July 2011, the editor in chief will be Howard C. Bauchner, vice chairman of pediatrics at Boston University’s School of Medicine, replacing ...

concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common" between observational studies and RCTs.

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
    Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...

     for metastatic
    Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...

     testicular cancer
    Testicular cancer
    Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system.In the United States, between 7,500 and 8,000 diagnoses of testicular cancer are made each year. In the UK, approximately 2,000 men are diagnosed each year. Over his lifetime, a man's risk of...

    , which increased the cure rate from 5% to 60% in a 1977 non-randomized study.

Difficulty in studying rare events

Interventions to prevent events that occur only infrequently (e.g., sudden infant death syndrome
Sudden infant death syndrome
Sudden infant death syndrome is marked by the sudden death of an infant that is unexpected by medical history, and remains unexplained after a thorough forensic autopsy and a detailed death scene investigation. An infant is at the highest risk for SIDS during sleep, which is why it is sometimes...

) 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.

Difficulty in studying outcomes in distant future

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

Pro-industry findings in industry-funded RCTs

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. 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." One possible reason for the pro-industry results in industry-funded published RCTs is publication bias
Publication bias
Publication bias is the tendency of researchers, editors, and pharmaceutical companies to handle the reporting of experimental results that are positive differently from results that are negative or inconclusive, leading to bias in the overall published literature...


Therapeutic misconception

Although subjects almost always provide informed consent
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...

 for their participation in an RCT, studies since 1982 have documented that many RCT subjects 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. Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception
Therapeutic misconception
Therapeutic misconception arises wherever human subjects misunderstand the primary purpose of a clinical trial as therapeutic. The phenomenon was first described in an article by Paul S. Appelbaum. Appelbaum PS, Roth LH, Lidz C: The therapeutic misconception: Informed consent in psychiatric...


Narrowing of the studied question

Randomized clinical trials are usually only inspect one variable or very few variables, rarely reflecting the full picture of a complicated medical situation; whereas the case report
Case report
In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrence....

, for example, can detail many different aspects of the patient’s medical
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....

 situation (e.g. patient history, physical examination
Physical examination
Physical examination or clinical examination is the process by which a doctor investigates the body of a patient for signs of disease. It generally follows the taking of the medical history — an account of the symptoms as experienced by the patient...

, diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...

, psychosocial
For a concept to be psychosocial means it relates to one's psychological development in, and interaction with, a social environment. The individual needs not be fully aware of this relationship with his or her environment. It was first commonly used by psychologist Erik Erikson in his stages of...

 aspects, follow up).

Statistical error

RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors
Type I and type II errors
In statistical test theory the notion of statistical error is an integral part of hypothesis testing. The test requires an unambiguous statement of a null hypothesis, which usually corresponds to a default "state of nature", for example "this person is healthy", "this accused is not guilty" or...

. 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. Regarding Type II errors, despite the publication of a 1978 paper noting that the sample size
Sample size
Sample size determination is the act of choosing the number of observations to include in a statistical sample. The sample size is an important feature of any empirical study in which the goal is to make inferences about a population from a sample...

s of many "negative" RCTs were too small to make definitive conclusions about the negative results, by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely-reported sample size calculations.

Cultural effects

The RCT method creates cultural effects that have not been well understood. For example, patients with terminal illness may attempt to join trials as a last ditch attempt at treatment, even when treatments are unlikely to be successful.

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
Cochrane is a surname with multiple independent origins, two Scottish and one Irish. One Scottish version originates from a place in Scotland, and both the Irish surname and the other Scottish surname are anglicisations for a Gaelic language surname....

 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.”


A 2005 review found 83 randomized experiments in criminology published in 1982-2004, compared with only 35 published in 1957-1981. The authors classified the studies they found into five categories: "policing", "prevention", "corrections", "court", and "community". 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
Quasi-experimental design
The design of a quasi-experiment relates to a particular type of experiment or other study in which one has little or no control over the allocation of the treatments or other factors being studied. The key difference in this empirical approach is the lack of random assignment...

 are still necessary.


RCTs have been used in evaluating a number of educational interventions. 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. 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.

International development

RCTs are currently being used by a number of international development experts to measure the impact of development interventions worldwide. Development economists
Development economics
Development Economics is a branch of economics which deals with economic aspects of the development process in low-income countries. Its focus is not only on methods of promoting economic growth and structural change but also on improving the potential for the mass of the population, for example,...

 at research organizations including Abdul Latif Jameel Poverty Action Lab
Abdul Latif Jameel Poverty Action Lab
The Abdul Latif Jameel Poverty Action Lab is an academic center located at the Massachusetts Institute of Technology Department of Economics which is dedicated to evaluating the impact of anti-poverty programs through randomized controlled trials similar to those used in medical research...

 and Innovations for Poverty Action 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). After estimating "missing expenditures" (a measure of corruption
Political corruption
Political corruption is the use of legislated powers by government officials for illegitimate private gain. Misuse of government power for other purposes, such as repression of political opponents and general police brutality, is not considered political corruption. Neither are illegal acts by...

), Olken concluded that government audits were more effective than "increasing grassroots participation in monitoring" in reducing corruption.
However, similar conclusions can also be reached by suitable modeling of the data from longitudinal studies. Overall, it is important in social sciences to account for the intended as well as the unintended consequences of interventions for policy evaluations.

See also

  • Drug development
    Drug development
    Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...

  • Hypothesis testing
  • Impact evaluation
    Impact evaluation
    Impact evaluation assesses the changes that can be attributed to a particular intervention, such as a project, program or policy, both the intended ones, as well as ideally the unintended ones...

  • Jadad scale
    Jadad scale
    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...

  • Statistical inference
    Statistical inference
    In statistics, statistical inference is the process of drawing conclusions from data that are subject to random variation, for example, observational errors or sampling variation...

Further reading

  • Bhargava, Alok "Randomized controlled experiments in health and social sciences: Some conceptual issues". Economics and Human Biology, 2008, 6, 293-298.
  • Domanski MJ, McKinlay S. Successful randomized trials: a handbook for the 21st century. Philadelphia: Lippincott Williams & Wilkins, 2009. ISBN 978-0-7817-7945-6.
  • Jadad AR, Enkin M. Randomized controlled trials: questions, answers, and musings. 2nd ed. Malden, Mass.: Blackwell, 2007. ISBN 978-1-4051-3266-4.
  • Matthews JNS. Introduction to randomized controlled clinical trials. 2nd ed. Boca Raton, Fla.: CRC Press, 2006. ISBN 1-58488-624-2.
  • Nezu AM, Nezu CM. Evidence-based outcome research: a practical guide to conducting randomized controlled trials for psychosocial interventions. Oxford: Oxford University Press, 2008. ISBN 978-0-19-530463-3.
  • Solomon PL, Cavanaugh MM, Draine J. Randomized controlled trials: design and implementation for community-based psychosocial interventions. New York: Oxford University Press, 2009. ISBN 978-0-19-533319-0.
  • Torgerson DJ, Torgerson C. Designing randomised trials in health, education and the social sciences: an introduction. Basingstoke, England, and New York: Palgrave Macmillan, 2008. ISBN 978-0-230-53735-4.

External links

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