In designing an RCT, researchers must carefully select the population, the interventions to be compared and the outcomes of interest. Once these are defined, the number of participants needed to reliably determine if such a relationship exists is calculated power calculation. Participants are then recruited and randomly assigned to either the intervention or the comparator group. This is often ensured by using automated randomization systems e.
RCTs are often blinded so that participants and doctors, nurses or researchers do not know what treatment each participant is receiving, further minimizing bias.
RCTs can be analyzed by intentionto-treat analysis ITT; subjects analyzed in the groups to which they were randomized , per protocol only participants who completed the treatment originally allocated are analyzed , or other variations, with ITT often regarded least biased. All RCTs should have pre-specified primary outcomes, should be registered with a clinical trials database and should have appropriate ethical approvals.
RCTs can have their drawbacks, including their high cost in terms of time and money, problems with generalisabilty participants that volunteer to participate might not be representative of the population being studied and loss to follow up.
While expensive and time consuming, RCTs are the gold-standard for studying causal relationships as randomization eliminates much of the bias inherent with other study designs. To provide true assessment of causality RCTs need to be conducted appropriately i.
Disclosures: The authors have no financial interests to disclose. National Center for Biotechnology Information , U. Author manuscript; available in PMC Dec 1.
Locascio , PhD 2. Joseph J. Author information Copyright and License information Disclaimer. RCTs are used to answer patient-related questions and are required by governmental regulatory bodies as the basis for approval decisions. To help readers understand and evaluate RCTs, we discuss the methods and qualitative requirements of RCTs with reference to the literature and an illustrative case study. The quality of an RCT depends on an appropriate study question and study design, the prevention of systematic errors, and the use of proper analytical techniques.
All of these aspects must be attended to in the planning, conductance, analysis, and reporting of RCTs. RCTs must also meet ethical and legal requirements. RCTs cannot yield reliable data unless they are planned, conducted, analyzed, and reported in ways that are methodologically sound and appropriate to the question being asked.
The quality of any RCT must be critically evaluated before its relevance to patient care can be considered. C linical research lays the groundwork for progress in medicine and is an indispensable prerequisite for evidence-based medicine. Randomized controlled clinical trials RCTs are the gold standard for ascertaining the efficacy and safety of a treatment.
RCTs can demonstrate the superiority of a new treatment over an existing standard treatment or a placebo. Alongside meta-analyses, high-quality RCTs with a low risk of systematic error bias provide the highest level of evidence 1 , 2. The aim of this article is to provide an introduction into the methods and quality requirements of RCTs in order to help the reader understand and evaluate publications that present the results of such studies.
Since RCTs are by definition interventional, often investigating drugs or medical devices, ethical and legal aspects will also be discussed. In this study, women who had had two or more miscarriages were assigned randomly to one of three treatment groups: aspirin plus heparin, aspirin alone, or placebo. The primary objective of the study was to investigate the efficacy of the different treatments as shown by the rate of live births.
The primary study question, i. To answer the primary study question, a primary endpoint is required. This is a parameter measured or observed that is recorded at a defined time and can be assumed to reflect the effect of a treatment.
The endpoint may be clinical, e. In a confirmatory study hypotheses are formulated a priori according to the primary study question. If the primary objective of the trial is to demonstrate the superiority of a new treatment over an existing treatment or placebo, then the initial assumption null hypothesis is that the two treatments do not differ in efficacy.
Based on statistical analysis the null hypothesis can be retained or must be rejected in favor of the alternative hypothesis. The alternative hypothesis is assumed when a statistically significant difference is ascertained between the two treatments. A detailed description of methods for statistical evaluation is given in an earlier article in this series [ 15 ]. The primary study question is accompanied by one or more ancillary study questions, i.
The secondary endpoints investigate other effects of the treatment, e. In the ALIFE study, the secondary endpoints included the rate of miscarriage, the premature birth rate, and the rate of maternal thrombopenia. From the statistical viewpoint it is vital to distinguish between the primary and secondary study questions, because the number of study subjects depends solely on the primary endpoint Study planning includes calculation of the number of subjects necessary for detection by statistical analysis of a minimally relevant difference in efficacy, from the clinical viewpoint, between the treatments.
The number of patients is therefore crucial for the statistical power of a study. Sample size calculation is described in detail in a previous article in this series [ 17 ]. In order to demonstrate the postulated positive effect of the combination therapy, women were enrolled in the trial.
In trials with randomized and controlled design e. The patients in the control group receive either another treatment or a placebo. The ALIFE trial is a three-armed parallel group study to establish whether the combination treatment or the monotherapy improve the live birth rate compared with placebo.
The use of placebos in clinical trials is ethically justified provided that no standard treatment is available. If comparison with placebo is indispensable for methodological reasons, it can be justified as long as patients will not be harmed That is the case, for example, if the study is of only short duration or if the severity of disease permits postponement or interruption of treatment.
As in any study of human subjects, the study population of an RCT must be clearly defined. Precise inclusion and exclusion criteria are elaborated to ensure that only eligible patients are recruited.
The study participants must be homogeneous with regard to demographic characteristics, disease state, and possibly even comorbidity and comedication. This can be achieved by standardization of, for example, the time s of intake of the study medication and the methods used to measure clinical parameters, but most important for comparability is randomization of the participants.
In RCTs the patients are randomly assigned to the different study groups. This is intended to ensure that all potential confounding factors are divided equally among the groups that will later be compared structural equivalence. Only if the groups are structurally equivalent can any differences in the results be attributed to a treatment effect rather than the influence of confounders.
If the confounders are known, structural equivalence of the patient groups can be attained by stratified randomization Box. In the ALIFE study the patients were assigned to the three treatment groups with a randomization ratio of If patients were allocated to treatment groups by conscious or unconscious selection for prognosis-related characteristics, rather than randomly, this could lead to biased treatment comparison and distorted results selection bias.
The assignment to study groups must not be in any way predictable. Predictability of group allocation is avoided by ensuring the study staff are unaware to which treatment the next patient will be allotted. Alternating assignment to the different treatments is not truly random. Bias is avoided not only by randomization but also by blinding. A study may be double blind, single blind, or open. In a double-blind study neither patient nor study physician knows to which treatment the patient has been assigned.
Double-blind studies are advantageous if knowledge of the treatment might influence the course and therefore the results of the study. Thus it is particularly important that the study physician is blinded to treatment if the endpoints are subjective. Blinding of patients to their treatment is important, for example, if their attitude could potentially affect their reliability in taking the test medication compliance or even their response to treatment. If only one party, either patient or study physician, is blinded to the treatment, the study is called single blind; a study with no blinding is described as open.
The highest possible degree of blinding should be chosen to minimize bias. The data subjected to statistical analysis in RCTs are those gathered from patient populations defined in the study protocol. The primary population for analysis is the so-called intention-to-treat ITT population, comprising all randomized patients. In analysis according to the ITT principle, patients are allocated to the group to which they were randomized, thus retaining the advantages of randomization such as structural equivalence.
Because the ITT population includes all patients who were randomized, the data for analysis include some patients whose treatment was interrupted, prematurely discontinued, or did not take place at all. The analysis strategy for ITT data is therefore conservative, i.
Many studies define a modified ITT mITT population, which may for example comprise the patients who received at least a defined amount of study treatment. An alternative strategy is to restrict analysis to the data from the per-protocol PP population.
Patients in whom study conduct deviated from the protocol are excluded from analysis. These so-called protocol violations include, for example, failure concerning the application of inclusion or exclusion criteria and incorrect administration of the study treatment.
In analysis according to the PP principle, patients are allocated to the treatment groups depending on the treatment they actually received. Because the PP population includes only those patients who completed the study according to the protocol, the results may be distorted in favor of the investigational intervention To assess the robustness of the study findings, PP evaluation is carried out as a sensitivity analysis if the ITT population is the patient population for the primary efficacy analysis If the results of PP and ITT evaluation of the primary endpoint are very similar, they can be regarded as reliable.
Should this not be the case, the possible reasons for the discrepancy between the results of the ITT and PP analyses must be discussed in the results section of the publication. The rates of live births in the three treatment groups did not differ significantly Table 1. Analysis according to the PP principle confirmed this finding.
Neither aspirin and heparin combined nor aspirin alone were demonstrated to have a greater effect than placebo on the live birth rate. Relative risk and absolute difference were calculated for the comparisons between aspirin plus heparin and placebo and between aspirin alone and placebo.
The p-value applies to all treatment group comparisons. Clinical trials have to be performed according to national and international regulations. The Declaration of Helsinki, first formulated by the World Medical Association in and revised several times in the intervening years 20 , lays down fundamental ethical principles for research on human beings. The aim of GCP is to protect study participants and ensure high quality of study data.
In the International Committee of Medical Journal Editors made registration of a clinical trial in a public registry a precondition for its publication The professional code of conduct for physicians in Germany demands that every study in human subjects be submitted to the responsible ethics committee for approval.
The applications have to be accompanied by the study protocol, the information to be supplied to the patients, the consent form for participation, and confirmation that adequate insurance has been arranged.
Trials of drugs and medical devices also have to be registered with state authorities. There are legally defined obligations to report suspected unexpected serious adverse reactions or early termination of a study, and the final study report must also be submitted.
In other words, information revealing the identity of a patient name or initials must be replaced by a code. Only patients who have agreed in advance to the recording, storage, processing and dissemination of their data may participate in a clinical study. Any publication of an RCT must lucidly describe the planning, conduct, and analysis of the study. The most important aspects that have to be described in the publication are listed in Table 2.
The progress of patients through an RCT and the numbers of patients whose data were analyzed can be depicted in a flow diagram Figure. Patient flow in a randomized controlled trial adapted from [ 23 ].
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