Controlled randomized trials

Published by Elsevier Inc. All rights reserved. Abstract Randomized controlled trials RCTs are considered the highest level of evidence to establish causal associations in clinical research.

Clinical Rehabilitation, 29 1 , When the groups that have been randomly selected from a population do not know whether they are in the control group or the experimental group. Being able to show that an independent variable directly causes the dependent variable. This is generally very difficult to demonstrate in most study designs.

Confounding Variables. These variables render it difficult or impossible to distinguish the relationship between the variable and outcome being studied. A relationship between two variables, but not necessarily a causation relationship.

When the researchers conducting a blinded study do not know which participants are in the control group of the experimental group. That the relationship between the independent and dependent variables the researchers believe they will prove through conducting a study does not exist.

Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at BJOG. See other articles in PMC that cite the published article. Footnotes Disclosures: The authors have no financial interests to disclose. References 1. Sibbald Bonnie, Roland Martin. Understanding controlled trials: Why are randomised controlled trials important? 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 ]. The study results and their interpretation must be discussed in detail in the study report and any subsequent publication, and the limitations of the methods used should be described, all with reference to the study design, the recent literature, and the current state of knowledge.

Critical discussion plays a decisive part in clinical evaluation of the results. In the publication of the ALIFE study, the findings were compared with those of other RCTs investigating the effects of heparin on reduction of miscarriages and inconsistencies were discussed. Ultimately, the available study data did not justify the recommendation of anticoagulants for women with recurring miscarriages. Although RCTs are the gold standard with regard to level of evidence, their generalizability, i.

Moreover, the patients selected for a study are not necessarily representative, in that those seen in routine daily practice will often have numerous comorbidities and comedications. After marketing approval of a new treatment, phase-IV studies are carried out to establish its efficacy and safety in a larger and more heterogeneous population; as a rule these studies are RCTs.

Epidemiological studies, e. RCTs are the best type of study for determining whether there is a causal relationship between intervention and effect However, it seems clear that post-marketing studies comparing new and established treatments are still required.

In clinical research, randomized controlled trials are the gold standard for demonstrating the efficacy and safety of a new treatment. Randomized controlled trials cannot yield robust data unless they are planned, conducted, and analyzed in ways that are methodologically sound and appropriate to the question being asked.

Methods to avoid bias, such as randomization and blinding, can help to prevent distortion of the study results. The robustness of the results is tested by statistical analysis of the data from patient populations defined a priori.

The quality of a randomized controlled trial depends crucially not only on adherence to methodological standards but also on strict compliance with the protocol regarding the clinical conduct of the study. Conflict of interest statement. National Center for Biotechnology Information , U.