Randomised controled trials

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 ].

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.

Journal List Dtsch Arztebl Int v. Dtsch Arztebl Int. Published online Sep Maria Kabisch , Dipl. Author information Article notes Copyright and License information Disclaimer. Received Feb 23; Accepted Jun Copyright notice. This article has been cited by other articles in PMC. Abstract Background In clinical research, randomized controlled trials RCTs are the best way to study the safety and efficacy of new treatments.

Methods 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.

Results 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. Conclusion 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. Study design In trials with randomized and controlled design e. Randomization In RCTs the patients are randomly assigned to the different study groups.

Box Stratified randomization. Blinding Bias is avoided not only by randomization but also by blinding. Analysis population The data subjected to statistical analysis in RCTs are those gathered from patient populations defined in the study protocol. Open in a separate window. Quality standards and legal requirements in Germany Clinical trials have to be performed according to national and international regulations. Discussion Any publication of an RCT must lucidly describe the planning, conduct, and analysis of the study.

Table 2 Minimal requirements for a publication reporting a randomized controlled trial adapted from [ 23 ]. Study design Description of study design e. Conclusion RCTs are the best type of study for determining whether there is a causal relationship between intervention and effect Key Messages In clinical research, randomized controlled trials are the gold standard for demonstrating the efficacy and safety of a new treatment. Acknowledgments Translated from the original German by David Roseveare.

Footnotes Conflict of interest statement The authors declare that no conflict of interest exists. References 1. Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. This is because the act of randomization balances participant characteristics both observed and unobserved between the groups allowing attribution of any differences in outcome to the study intervention.

This is not possible with any other study design. 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.