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 In a double-blind study, both the participants and the experimenters do not know which group got the placebo and which got the experimental treatment.
This is considered to be the superior model of clinical research since it eliminates outcomes that are produced due to placebo effect, as well as observer bias by the experimenter. The fact that the experimenter does not know which group received the placebo or the experimental drug means that the risk of conscious and unconscious observer bias is reduced, making the study more accurate.
Login: Training Managers Login: Students. The present section introduces the readers to randomised controlled study design. Intervention studies are considered to provide the most reliable evidence in epidemiological research.
Intervention studies can generally be considered as either preventative or therapeutic [1]. Therapeutic trials are conducted among individuals with a particular disease to assess the effectiveness of an agent or procedure to diminish symptoms, prevent recurrence, or reduce mortality from the disease. Preventative trials are conducted to evaluate whether an agent or procedure reduces the risk of developing a particular disease among individuals free from that disease at the beginning of the trial, for example, vaccine trials.
Preventative trials may be conducted among individuals or among entire communities. Thus, the subjects act as their own control at the end of the study. However, such studies are not feasible if there is mortality, or if the disease is easily cured by one of the interventions. The randomised controlled trial is considered as the most rigorous method of determining whether a cause-effect relationship exists between an intervention and outcome [2].
The strength of the RCT lies in the process of randomisation that is unique to this type of epidemiological study design. Generally, in a randomised controlled trial, study participants are randomly assigned to one of two groups: the experimental group receiving the intervention that is being tested and a comparison group controls which receives a conventional treatment or placebo.
These groups are then followed prospectively to assess the effectiveness of the intervention compared with the standard or placebo treatment. The random allocation of subjects is used to ensure that the intervention and control groups are similar in all respects distribution of potential confounding factors with the exception of the therapeutic or preventative measure being tested.
The choice of comparison treatments may include an existing standard treatment or a placebo a treatment which resembles the intervention treatment in all respects except that it contains no active ingredients.
Selection of intervention and control groups, including source, inclusion and exclusion criteria, and methods of recruitment. Collection of baseline measurements, including all variables considered or known to affect the outcome s of interest. Follow-up of all treatment groups, with assessment of outcomes continuously or intermittently. Interpretation assess the strength of effect, alternative explanations such as sampling variation, bias.
The aim of randomisation is to ensure that any observed differences between the treatment groups are due to differences in the treatment alone and not due to the effects of confounding known or unknown or bias.
That is, that the groups are similar in all respects with the exception of the intervention under investigation. Methods of random allocation are used to ensure that all study participants have the same chance of allocation to the treatment or control group, and that the likelihood of receiving an intervention is equal regardless of when the participant entered the study.
The assignment of study subjects to each intervention is determined by formal chance process and cannot be predicted or influenced by the investigator or participant. In a well designed RCT, random allocation is determined in advance. Block randomisation is a method used to ensure that the numbers of participants assigned to each group is equally distributed and is commonly used in smaller trials.
Stratified randomisation is used to ensure that important baseline variables potential confounding factors are more evenly distributed between groups than chance alone may assure. However, there are a limited number of baseline variables that can be balanced by stratification because of the potential for small numbers of subjects within each stratum.
This method may be used when the study is sufficiently small and simple randomisation will not result in balanced groups. Note that deterministic methods of allocation such as by date of birth or alternate assignment to each group are not considered as random. Doing more good than harm: the evaluation of health care interventions. Sackett DL.
Bias in analytic research. J Chronic Dis. Statistics notes: concealing treatment allocation in randomised trials. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Correlation of quality measures with estimates of treatment effect in meta-analyses of randomized controlled trials. Systematic reviews in health care: assessing the quality of controlled clinical trials.
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