The controlled-randomized study: the queen among studies

It is considered the gold standard among studies, the queen against which all other studies must be measured: The controlled-randomized study. It is used whenever evidence of the efficacy and safety of a new therapy is needed. Therefore, it also serves as the basis for approval decisions.

Without clinical research, there would be no progress in medicine. It is a prerequisite for providing evidence-based treatment. Until that happens, many experimental approaches must be pursued, discarded, and rebuilt. But at some point, the time has come when the efficacy and safety of the therapy can and must be examined more closely. At this point, the controlled-randomized trial (RCT; “randomised controlled trials”) comes into play. It is considered the gold standard among investigational methods because they generally have a low risk of systematic error and, along with meta-analyses, are characterized by the highest level of evidence.

Study design for experimental studies

RCTs are interventional studies that demonstrate the superiority of a new therapy compared with a standard therapy or a sham therapy (placebo). The basis of every RCT is a study protocol that specifies, among other things, the medical-scientific background, the benefit-risk assessment, the study design, the study methodology, and the entire planning, conduct, and evaluation. A primary objective criterion is defined that aims to answer the main research question. For example, if the superiority of a new therapy is to be demonstrated, a null hypothesis is first assumed. This assumes that there is no difference in efficacy between the therapies studied. During the evaluation, statistical tests are then used to decide whether the assumed null hypothesis holds or must be rejected. In addition, secondary objectives that capture other effects of treatment such as adverse events will be investigated.

Case number planning is an indispensable parameter to achieve statistical power of the study. It is based on the number of participants necessary to detect a minimally relevant difference in the effectiveness of the therapies from a clinical point of view with a high probability of being significant – if it exists. A study population with clear inclusion and exclusion criteria is then defined for the study design. This ensures homogeneity of the group in terms of demographic characteristics, disease state, and concomitant diseases and medications, if any. This is the only way to ensure comparability between the different groups.

Randomization determines the allocation of patients to each treatment group. This is done randomly. This is because the aim is to ensure that all potential confounding variables are equally distributed in all groups. Confounding variables include weight, age, or gender – characteristics that could influence treatment response. Furthermore, the blinding of the study helps to avoid systematic errors. It is possible to double-blind or single-blind a study. In a double-blind study, neither the patient nor the investigator knows which treatment the patient has been randomized to. In simple blinding, usually only the patient is blinded as to the assigned treatment.

Evaluation of the causal relationship between therapy and efficacy

Clinical trials are generally subject to national and international scientific and ethical requirements. In 1964, the World Medical Association formulated ethical principles for research involving human subjects in the Declaration of Helsinki, which has since been revised several times. When publishing an RCT, the study design, conduct, and analysis must be described in a comprehensible manner. Against the background of the study design, current literature and taking into account the state of the art, the study results and their interpretation are to be discussed in detail in the study report and in a publication, and existing methodological limitations are to be presented. Critical discussion is a key contributor to the clinical evaluation of the results.

Nevertheless, the gold standard is repeatedly questioned because RCTs are an ideal instrument to answer the question of a causal relationship between therapy and efficacy. But the clinical care reality is insufficiently represented. Experts therefore expect RCTs to remain the standard for approval decisions, but to be supplemented by additional data from real-world studies, for example.