Clinical research on rare disease faces many constraints. Research waste, however, in the field of rare diseases has been shown to be high. Carefully planned and well-executed RCTs give us the best estimates of the treatment effect. The aim of this study was to assess the methodological quality, the validity and the relevance of the evidence generated in this field.

Randomized controlled clinical trials studying rare diseases were selected after searching MEDLINE database between January 1, 1963, and December 31, 2021. Our main outcome measure was the assessment of the risk of bias of RCTs in rare diseases. We used the ROB-2 Cochrane tool to assess trial's quality. A first literature search was performed by 3 investigators and reviewed and updated by the first author (PL). Orphanet Rare Disease Information Center database was screened to confirm that the disease is rare. Three authors will independently carry out data extraction using a standard data extraction form, and then independently enter the data on the ROB 2 excel tool.

1305 studies on RCTs were identified, 87 articles met our inclusion criteria and had provided data on nearly 11542 participants and 61 rare diseases listed on Orphanet, 83 (95,41%) of the studies were phase III, 4 (4.59%) were phase IV (cf. Figure 1). Twenty two articles were assessed so far, these results are preliminary results. Five domains of bias were judged and of these studies, 95% (21 trials) were judged to be at low risk of bias for the randomization process domain. 77% (17 trials) had a low risk of bias and deviation from intended intervention. 86% (19 trials) had a low risk of bias for missing outcome data domain. 63% (14 trials) had a low risk of bias for the measurement of the outcome domain and 36% (8 trials) had an uncertain risk of bias for the selection of the reported results. Overall, the results of this study suggest that 35% (8) of the included trials are not powerful enough, 50% (11) of the trials have a high risk of bias and 9% (2) of the trials are incompletely registered on Clinicaltrials.gov.

The overall quality of randomized clinical trials in rare diseases seems poor but improving over the years. For future RCT in rare diseases, researchers should maximize the quality of RCT and reduce waste in this orphan clinical research realm.

Rare diseases , Randomized controlled clinical trial , Quality , Bias , Design

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