Background: Through Cochrane, we have recently reviewed treatment options for Gaucher disease (GD) - an ultra-orphan, rare metabolic disorder, caused by a deficient/malfunctioning enzyme. Untreated, GD may lead to significant disability and death. A breakthrough discovery 30 years ago revolutionized the lives of patients by providing the replaced enzyme. Despite the emergence of various treatment options in the last decade, there are no evidence-based recommendations regarding treatment regimens/drugs, and treatment costs remain very high. Other inborn metabolic disorders suffer from similar unanswered questions regarding treatment - currently, there are 17 published Cochrane Reviews on other rare inborn errors of metabolism, and 16 are listed as high priority titles for analyses (defined by the genetic disorders group together with the UK National Health Service (NHS)).

Methods: Applying Cochrane criteria, eight randomized clinical trials (RCT) (300 participants) were filtered after an extensive searching of medical databases. Numerical data regarding organ volumes, disease activity markers and blood counts were collected, as well as data about possible biases. Different drugs and doses were compared.

Conclusions: We contend that limiting analyses to RCTs in fields where these studies represent only small proportion of the total body of literature (such as in the case of rare diseases) may distort the conclusions and significantly constrain the recommendations that can be concluded.
Therefore, despite being labeled as inferior to RCTs, inclusion of non-randomized trials should be positively considered when attempting to answer delicate questions (such as the optimization of treatment doses), when dealing with a high non-RCT to RCT ratio, or when discussing a disease affecting few patients (as in the case of rare diseases).