Data source and items
ODD, disability
DISEASE
Newly approved drugs with an orphan drug designation (ODD) in the US between April 1, 2001, and March 31, 2021 were extracted from the approved drug list on the website of the US FDA (Furthermore, for each approved drug, a pivotal trial, typically a clinical trial to confirm the safety and efficacy of the drug, was selected from the FDA review report. This selection was performed based on the following hierarchy: trial phase (phase 3, 2), trial design (RCT, single-arm trial [SAT]), and the number of enrolled patients (large, small). The pivotal trial design was categorized as RCT or SAT. If several indications were approved in a single new drug application (NDA) based on different pivotal trials, each indication was treated as distinct approval. The following data were extracted for the selected drugs: approval year, prevalence of the target disease, modality, Anatomical Therapeutic Chemical (ATC) classification [When assessing the potential association with the presence or absence of an RCT in the clinical data package as a response variable, the following factors were considered as explanatory variables: prevalence (< 1/100,000 vs. ≥ 1 /100,000 patients), severity of disease outcome (high mortality vs. others), type of drug usage (monotherapy vs. combination therapy), therapeutic classification (oncology vs. non-oncology), target age segment (children with or without adult vs. adult only), and type of primary endpoint (biomarker vs. clinical outcome).The severity of the disease outcome was categorized as high mortality or others (e.g., progressing disability early in life or chronic but manageable with treatments and lifestyle adjustments) based on the information available on the review reports and the Orphanet website (The primary endpoint of the selected pivotal trial was categorized as a biomarker or clinical outcome. We referred to the pharmacodynamic or response biomarker definition, “a biomarker used to show that a biological response has occurred in an individual who has been exposed to a medical product or an environmental agent.” Clinical outcome was defined as “an outcome that describes or reflects how a patient feels, functions, or survives [We assessed these two explanatory variables independently. Disagreements between the reviewers were resolved by consensus, and a 100% consensus was reached for all data included in the analysis.The definitions and criteria of the other explanatory variables are summarized in 