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Table 3 Comparison of clinical trials design of ultra-orphan drugs

From: Points to consider: efficacy and safety evaluations in the clinical development of ultra-orphan drugs

  Anticancer drug n = 11 Metabolic drug n = 16 Others n = 16
Efficacy endpoint (Example)    
 True endpoint • Overall survival (vemurafenib) • Ventilator-free survival (alglucosidase alfa)  
 Surrogate endpoint • Major CyR (dasatinib)
• Reduction in spleen volume (ruxolitinib)
• Forced expiratory volume 1 s (sirolimus)
• The 12-min walking distance (galsulfase)
• Blood alkaline phosphatase (risedronate)
• Blood phenylalanine (sapropterin)
• Manual muscle test (freeze-dried sulfonated human normal immunoglobulin)
• Haemoglobin stabilization (eculizumab)
• Transcranial sonography (tetrabenazine)
Controls (RCT)
 Placebo 3/7 trials 13/17 trials 11/14 trials
 Active controls 3/7 trials 1/17 trials 1/14 trials
 Different dosage 1/7 trials 3/17 trials 2/14 trials
Number of patients (Min-Max)
 RCT 89–675 6–176 18–965
 Single-arm trial 6–724 1–168 1-7252a
Statistical evidence (RCT)
 Significance level 5% 5% 5%
 Power 80–90% 80–90% 80–90%
  1. Classification of clinical trials designs of the ultra-orphan drugs for each therapeutic category. Others: drugs other than metabolic drugs, anticancer drugs
  2. a Study on preventive administration of mefloquine and next was 168 patients of eculizumab