There are rich biostatistical methods for analyzing clinical trial data, typically performed by biostatisticians with experience in clinical trials. There are also many epidemiological methods for analyzing natural history data. There are no reliable methods or expertise available for comparative analysis of efficacy involving both clinical trials and natural history studies. Because of the small sample size in both a single arm trial and natural history study, it is often very difficult, inadequate if not impossible, or grossly incorrect to apply existing methods.