OBJECTIVES: Alpha 1 Anti Trypsin Deficiency Disorder (A1ATD) is a serious ultra orphan disease which significantly lowers patient’s life expectancy and quality of life. Clinical guidelines  have suggested need for new outcome measures to effectively assess the value of pharmaceutical treatments. The objective of this study was to review the trends in design of pivotal clinical trials for Alpha 1 Anti Trypsin Deficiency Disorder. METHODS: Systematic review was conducted to identify new and on-going pivotal clinical for Alpha 1 Anti Trypsin Deficiency Disorder. The inclusion criteria were the indication of Alpha 1 Anti Trypsin Deficiency Disorder and study start date of 2001 or after. The data field extracted were study title, intervention, sponsor, age subgroups, planned enrollment, study type, study design, completion date and outcome measures. RESULTS: Overall, 7 Phase III clinical studies with total enrollment of 674 patients were identified. The median enrollment for the studies was 38 patients. Three of the 7 studies were for biologics, another 3 were for drugs and 1 was for a medical device. The primary outcomes varied significantly across the trials, with some measures being Lung density, PD 15, FEV1, area under the curve and exacerbation events. For secondary outcomes, most trials measured adverse events, lung function and exacerbation events. None of the trials reported measurement of survival, quality of life, hospitalization or economic outcomes. Regarding sponsorship, 6 of 7 were sponsored by the industry (4 by Grifols and 2 by Kamada). CONCLUSIONS: This review provides an overview of on-going and future Phase III clinical trials for Alpha 1 Anti Trypsin Deficiency Disorder. Study findings might be useful for design and conduct of new studies.