Discussion
ODD
DISEASE, DISEASE, RARE DISEASES
In this study, we investigated the presence or absence of RCTs in the clinical data package of new drug applications with ODD in the US. We found that the severity of disease outcome, type of drug usage, and type of efficacy endpoint were associated with the presence or absence of RCTs. These results suggest the importance of understanding the target disease and its treatment environment.Disease severity, defined by high mortality, was positively associated with the absence of RCT in the package, implying that RCTs are more difficult to conduct in such disease areas. This result was expected because there is no authorized treatment available for most rare diseases [Second, the utilization of combination therapy for a test arm showed a positive association with the presence of RCT. From an ethical perspective, this is another expected result. When the test arm is a combination therapy in which an investigational drug is added to a standard therapy, a standard of care is warranted, which would lower ethical barriers and make it easier to justify conducting RCTs to pursue high-level evidence.Third, the use of clinical outcomes as an efficacy endpoint was positively associated with the presence of an RCT. This result is similar to that of our previous study using the Japanese data package [It was unexpected for no association to be found between the prevalence of the disease and the presence or absence of RCT. In general, an appropriate sample size is required to conduct an RCT. Thus, we assumed that a lower prevalence of the target disease would be associated with fewer RCTs due to decreased feasibility. In our previous study in Japan, a negative association was confirmed between RCTs and lower prevalence disease prevalence [This study had several limitations. First, the study was conducted only for approved drugs, which could be regarded as a source of bias. The information available on negative results is less extensive than that available for approved drugs. Second, the data were collected only for drugs that had an ODD. There may be drugs that did not apply for ODD, although they met the ODD criteria. Third, the association between clinical equipoise or natural history data and the presence or absence of RCTs was not investigated. Clinical equipoise is an important ethical consideration for determining the feasibility of RCTs [Orphan drugs target various rare diseases with unmet medical needs. If drug development is conducted using SAT data based on sufficient research, discussion, and consideration, it will streamline the development timeline. Thus, patients with rare diseases and unmet medical needs may be afforded early access to these drugs. Conversely, RCTs may impact the feasibility and development period of drug development. However, they are recommended by various guidelines as the results obtained through RCTs are highly reliable and ultimately benefit patients. This argument is unavoidable in orphan drug development, emphasizing the importance of utilizing available evidence.Our results indicated the importance of selecting a target disease and potential efficacy variables to be used in the clinical trials to examine the need for RCT data for NDA. From a pharmaceutical company perspective, target disease selection is one of the initial steps in drug development. Preparation of a clinical development plan including pivotal study designs is initiated during this step, which significantly impacts the costs and timelines of drug development, consequently affecting corporate investment decisions. In addition, we believe that strategic collection of relevant information is necessary to establish efficacy variables for potential drug development. This can be achieved through collaboration among the industry, government, and academia, which will help facilitate orphan drug development.