BACKGROUND: The traditional design of the randomized clinical trial (RCT) is challenged by the peculiarities of the genotype and phenotype of neurological disorders. SUMMARY: RCTs are intended to verify the net effect of an investigational treatment on the outcome of a disease. This implies the inclusion of strictly homogeneous sample of patients that represent only in part the full disease spectrum. For this reason, pragmatic trials on representative samples of the general population are welcome. In neurodegenerative disorders, RCTs are generally performed in symptomatic individuals, when the pathologic process is already in course. Although genetic, biological and structural markers are the ideal instruments to detect the disease at a preclinical stage, the development of biomarkers is still in its infancy and even identified markers require in most of cases validation. Given the limited duration of an RCT, prospective studies with prolonged follow-up in well-defined inception cohorts are needed to assess the effectiveness of the treatment in all affected individuals seen in everyday practice. RCT are conducted mainly in Caucasians excluding other ethnicities. The difference of brain biology between men and women are still underestimated in RCTs. Patients, treating physicians, pharmaceutical companies, and regulatory authorities have differing needs, which may have important implications in planning and conducting RCTs. New therapeutic approaches are represented by personalized and precision medicine. Although largely investigational, these approaches may challenge the traditional RCT design. KEY MESSAGES: All those interested in the development of new treatments and treatment strategies for neurological disorders should be involved when planning an RCT and ad-hoc designs should be developed to address the peculiarities of neurological disorders. Differences in age, sex and ethnicity should have a primary role in the design of an RCT. The traditional structure of the RCT should be also revised taking into account the new perspectives of personalized and precision medicine.
BACKGROUND: The traditional design of the randomized clinical trial (RCT) is challenged by the peculiarities of the genotype and phenotype of neurological disorders. SUMMARY: RCTs are intended to verify the net effect of an investigational treatment on the outcome of a disease. This implies the inclusion of strictly homogeneous sample of patients that represent only in part the full disease spectrum. For this reason, pragmatic trials on representative samples of the general population are welcome. In neurodegenerative disorders, RCTs are generally performed in symptomatic individuals, when the pathologic process is already in course. Although genetic, biological and structural markers are the ideal instruments to detect the disease at a preclinical stage, the development of biomarkers is still in its infancy and even identified markers require in most of cases validation. Given the limited duration of an RCT, prospective studies with prolonged follow-up in well-defined inception cohorts are needed to assess the effectiveness of the treatment in all affected individuals seen in everyday practice. RCT are conducted mainly in Caucasians excluding other ethnicities. The difference of brain biology between men and women are still underestimated in RCTs. Patients, treating physicians, pharmaceutical companies, and regulatory authorities have differing needs, which may have important implications in planning and conducting RCTs. New therapeutic approaches are represented by personalized and precision medicine. Although largely investigational, these approaches may challenge the traditional RCT design. KEY MESSAGES: All those interested in the development of new treatments and treatment strategies for neurological disorders should be involved when planning an RCT and ad-hoc designs should be developed to address the peculiarities of neurological disorders. Differences in age, sex and ethnicity should have a primary role in the design of an RCT. The traditional structure of the RCT should be also revised taking into account the new perspectives of personalized and precision medicine.