MARCH 2026 9TECH OUTLOOKRoctavian for treatment of hemophilia A is a good example - Historical data plus 6-month of prospective noninterventional data have been used as historical control to assess clinical outcomes in its pivotal registration study. The disease course is predictable and treatment effects were dramatic. The same FDA Guidance also states that "data and information from a natural history study may provide an untreated, external control group for use as the comparator to the treatment group(s) in an investigational drug trial." There are multiple Guidance documents reiterate the usefulness of natural history data as external control group.Prospective longitudinal natural history study can inform the design of the first-in-human and pivotal registration studies for gene therapy. It informs natural history of the disease regarding disease manifestation, onset and progression over time. In clinical trials, it can help to determine what stage and type of the disease to target, ideal time for intervention, patient eligibility criteria, duration of the trials, frequency and timing of data collection, clinically meaningful outcome measurements, and biomarkers, etc. Zolgensma is an approved gene therapy for spinal muscular atrophy (SMA). SMA is an autosomal recessive neurodegenerative disorder caused by mutation of the SMN1 gene. SMA Type 1 is the most common monogenic cause of infant mortality. Disease progresses rapidly and resulted in mortality or requiring respiratory support by 2 years of age. During Zolgensma clinical development, it took advantage of the available data from a previously conducted natural history study. Natural history study data helped both phase 1 and 3 studies to pick the ideal birth months for gene therapy intervention (initially =<9 months, later revised to =<6 months), determine the clinically meaningful endpoints (coprimary endpoints of survival at 14 months of age and sitting without support for 30 seconds), and study duration (individualized follow-up duration of reaching age 18 months in the pivotal registration study) to name a few. And most importantly, natural history data served as the control in both phase 1 and 3 studies to demonstrate robust efficacy and favorable safety profile of Zolgensma treatment.While natural history study can be very informative, it demands careful early planning. It necessitates a decision to conduct it in-house or work with others such as disease foundations, or with other companies in the precompetitive space. It takes much longer time to conduct such a study, and it can be costly as well as resource intensive. Ref: Zolgensma - FDA BLA Clinical Review MemorandumProspective longitudinal natural history study can inform the design of the first-in-human and pivotal registration studies for gene therapy.
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