Pediatric oncology is a critical area where the more efficient development of new treatments is urgently needed. The speed of approval of new drugs is still limited by regulatory requirements and a lack of innovative designs appropriate for trials in children. Childhood cancers meet the criteria of rare diseases. Personalized medicine brings it even closer to the horizon of individual cases. Thus, not all the traditional research tools, such as large-scale RCTs, are always suitable or even applicable, mainly due to limited sample sizes. Small samples and traditional versus subject-specific evidence are both distinctive issues in personalized pediatric oncology. Modern analytical approaches and adaptations of the paradigms of evidence are warranted. We have reviewed innovative trial designs and analytical methods developed for small populations, together with individualized approaches, given their applicability to pediatric oncology. We discuss traditional population-based and individualized perspectives of inferences and evidence, and explain the possibilities of using various methods in pediatric personalized oncology. We find that specific derivatives of the original N-of-1 trial design adapted for pediatric personalized oncology may represent an optimal analytical tool for this area of medicine. We conclude that no particular N-of-1 strategy can provide a solution. Rather, a whole range of approaches is needed to satisfy the new inferential and analytical paradigms of modern medicine. We reveal a new view of cancer as continuum model and discuss the “evidence puzzle”.

Background: Fingolimod, an oral sphingosine 1-phosphate receptor immunomodulator, is approved in Europe for people with multiple sclerosis (pwMS) with highly active disease despite a full and adequate course of treatment with ≥ 1 disease-modifying therapy or patients with rapidly evolving severe relapsing–remitting MS. GOLEMS, a national, multicenter, non-interventional, single-arm, real-world study showed a favorable benefit–risk profile of 12-month treatment with fingolimod in pwMS in the Czech Republic. Here, we evaluated the long-term effectiveness and safety of fingolimod and its impact on disability progression and work capability for up to 48 months in pwMS. Methods: The endpoints assessed were the incidence and severity of MS relapses in fingolimod-treated patients and the proportion of relapse-free patients up to 48 months of fingolimod treatment, change from baseline in the Expanded Disability Status Scale (EDSS) score, and change from baseline in work capability assessment. Efficacy outcomes were analyzed in the completed and efficacy sets, and safety was evaluated in all the enrolled patients. Results: Of 240 enrolled patients, 237 were included into efficacy set. Patients with a minimum of a 12-month observation period in the core study who continued fingolimod treatment, were eligible to participate in the extension phase. Of 211 patients enrolled in extension study, 155 were evaluated in the completed set. Based on analysis of 48-month period of fingolimod treatment, 95/237 patients (40.1%) in the efficacy set, 54/155 (34.8%) in the completed set were free of relapses. The majority of relapses reported were moderate in intensity. Mean EDSS score remained stable throughout 48-month study period (Baseline, 3.4; Month 48, 3.6). No trend was observed in changes in work capability assessment or number of missed days of work. Of 240 enrolled patients, 147 (61.3%) had ≥ 1 treatment-emergent adverse event (AE) and 20 (8.3%) reported serious AEs. In total, 45 patients (18.8%) permanently discontinued treatment because of AEs related to study drug; two patients reported pregnancy after treatment initiation and subsequently discontinued the treatment; no deaths were reported. Conclusion: GOLEMS study demonstrated the sustained effectiveness and manageable safety profile of fingolimod under real-world conditions over 48 months in patients with MS. Trial registration: Not applicable.