Ceci Adriana, Conte Rosa, Didio Antonella, Landi Annalisa, Ruggieri Lucia, Giannuzzi Viviana, Bonifazi Fedele
Research Department, Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus, Bari, Italy.
Front Med (Lausanne). 2023 Jul 14;10:1113460. doi: 10.3389/fmed.2023.1113460. eCollection 2023.
Several new active substances (ASs) targeting neuroblastoma (NBL) are under study. We aim to describe the developmental and regulatory status of a sample of ASs targeting NBL to underline the existing regulatory gaps in product development and to discuss possible improvements.
The developmental and regulatory statuses of the identified ASs targeting NBL were investigated by searching for preclinical studies, clinical trials (CTs), marketing authorizations, pediatric investigation plans (PIPs), waivers, orphan designations, and other regulatory procedures.
A total of 188 ASs were identified. Of these, 55 were considered 'not under development' without preclinical or clinical studies. Preclinical studies were found for 115 ASs, of which 54 were associated with a medicinal product. A total of 283 CTs (as monotherapy or in combination) were identified for 70 ASs. Of these, 52% were at phases 1, 1/2, and 2 aimed at PK/PD/dosing activity. The remaining ones also included efficacy. Phase 3 studies were limited. Studies were completed for 14 ASs and suspended for 11. The highest rate of ASs involved in CTs was observed in the RAS-MAPK-MEK and VEGF groups. A total of 37 ASs were granted with a PIP, of which 14 involved NBL, 41 ASs with a waiver, and 18 ASs with both PIPs and waivers, with the PIP covering pediatric indications different from the adult ones. In almost all the PIPs, preclinical studies were required, together with early-phase CTs often including efficacy evaluation. Two PIPs were terminated because of negative study results, and eight PIPs are in progress. Variations in the SmPC were made for larotrectinib sulfate/Vitrakvi and entrectinib/Rozlytrek with the inclusion of a new indication. For both, the related PIPs are still ongoing. The orphan designation has been largely adopted, while PRIME designation has been less implemented.
Several ASs entered early phase CTs but less than one out of four were included in a regulatory process, and only two were granted a pediatric indication extension. Our results confirm that it is necessary to identify a more efficient, less costly, and time-consuming "pediatric developmental model" integrating predictive preclinical study and innovative clinical study designs. Furthermore, stricter integration between scientific and regulatory efforts should be promoted.
几种针对神经母细胞瘤（NBL）的新型活性物质（ASs）正在研究中。我们旨在描述一组针对NBL的ASs的研发和监管状况，以突出产品开发中存在的监管差距，并讨论可能的改进措施。
通过搜索临床前研究、临床试验（CTs）、上市许可、儿科研究计划（PIPs）、豁免、孤儿药认定及其他监管程序，调查已识别的针对NBL的ASs的研发和监管状况。
共识别出188种ASs。其中，55种因无临床前或临床研究被视为“未在研发中”。发现115种ASs有临床前研究，其中54种与药品相关。共为70种ASs识别出283项CTs（作为单一疗法或联合疗法）。其中，52%处于1期、1/2期和2期，旨在进行药代动力学/药效学/剂量研究。其余的还包括疗效研究。3期研究有限。14种ASs的研究已完成，11种已暂停。参与CTs的ASs在RAS-MAPK-MEK和VEGF组中发生率最高。共有37种ASs获得了PIP，其中14种涉及NBL，41种ASs获得豁免，18种ASs同时获得PIP和豁免，PIP涵盖的儿科适应症与成人不同。在几乎所有的PIP中，都需要进行临床前研究，以及通常包括疗效评估的早期CTs。两项PIP因研究结果为阴性而终止，八项PIP正在进行中。硫酸拉罗替尼/维泰凯（larotrectinib sulfate/Vitrakvi）和恩曲替尼/罗圣全（entrectinib/Rozlytrek）的摘要说明书（SmPC）因纳入新适应症而有变化。两者相关的PIP仍在进行中。孤儿药认定已被广泛采用，而优先药物认定（PRIME）的实施较少。
几种ASs进入了早期CTs，但不到四分之一进入了监管程序，只有两种获得了儿科适应症扩展。我们的结果证实，有必要确定一种更高效、成本更低且耗时更少的“儿科研发模式”，将预测性临床前研究和创新性临床研究设计整合起来。此外，应促进科学和监管努力之间更严格的整合。
