Micallef Joëlle, Boutouyrie Pierre, Blin Olivier
Service de Pharmacologie Clinique et Pharmacovigilance, AP-HM, 13385, Marseille, France.
Pharmacologie intégrée et interface clinique et industriel, Orphandev-FCRIN, Institut des Neurosciences Timone - AMU-CNRS 7289, Aix Marseille Université, 13385, Marseille, France.
Fundam Clin Pharmacol. 2017 Dec;31(6):685-694. doi: 10.1111/fcp.12314. Epub 2017 Aug 24.
Developing drugs for rare disease can be challenging due to specific rare disease characteristics. The French Medical Pharmacology is structured and positioned to play a major role in orphan drug research and development due to the required expertise concentrated into pharmacology departments, exclusively implemented within the French university hospitals, public hospitals that are linked to a medical school (and often a pharmacy school) with numerous INSERM or CNRS labelled research units. In addition, these structures allow a close collaboration between researchers, academic institutions and biotech start-up (most of them being spin-off of the academic structures). Also, within university hospitals are located the clinical investigation centres, linking to the F-CRIN network and also to Inserm and hospitals, that enable care staff and researchers to be associated and clinical research protocols to be carried out on site, in full respect with ethic and regulatory aspects. As a consequence, this intra and multidisciplinary expertise offers all resource to elaborate a tailored approach for orphan drug development, in new entities as well as in repositioning. For preclinical development: drug screening, candidate selection (taking into account PK, metabolism, variability and potential toxicity) and preclinical models (iPS, animal models) that could allow a better translation to human research. For clinical development, we will mention here dose determination, safety evaluation and Orphan Drug Designation and Protocol Assistance preparation and submission. For post marketing evaluation and surveys, the pharmacovigilance, addictovigilance and pharmacoepidemiology expertise, combined with access to large databases allow a better approach to orphan drug use and safety. As outlined through two success stories (Charcot Marie Tooth, vascular Ehlers-Danlos syndrome), the added value of French Medical Pharmacology structures and expertise has been evidenced in the know-how, multidimensional and multidisciplinary approaches, allowing the development of numerous drugs that have been granted with Orphan Drug Designation and later Market Approval. Even if specific and possibly even more, the field of orphan drugs requires the respect of highest standards of safety and quality. French Medical Pharmacology intends to continue on this way and constantly improve his involvement in this field, committed to a single objective: answer the unmet medical need of patients with rare diseases.
由于罕见病具有特定特征，开发罕见病药物可能具有挑战性。法国医学药理学的架构和定位使其能够在孤儿药研发中发挥重要作用，因为所需的专业知识集中在药理学部门，这些部门仅在法国大学医院、与医学院（通常还有药学院）相关联的公立医院中设立，且有众多法国国家健康与医学研究院（INSERM）或法国国家科学研究中心（CNRS）标记的研究单位。此外，这些机构使研究人员、学术机构和生物技术初创企业（其中大多数是学术机构的衍生企业）之间能够密切合作。而且，大学医院内设有临床研究中心，这些中心与法国临床研究基础设施网络（F-CRIN）以及法国国家健康与医学研究院和医院相连，这使得医护人员和研究人员能够协作，并在充分尊重伦理和监管要求的前提下在现场开展临床研究方案。因此，这种内部和多学科的专业知识为制定针对孤儿药开发的定制方法提供了所有资源，无论是在新实体还是在重新定位方面。在临床前开发方面：药物筛选、候选药物选择（考虑到药代动力学、代谢、变异性和潜在毒性）以及临床前模型（诱导多能干细胞、动物模型），这些模型能够更好地转化为人体研究。在临床开发方面，我们在此提及剂量确定、安全性评估以及孤儿药指定和方案协助的准备与提交。在上市后评估和调查方面，药物警戒、药物成瘾监测和药物流行病学专业知识，再加上能够访问大型数据库，使得对孤儿药的使用和安全性有更好的研究方法。正如通过两个成功案例（夏科-马里-图斯病、血管性埃勒斯-当洛综合征）所概述的那样，法国医学药理学机构和专业知识的附加值在技术诀窍、多维度和多学科方法中得到了体现，从而开发出了众多获得孤儿药指定并随后获得市场批准的药物。即使孤儿药领域有其特殊性，甚至可能更特殊，但它要求遵循最高的安全和质量标准。法国医学药理学打算继续沿着这条路走下去，并不断加强其在该领域的参与度，致力于一个单一目标：满足罕见病患者未得到满足 的医疗需求。
