Regulatory Science Lead Non Biological Complex Drugs at Vifor Pharma Ltd, Flughofstrasse 61, P.O. Box CH-8152, Glattbrugg, Switzerland; University of Basel, Department of Pharmaceutical Sciences, Division of Clinical Pharmacy & Epidemiology, Hospital Pharmacy, Spitalstrasse 26, CH-4031 Basel, Switzerland.
Adv Drug Deliv Rev. 2018 Jun;131:122-131. doi: 10.1016/j.addr.2018.06.024. Epub 2018 Jun 30.
Nanomedicines and follow-on versions (also called nanosimilars in the EU) have been on the market partially for decades although without recognition of their nano properties in the beginning; a substantial number is in clinical development. Nanomedicines are typically synthetic and belong to the non-biological complex drugs. They show a high variability in form, structure, and size. Additionally large molecule biologics show nano-characteristics meaning nano-dimension in size (1-100 nm) or specific properties related to these dimensions. The high complexity of nanomedicines with their heterogeneous structures do not allow a full physicochemical quality characterization, challenging the regulatory evaluation especially for follow-on versions upon comparison with the reference product. The generic paradigm with the sameness approach for quality and bioequivalence in blood plasma is not appropriate for nanomedicines where a similar approach is needed. After experiencing non-equivalence of authorized parenteral colloidal iron follow-on versions, EMA and FDA issued reflection papers and draft guidances for industry to present their current thinking on the evaluation of such complex products. A stepwise approach to evaluate the extent of similarity, from quality, including critical quality attributes (CQA) and assessment of nano properties, to a non-clinical biodistribution assay, required in the the EU but not in the US, and to clinical evaluation makes sense. The cumulated totality of evidence for the authorization of nanomedicine follow-on versions goes case-by-case. Interchangeability, or substitutability, is a challenge. However, a defined or even harmonized approval pathway for these follow-versions is still missing and causes potential differences in approval. To progress, a science-based discussion platform among stakeholders and experts in the field is necessary. An agenda has been agreed [5], namely CQA assessment, publication of scientific and clinical findings, consensus on nomenclature and labelling, and regulatory actions on substandard complex drug products. Consensus created in a public private approach will support progress towards a defined and harmonized regulatory pathway for nanomedicines and their follow-on versions. This will provide drug innovation but also larger access to follow-on versions of nanomedicines, both a benefit for the patient.
尽管最初纳米药物（在欧盟也被称为纳米类似物）部分已上市几十年，但并未被认可具有纳米特性；目前有相当数量的纳米药物处于临床开发阶段。纳米药物通常为合成药物，属于非生物复杂药物。它们在形态、结构和尺寸方面具有高度可变性。此外，大分子生物制剂也具有纳米特性，即尺寸为 1-100nm 的纳米尺寸或与这些尺寸相关的特定性质。由于纳米药物结构复杂，高度异构，无法进行全面的物理化学质量特征描述，因此在与参比制剂进行比较时，特别是对于后续版本，对监管评估提出了挑战。对于纳米药物，质量和生物等效性采用通用的同质性方法并不合适，需要采用类似的方法。在经历了授权的肠外胶体铁后续版本等效性问题后，EMA 和 FDA 发布了反思文件和行业指南草案，以阐述他们对这类复杂产品评估的当前思路。从质量评估开始，逐步评估相似程度，包括关键质量属性（CQA）和纳米特性评估，到非临床生物分布测定，这在欧盟是必需的，但在美国则不需要，然后进行临床评估是有意义的。对于纳米药物后续版本的授权，需要根据具体情况，累积证据。可互换性或可替代性是一个挑战。然而，这些后续版本的定义或甚至协调的批准途径仍然缺失，并导致批准方面的潜在差异。为了取得进展，需要在利益相关者和该领域专家之间建立一个基于科学的讨论平台。已达成一项议程[5]，即 CQA 评估、科学和临床发现的发表、命名法和标签的共识，以及对不合格复杂药物产品的监管行动。在公私合作的方式下达成的共识将支持为纳米药物及其后续版本制定明确和协调的监管途径取得进展。这将为药物创新提供支持，也为患者提供更多获得纳米药物后续版本的机会。
