Regulatory challenges of nanomedicines and their follow-on versions: A generic or similar approach?

Abstract

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.

Nanomedicine: Principles, Properties, and Regulatory Issues

“…Nanomedicine comprises both biological and non-biological medical products. The biological nanomedicines are obtained from biological sources, while non-biological are mentioned as non-biological complex drugs (NBCD), where the active principle consists of different synthetic structures (Tinkle et al, 2014 ; Hussaarts et al, 2017 ; Mühlebach, 2018 ).…”

Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines?

“…The FDA should revisit its suggestion that comparative physicochemical testing is sufficient to support generic approvals of drug products containing nanomaterials, given that the mechanisms of action by which these products impact biological targets within the body are not fully understood. The FDA presumes that comparable structural features will ensure compatible tissue distribution, when instead a totality-of-evidence approach that includes biological, preclinical, and clinical data evaluated in a stepwise manner is more appropriate for the complexity of these products (16,17). However, the requested factors outlined by the FDA, namely: & understanding of the mechanism by which the physicochemical properties of the material impact its biological effects (e.g., effect of particle size on pharmacokinetic parameters) and & understanding the in vivo release mechanism based on the material physicochemical properties are not met for numerous iron carbohydrates.…”

Generic Prescription in India – A Review

“…• This is a good-natured, however, unrealistic proposition -the current medication advertise in the nation makes it difficult to actualize, said Chandra Gulhati, a senior pharmacologist and supervisor of the [37] • Experts state the Prime Minister's promise, while good-natured will be difficult to actualize and refer to the disappointment of the Medical Council of India, the office that controls specialists, to authorize its proposal looking for remedies with nonexclusive names made in 2002 and again in 2016 • The medicines with conventional names just could bargain tolerant security because the decision of the medication to be given over to patients would move from the specialist to the retail scientist [38] • A representative with the Organization of Pharmaceutical Producers of India (OPPI) said the specialist quiet relationship included "trust and confidence" and was in this manner not the same as the retailer persistent relationship which was "just value-based" and likely determined by impulses of edges retailers make • "It winds up clear that any such move (to make nonexclusive names just compulsory) will bargain persistent security" T.K. Kanchana, executive general of the OPPI, said in an announcement sent to the paper [39] • "Indian patients may confront quality issues without value advantage as an extreme challenge among advertisers will prompt boosting a physicist," says D G Shah, secretary-general of the Indian Pharmaceutical Alliance • Sujay Shetty, the accomplice at consultancy firm PWC, said such an arrangement would be extremely hard to actualize.…”