Non-biological Complex Drugs (NBCDs): Complex Pharmaceuticals in Need of Individual Robust Clinical Assessment Before Any Therapeutic Equivalence Decision

Abstract

Non-Biological Complex Drugs (NBCDs) are complex non-biological drugs comprised of large high molecular weight molecules and, often, nanoparticular structures (including liposomes and block-copolymer micelles). In the case of NBCDs, the entire complex is the active pharmaceutical ingredient and its properties cannot be fully characterized by physicochemical analysis. Moreover, the manufacturing process is fundamental in creating the correct originator product. The same is true for generic versions of the product. A recent appraisal of approval procedures for NBCDs “follow-on products” approved in Europe shows a diversity of regulatory pathways. In fact, three different abridged application procedures, under European legislation, were used: the generic application procedure of Article 10(1), the hybrid application procedure of Article 10(3), and the biosimilar application procedure of Article 10(4). Three informed consent applications via Article 10(c) from innovator companies of glatiramer acetate and sevelamer carbonate were submitted shortly after the approval of the first follow-on products. Furthermore, a number of “well-established use” applications [via Article 10(a)] were approved for iron sucrose and iron dextran complexes. In order to protect patients from the increased risks of NBCD products and NBCD follow-on products, two complementary approaches should be considered: (i) improving the regulatory procedures and their guidance documents within the pre-registration phase, and (ii) not considering interchangeability whenever clinical data is not available. With regards to the latter, the need for adequate safety and efficacy data might also include risk management programmes within post-approval pharmacovigilance actions. This, however, would depend on a risk appraisal that must be considered for individual medicinal products, based on the nature of the submitted relevant set of safety/efficacy data.

How Do Hospital Pharmacists Approach Substitution of Nanomedicines? Insights from a Qualitative Pilot Study and a Quantitative Market Research Analysis in Five European Countries

“…Irrespective of their country of practice, many of the pharmacists interviewed stated that head-to-head clinical trial data confirming therapeutic equivalence and, therefore, the interchangeability of follow-on and originator products would be required to permit substitution of these products in the hospital formulary, especially when considering biosimilars and NBCDs, including nanomedicines. This is in line with recommendations from a recent publication from a group of regulators and hospital pharmacists, which highlighted the need for robust clinical assessment of comparability and/or therapeutic bioequivalence of NBCDs and their follow-ons, rather than the current focus on preclinical and/or physicochemical characterization [6]. Many pharmacists also believed that clinical studies are conducted to specifically demonstrate therapeutic equivalence of originator and follow-on products, and wrongly assumed that such data are required by the EMA as part of the associated approval processes.…”

“…The nanomaterial part of a nanomedicine formulation may be the active ingredient itself, a drug carrier, a novel excipient, or a drug complex/conjugate [4]. Nanomedicines include, but are not limited to, drug nanocrystals (e.g., olanzapine), liposomes (e.g., doxorubicin hydrochloride), polymeric drugs (e.g., glatiramer acetate), iron-polymer complexes (e.g., ferric carboxymaltose), virus-like particles (e.g., formalin inactivated hepatitis A virus) and virosomes (e.g., recombinant adenovirus expressing wildtype-p53) [5,6]. Between 1973 and 2015, liposomal agents were the most prevalent type of nanomedicine to be submitted for regulatory approval, followed by products containing nanocrystals, emulsions and iron-polymer complexes [4].…”

“…This approach may facilitate the substitution of generics/follow-ons in the formulary, as they may be cheaper than the originator products. However, there may not be sufficient data to support an equivalent efficacy or safety of these follow-on products and the prescribing clinician may be unaware of the active substitution carried out by other stakeholders [ 6 ]. This strategy encompasses all follow-on medicinal products, irrespective of either their characteristics (small molecules, biologics or nanomedicines) or their approval pathway [ 20 , 21 , 22 ], even if prescribing physicians may counsel against substitutions under certain specific circumstances [ 23 ].…”

Future perspectives for advancing regulatory science of nanotechnology-enabled health products

“…In July 2021, the US FDA and the EMA launched a pilot programme discussing the specific questions regarding complex generic drugs/hybrid products that are generally more challenging to develop with traditional bioequivalence methods. In this programme, the identified challenge on the assessment of "nanosimilars" [22][23][24] will now be addressed by the two major regulatory agencies. Product developers will benefit from this initiative and will be able to optimise their product development by avoiding unnecessary replication of testing when seeking for product authorisation for either the American Fig.…”

“…Fig.1Relevance of the regulatory challenges for nanotechnology-enabled products as acknowledged by the participants of the online survey (no of respondents was equal to 15) and participants of the 2nd KEC (no of respondents in the Slido survey was equal to24) …”