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no follow-on iron sucrose authorised in the US as yet. Recently the FDA contracted out a prospective randomised, two-way crossover study on the comparison of the iron-gluconate innovator product and the follow-on version21

previously authorised.

Liposomal drugs Liposomes are vesicles with (phospho) lipid bilayer membranes that can carry drugs. The safety and efficacy of these liposomal drugs depend on their lipid composition, size, charge, the rigidity of the bilayer and their production process.22

Clinical work on new

liposomal formulations of a variety of drugs is thriving.

The discussion on the regulatory aspects of the introduction of follow-on versions of liposome products focuses on those containing doxorubicin (Doxil®

/Caelix® ). Recently, the

innovator published findings showing that doxorubicin liposomes with a different lipid composition differed in their antitumor activity in animals although they had similar pharmacokinetic profiles.23

madefor clinical studies to show therapeutic equivalence between original and follow-on versions of liposomal drugs.24

The FDA has published a draft guidance paper on follow-on versions of doxorubicin hydrochloride liposomes.25 The applicant of a follow-on version needs to show that the physicochemical characteristics of the follow-on version are equivalent to the originator’s product. In addition, in vitro studies are needed to measure particle size distribution and doxorubicin release characteristics in different media and a clinical bioequivalence study measuring both free and encapsulated doxorubicin. Clinical efficacy and safety studies are not necessary. In 2013, the FDA approved the first follow-on liposome containing doxorubicin. So far, no follow-on versions of liposomal formulations have been approved by the EMA.


Glatiramoids comprise a family of synthetic copolymer mixtures comprising the four amino acids, L-glutamic acid, L-alanine, L-lysine and L-tyrosine, in a defined molar ratio. The prototype is glatiramer acetate (Copaxone®

), a mixture of hundreds of

thousands of polypeptide sequences with immune-modulating activity authorised for the treatment of multiple sclerosis. The composition of glatiramer acetate is highly dependent on the manufacturing process. Minor changes in this process can produce altered entities that are likely to significantly affect the safety and efficacy of the product.26

In addition to its inherent

compositional complexity, glatiramer acetate comprises a nano-sized polypeptide mixture with molecules and molecular structures ranging from 1.5 to 550nm in size; some of them to be deemed proteins because of their size.27 Due to these sizes, Copaxone®


considered to be a colloidal solution. Its biological activities are related to cytokine induction and its

immunogenicity – a key parameter of the quality, safety and efficacy of the drug – is very sensitive to any modification of chemical and physical characteristics. Recently, the FDA refused to approve a supplemental new drug application in relation with Copaxone®

. Although not a biological A plea was

drug as defined by the FDA/EMA, Copaxone®

is at least as complicated to

characterise as biological medicinal products.

Nanosimilars and follow-on nanosized therapeutics

Other drug products will be recognised as NBCDs in addition to the products discussed in the sections above; these include the nanomedicines. Nanomedicines have been successfully used as medicinal products in clinical routine over the last several decades, frequently without taking into account either their specific nanoparticular structure or the resulting complexity of their mechanical, chemical, and pharmacological properties.28

albumin-bound anticancer drug is the first protein-based nanoparticle medicinal product approved as a nanosimilar. The manufacturing processes, and the use of proteins from different sources, result in variations in quality, purity, and difficulties in scaling-up production. The performed tests with intended copies suggest fundamental differences in manufacturing and resulting product composition: these differences may potentially lead to undesirable effects and safety concerns.29

Biologics of very

high molecular weight, such as antibody-drug conjugates may also be considered as nanomedicines.30 Acknowledging the complexity of biologics such as therapeutic proteins and the impossibility to exactly reproduce biological products, a specific biosimilar regulatory approach for follow-on versions was elaborated and established by the EMA.1 Up until now, 17 biosimilar products received marketing authorisation by EMA.31


FDA developed a regulatory approach for such products, but accepted the similarity instead of the sameness approach.32

concept for therapeutic follow-on products, the term ‘nanosimilar’ has been coined in the context of NBCDs follow-on versions.28

The mostly Examples

include polymer–drug conjugates, polymeric nanoparticles, polymeric micelles, iron oxide particles, and innovative biological complex therapeutics such as monoclonal antibodies. It is also expected that these will include older products that are in fact colloidal nanoparticle systems and will be reclassified as nanoparticles and NBCDs or nanosimilars. There is a lack of knowledge on which parameters are critical for the evaluation of nanomedicines during early development. For example, nab- paclitaxel (Abraxane®

) a nanoparticle,

unknown existence and nature of clinically meaningful components in nanomedicines or NBCDs result from the manufacturing process. It makes it so difficult, or even impossible, to appropriately characterise such products physicochemically and has a special importance for the regulatory evaluation in follow-on versions. Therefore, non-clinical and clinical evaluations are needed to characterise such products and to obtain the totality of evidence to achieve comparability.


NBCDs are defined as medicinal products of non-biological origin with an active substance that is not a homo-molecular structure, but consists of different closely related and mostly nanoparticulate structures. NBCDs and related nanomedicines regulatory awareness is documented by a series of reflection papers and industry guidances released from important authorities on evaluation of follow-on versions of established NBCDs like the nanocolloidal IV iron carbohydrates or

In analogy to the biosimilar


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