How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider

Abstract

The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the 'families' of liposomes, iron-carbohydrate ('iron-sugar') drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well and only switch if unavoidable and (3) monitor the safety and efficacy of the new product if switching occurs.

Fig. 1

Observational study comparing two subsequent 27-week periods in 75 stable haemodialysis (HD) patients who had received IV iron weekly and an erythropoiesis-stimulating agent (ESA; darbepoetin alfa) once every 2 weeks. Patients received the originator product Venofer® in the period 1 and an iron sucrose similar in period 2. Based on the study by Rottembourg et al. (14)

Fig. 2

Comparative peptide mapping of originator product Copaxone (blue, upper trace) and a follow-on glatiramoid (black, lower trace) showing clear indication of differences in the primary structure of the drug amino acid sequences (22)

Fig. 3

Gene-wise hierarchical clustering of 98 genes with FDR-adjusted p value <0.05 and fold change $1.3 between GA reference standard and eight follow-on Natco lots (23). a Heat map showing clustering results with samples (columns) ordered by sample name and genes (rows) ordered by hierarchical clustering. Four major gene clusters are marked A–D on the right; their root nodes are marked with blue circles on the dendrogram on the left. Yellow bars separate between treatment groups and clusters. b Average expression profile per cluster. For each gene, the mean expression signal per treatment group was calculated. The distribution of these values across genes in each cluster is shown as a box plot. GA-DP glatiramer acetate drug product, GA-N Natco lots, GA-RS glatiramer acetate reference standard, M medium