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

We conducted research to assess hospital pharmacists' familiarity with/interpretation of data requirements for the different regulatory approval frameworks and the impact of this on their approach to substitution in the formulary. The online questionnaire included a small molecule (acetylsalicylic acid-follow-ons approved via the generic pathway), two biologic drugs (insulin glargine and etanercept-follow-ons approved via the biosimilar pathway), a non-biologic complex drug (NBCD; glatiramer acetate-follow-ons approved via the hybrid pathway) and a nanomedicine, ferric carboxymaltose (no follow-ons approved as yet). The study was conducted in two phases: an initial qualitative pilot study with 30 participants, followed by a quantitative stage involving 201 pharmacists from five European countries. Most expected negligible safety/efficacy differences between reference and follow-on products. Head-to-head clinical data showing therapeutic equivalence as a prerequisite for reference product/follow-on substitution was perceived to be needed most for biologics (47%), followed by NBCDs (44%)/nanomedicines (39%) and small molecules (23%). Overall, 28% did not know the data requirements for follow-on approval via the hybrid pathway; 16% were familiar with this pathway, compared with 50% and 55% for the generic and biosimilar pathways, respectively. Overall, 19% of respondents thought the European Medicines Agency (EMA) was responsible for defining the substitutability of follow-ons. Education is required to increase hospital pharmacist's knowledge of regulatory approval frameworks and their relevance to substitution practices.

Tackling the challenges of nanomedicines: are we ready?

PURPOSE: This review provides an overview of the proceedings of the symposium "Tackling the Challenges of Nanomedicines: Are We Ready?" organized by the International Pharmaceutical Federation (FIP) Hospital Pharmacy Section and Non-Biological Complex Drugs (NBCDs) Working Group at the 2019 FIP World Congress of Pharmacy and Pharmaceutical Sciences. Debate centered on reasons underlying the current complex regulatory landscape for nanomedicines and their follow-on products (referred to as nanosimilars) and the pivotal role of hospital pharmacists in selecting, handling, and guiding usage of nanomedicines and nanosimilars. SUMMARY: The evaluation and use of nanomedicines are recognized among scientific, pharmaceutical, and regulatory bodies as complex. Interchangeability and substitutability of nanomedicines and nanosimilars are confounded by a lack of pharmaceutical and pharmacological equivalence, reflecting the inherent complex nature of these drug products and manufacturing processes. Consequences include implications for clinical safety and efficacy and, ultimately, comparability. Local regulatory approvals of some nanomedicines have occurred, but there is no standard to ensure streamlined evaluation and use of consistent measures of therapeutic equivalence of reference products and their nanosimilars. Hospital pharmacists are expected to be experts in the selection, handling, and substitution of nanomedicines and familiarize themselves with the limitations of current methods of assessing pharmaceutical and clinical equivalence of nanosimilars in order to ensure informed formulary decision-making and eventual patient benefit. CONCLUSION: Supportive guidance for pharmacists focusing on the substitutability and/or interchangeability of nanomedicines and their nanosimilars is needed. Current FIP guidance for pharmacists on therapeutic interchange and substitution should be extended to include nanomedicines and nanosimilars.

Iron polymaltose complexes: Could we spot physicochemical differences in medicines sharing the same active pharmaceutical ingredient?

Oral iron therapy can efficaciously treat both iron deficiency and iron deficiency anemia. To overcome the recurrent side effects of iron(II) salts, medicines containing iron(III) such as iron polymaltose complex (IPC) have been introduced in several markets. Despite the claimed improved safety versus iron(II) preparations, divergent evidences are currently available on IPC efficacy. Indeed, the use of either an originator drug or a follow-on version ("similar") of this medicine might result in different clinical performances. The aim of this work was the pioneer evaluation of physicochemical properties of IPC vs. iron polymaltose complex similars (IPCSs) as nanomedicines. This, to assess the presence of deviations for commercially available products supposedly containing the same active pharmaceutical ingredient and currently considered as generics. Significant differences with respect to size, size distribution, stability and degradation kinetics of the products are reported here. Therapeutic equivalence of IPC and IPCSs is not proven, and new guidelines are needed to determine whether these nanomedicines can be regarded as interchangeable.

Bridging communities in the field of nanomedicine.

An early dialogue between nanomedicine developers and regulatory authorities are of utmost importance to anticipate quality and safety requirements for these innovative health products. In order to stimulate interactions between the various communities involved in a translation of nanomedicines to clinical applications, the European Commission's Joint Research Centre hosted a workshop titled "Bridging communities in the field of Nanomedicine" in Ispra/Italy on the 27th -28th September 2017. Experts from regulatory bodies, research institutions and industry came together to discuss the next generation of nanomedicines and their needs to obtain regulatory approval. The workshop participants came up with recommendations highlighting methodological gaps that should be addressed in ongoing projects addressing the regulatory science of nanomedicines. In addition, individual opinions of experts relevant to progress of the regulatory science in the field of nanomedicine were summarised in the format of a survey.

Nanomedicines in clinical practice: Are colloidal iron sucrose ready-to-use intravenous solutions interchangeable?

The assessment of interchangeability of nanomedicines and nanosimilars is required for ensuring the safety, quality and efficacy of these complex drugs. Since 2011, regulatory agencies and researchers focused their attention on the characterization of iron sucrose, a colloidal solution parenterally used for the treatment of iron deficiency anemia, as well as on their follow-on versions, the so-called iron sucrose similars (ISSs). The purpose of this study was the evaluation of the size and size distribution of both IS and ISSs after dilution in polypropylene bags containing saline, mimicking the preparation of ready-to-use infusions to be administered in a hospital environment. The assays were carried out for 72 h, determining a general stability of the colloidal solutions investigated. Nevertheless, a dissimilar size and size distribution but also different visual appearance of IS and ISSs were recorded when the drugs diluted for therapeutic use. These results agree with previously published physicochemical and clinical data supporting the lack of exchangeability between IS and ISSs.

A robust and easily reproducible protocol for the determination of size and size distribution of iron sucrose using dynamic light scattering.

Iron sucrose (IS), a nanocolloidal solution used in the treatment of iron deficiency anemia, is currently under investigation for the elucidation of its critical quality attributes. Assessment of IS's size and size distribution has been recently attempted using dynamic light scattering (DLS). However, due to heterogeneous interpretation of DLS data, variable results were retrieved. The aim of this work was to establish a simple and reproducible DLS protocol to unequivocally define the size and size distribution of IS by using size distribution approximation in Number. Underlining the limitations of the commonly used DLS approximations, we identified the drug as being composed of a population of monodisperse nanoparticles of about 7 nm in diameter. The method here described might therefore be useful for the evaluation of quality, safety and efficacy of IS and its follow-on versions.

Iron sucrose: assessing the similarity between the originator drug and its intended copies.

Iron sucrose (IS) is a complex nanocolloidal intravenous suspension used in the treatment of iron-deficiency anemia. Follow-on IS products (iron sucrose similars (ISSs)) have obtained marketing authorization by the generic pathway, implying that identical copies of IS may be manufactured. However, recent prospective and retrospective clinical studies showed discrepancies in clinical outcomes, which might be related to differences in physicochemical properties. The aim of this work is to measure and compare the physicochemical properties of IS and three ISSs available in the market using innovative analytical procedures. The comprehensive elucidation of size, size distribution, morphology, and stability of these complex drugs revealed very significant differences between the products. This study serves to provide the basis to define critical quality attributes that may be linked to differences in clinical outcome and thus may contribute to an adequate regulatory approach for IS and its follow-on products.

Preparation and evaluation of nanoparticles for directed tissue engineering.

Herein we describe the preparation of a nanoparticulate system formed from an RGD-functionalized chitosan derivative by complexation with chondroitin sulfate. These bioactive complexes were developed to promote wound healing by inducing adhesion and subsequently migration of skin cells. The particles were characterized for their size, surface charge, stability and shape. Briefly, the nanoparticles were found to be stable up to 7 days in water at a diameter of 150-200 nm and a positive charge of 20 mV. In physiological media the particles swell significantly but remain intact. Tested in an in vitro cell model of human dermal fibroblasts, the particles were shown to promote cell adhesion and induce spreading in human dermal fibroblasts. The mean surface area per cell was found to be increased by three-fold (n=3 assays, p<0.01), for the cells plated on particles exposing RGD-peptides when compared to cells on control particles. This indicates a stimulation of the cells due to the exposure of the bioactive RGD-moieties and an enhanced cell-biomaterial interaction. Using nanoparticles is a novel approach to direct cellular behavior with numerous possible applications in tissue engineering such as substrate for dermal and epithelial cells, injectable suspensions or as building blocks to form scaffolds.