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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. [ABSTRACT FROM AUTHOR]

The application of the nanotechnology in medicine and pharmaceutics opens new horizons in therapeutics. Several nanomedicines are in the market and an increasing number is in clinical trials. But which is the advantage of the medicines in nanoscale? The scientists and the regulatory authorities agree that the size and consequently the physiochemical/biological properties of nanomaterials play a key role in their safety and effectiveness. Additionally, all of them agree that a new scientific-based regulatory landscape is required for the establishment of nanomedicines in the market. The aim of this review is to investigate the parameters that the scientists and the regulatory authorities should take into account in order to build up a dynamic regulatory landscape for nanomedicines. For this reason, we propose an "astrolabe-like system" as the guide for establishing the regulatory approval process. Its function is based on the different physicochemical/biological properties in comparison to low molecular weight drugs. [ABSTRACT FROM AUTHOR]

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.

Abstract 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. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed. Many healthcare professionals may be unaware of this issue and must be informed of these clinically relevant variances. This article provides a tool for rational decision making for the inclusion of nanomedicines into the hospital formulary, including defined criteria for evaluation of substitutability or interchangeability. The tool was generated by conducting a roundtable with an international panel of experts and follows the same thought process that was developed and published earlier for the selection of biologicals/biosimilars. In addition to the existing criteria for biosimilars, a set of seven criteria was identified that specifically apply to nanosimilars. These include (1) particle size and size distribution, (2) particle surface characteristics, (3) fraction of uncaptured bioactive moiety, (4) stability on storage, (5) bioactive moiety uptake and (6) distribution, and (7) stability for ready-to-use preparation. Pharmacists should utilize their pharmaceutical expertise to use the appropriate criteria to evaluate the comparability of the drug to decide on interchangeability or substitutability. [ABSTRACT FROM AUTHOR]

In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil® and its European analog Caelyx® with the two follow-on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We found subtle physicochemical differences between the tested liposomal products and even between the tested batches of Doxil® and Caelyx®. Notably, these included differences in vesicular population aspect ratios and particle number. Among the tested products, only SinaDoxosome, in addition to the presence of unilamellar vesicles with entrapped doxorubicin crystals, contained empty circular disks. Differences were also found in complement responses, which may be related to some morphological differences. This study has demonstrated an integrated biophysical and immunological toolbox for improved analysis and detection of physical differences among vesicular populations that may modulate their clinical performance. Combined, these approaches may help better product selection for infusion to the patients as well as for improved design and characterization of future vesicular NBCDs with enhanced clinical performance and safety. [ABSTRACT FROM AUTHOR]

Nanosimilars are considered as new medicinal outcomes combining the generic drugs and the nanocarrier as an innovative excipient, in order to evaluate them as final products. They belong to the grey area – concerning the evaluation process – between generic drugs and biosimilar medicinal products. Generic drugs are well documented and a huge number of them are in market, replacing effectively the off-patent drugs. The scientific approach for releasing them to the market is based on bioequivalence studies, which are well documented and accepted by the regulatory agencies. On the other hand, the structural complexity of biological/biotechnology-derived products demands a new approach for the approval process taking into consideration that bioequivalence studies are not considered as sufficient as in generic drugs, and new clinical trials are needed to support their approval process of the product to the market. In proportion, due to technological complexity of nanomedicines, the approaches for proving the statistical identity or the similarity for generic and biosimilar products, respectively, with those of prototypes, are not considered as effective for nanosimilar products. The aim of this note is to propose a complementary approach which can provide realistic evidences concerning the nanosimilarity, based on fractal analysis. This approach is well fit with the structural complexity of nanomedicines and smooths the difficulties for proving the similarity between off-patent and nanosimilar products. Fractal analysis could be considered as the approach that completely characterizes the physicochemical/morphological characteristics of nanosimilar products and could be proposed as a start point for a deep discussion on nanosimilarity. [ABSTRACT FROM AUTHOR]

Nanomedicine is the application of nanotechnology to the discipline of medicine: the use of nanoscale materials for the diagnosis, monitoring, control, prevention, and treatment of disease. Nanomedicine holds tremendous promise to revolutionize medicine across disciplines and specialties, but this promise has yet to be fully realized. Beyond the typical complications associated with drug development, the fundamentally different and novel physical and chemical properties of some nanomaterials compared tomaterials on a larger scale (i.e., their bulk counterparts) can create a unique set of opportunities as well as safety concerns, which have only begun to be explored. As the research community continues to investigate nanomedicines, their efficacy, and the associated safety issues, it is critical to work to close the scientific and regulatory gaps to assure that nanomedicine drives the next generation of biomedical innovation. [ABSTRACT FROM AUTHOR]

The article offers information about the nanomedicines, as the application of nanotechnology to achieve innovation in healthcare. It mentions that nanomedicine ranges from the medical applications of nanomaterials and biological devices, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology such as biological machines.

The article offers information about the complex drugs. It mentions the rise of bio- and nano-technologies has accelerated the development of complex medicines, and at the same time it has revealed new hurdles in regulatory science and accelerating patient access to new therapies. It discusses that complex medicines poses challenges for the development of regulatory guidelines.

Background: Nanopharmaceuticals serve as emerging forms of modern medicines, which include nanomedicines, nanosimilars, nanotheranostics, nanodevices, and many more. In the last two decades, a large number of nano-based products have reached the market and are being used clinically., Objectives: Unlike conventional pharmaceutical products, nanopharmaceuticals behave differently both in vitro and in vivo, and therefore, the development of their generic versions needs special attention to replicate the similar drug release pattern leading to an identical therapeutic outcome. Further, drug-device combinations and 3D products are the latest advancements in precision medicine delivery and development., Methods: The regulatory guidelines for these products are being framed at many stages by various regulatory agencies like USFDA/EMA and still are in infancy at the moment if we look at wider perspectives and applications of nanomedicine., Results: For a formulation scientist, it is much needed that well-explained and directive guidelines should be made available before leading to the development of the generic versions of these nano-cargos., Conclusion: Here, in this review, we have summarized the silent features of the regulatory perspectives related to nanotechnology based next generation therapeutics and diagnostics., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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. [ABSTRACT FROM AUTHOR]

Nanomedicines are highly complex products and are the result of difficult to control manufacturing processes. Nonbiological complex drugs and their biological counterparts can comprise nanoparticles and therefore show nanomedicine characteristics. They consist of not fully known nonhomomolecular structures, and can therefore not be characterized by physicochemical means only. Also, intended copies of nanomedicines (follow-on similars) may have clinically meaningful differences, creating the regulatory challenge of how to grant a high degree of assurance for patients' benefit and safety. As an example, the current regulatory approach for marketing authorization of intended copies of nonbiological complex drugs appears inappropriate; also, a valid strategy incorporating the complexity of such systems is undefined. To demonstrate sufficient similarity and comparability, a stepwise quality, nonclinical and clinical approach is necessary to obtain market authorization for follow-on products as therapeutic alternatives, substitution and/or interchangeable products. To fill the regulatory gap, harmonized and science-based standards are needed.