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Essay: Regulation Review of the Nanomedicine Field: A Monography by Rafaela Oliveira Schouten

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Rafaela Oliveira Schouten

Relatórios de Estágio e Monografia intitulada “Regulation Review of the Nanomedicine Field” referentes à Unidade Curricular “Estágio”, sob orientação, respetivamente, da Dra. Olga Borges apresentados à Faculdade de Farmácia da Universidade de Coimbra, para apreciação na prestação de provas públicas de Mestrado Integrado em Ciências Farmacêuticas.

Setembro 2018

 

Eu, Rafaela Oliveira Schouten, estudante do Mestrado Integrado em Ciências Farmacêuticas, com o nº 2012154602, declaro assumir toda a responsabilidade pelo conteúdo do Documento Relatório de Estágio e Monografia intitulada “Regulation Review of the Nanomedicine Field” apresentados à Faculdade de Farmácia da Universidade de Coimbra, no âmbito da unidade curricular de Estágio Curricular.

Mais declaro que este Documento é um trabalho original e que toda e qualquer afirmação ou expressão, por mim utilizada, está referenciada na Bibliografia, segundo os critérios bibliográficos legalmente estabelecidos, salvaguardando sempre os Direitos de Autor, à exceção das minhas opiniões pessoais.

Coimbra, 1 de setembro de 2018.

________________________________________________

Agradecimentos

Xxxxxxxx

Index

Part 1

“Regulation Review of the Nanomedicine Field” 5

Abbreviation List 6

Resumo 8

Abstract 9

I) Introduction 10

II) Concept Review 13

III) Market Assessment 16

IV) Nanopharmaceuticals: An overview of the current regulatory framework. 18

a. Current EMA and FDA regulations for nanopharmaceutical products 18

b. Decisive factors on the translation from bench to clinic of nanopharmaceuticals and a European Commission Program 22

V) Nanosimilar Products: Identifying the future need for regulatory growth. 25

VI) Conclusion 30

VII) Bibliography 31

ANNEXES 33

1st Part

“Regulation Review of the Nanomedicine Field”

Monography

Abbreviation List

AS – Active Substance

AIDS – immune deficiency syndrome

CHMP – Committee for Human Medicinal Products

CTD – Common Technical Document

EMA – European Medicines Agency

ETPN – European Technology Platform on Nanomedicines

EU – European Union

EUNCL – European Nano-Characterisation Laboratory

FDA – Food and Drug Administration

GMP – Good Manufacturing Practices

HIV – Human immunodeficiency virus

ICH – International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

MA – Marketing authorisation

MAH – Marketing authorisation holder

NBCD – Non-biological complex drugs

NDDSs – Nanoparticle-based drug delivery systems

PC – Physicochemical

PD – Pharmacodynamics

PK – Pharmacokinetics

R&D – Research and Development

RES – Reticuloendothelial system

SME – Small and medium enterprises

TAB – Nanomedicine Translation Advisory Board

Resumo

xxxxx 

Abstract

xxxxxxxx

I) Introduction

Nanomedicine is a translational science that has the goal to provide more effective therapies and diagnostics using the expanding world of Nanotechnology. 1

Broadly, nanomedicine is defined as engineered nanoscale material whose nanostructure offers unique therapeutic properties that can be beneficial for a range of medical indications.2

In the following table there is a compilation of nanomaterial/nanotechnology definitions set by some medicine products authorities.

Table 1- Nanomaterial/nanotechnology definitions set by European Medicines Agency (EMA) 3, Food and Drug Administration (FDA)4 and Health Canada5

European Union FDA (2011) Health Canada

"Nanomaterial means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size EU distribution, one or more external dimensions is in the size range 1–100 nm."

"Nanotechnology is defined as the use of tiny structures – less than 1000 nm across – that are designed to have specific properties".

3

“Considering Whether an FDA Regulated Product Involves the Application of Nanotechnology”, a guidance to help understand if the product in development falls in the nanomedicine category with questions, like:  

“–Whether an engineered material or end product has at least one dimension in the nanoscale range (approximately 1 nm to 100 nm); or

–Whether an engineered material or end product exhibits properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometre.” 4

“Any manufactured substance or product and any component material, ingredient, device, or structure if:

a. It is at or within the nanoscale in at least one external dimension, or has internal or surface structure at the nanoscale, or;

b. It is smaller or larger than the nanoscale in all dimensions and exhibits one or more nanoscale properties/phenomena 5 *

*

i. The term “nanoscale” means 1 to 100 nanometres, inclusive;

ii. The term “nanoscale properties/phenomena” means properties which are attributable to size and their effects; these properties are distinguishable from the chemical or physical properties of individual atoms, individual molecules and bulk material; and,

iii. The term “manufactured” includes engineering processes and the control of matter.” 5

As it is a newly evolving science it’s not necessary to have a perfect definition for nanomedicine, as it may become too restrictive. However, it is important to develop at least a common working description with the purpose of classifying medicinal products, medical devices and other materials traversing through different fields into a defined class to properly account for their characterisation, toxicity and environmental risk assessment.

Nanomedicines include nanopharmaceuticals (intended for drug delivery), nanodiagnostics (used for imaging and diagnostics), nanotheranostics (combined therapeutic and diagnostic), and nanobiomaterials (medical implants). 2

Nanopharmaceuticals represent 75% of the actual nanomedicines market. 2

Despite the advances in academic research, the clinical translation of next-generation nanopharmaceuticals remains challenging, particularly from the manufacturing and regulatory perspectives. The dimensions and structural complexity of nanopharmaceuticals require specific characterization and analytics. The knowledge of the critical proprieties and steps of their production is of extreme importance to archive a robust manufacturing process that leads to the production of high-quality, safe, and effective products.6

Nanotherapeutic products are currently regulated within a conventional regulatory framework. However, additional expert evaluations are necessary to confirm the quality, safety, and efficacy of nanotherapeutics because of their complexity.7

The final goal of the research and development of a nanotherapeutic product is its successful translation from bench to clinic. However, there are significant obstacles and challenges in bringing nanotherapeutic products to the market, including the lack of quality control; separation from undesired nanostructures; scalability issues; enhancing the production rate; reproducibility from batch to batch; high fabrication costs; lack of knowledge regarding the interaction between nanosystems and living cells; nanotherapeutic optimization for maximum therapeutic potential; relative scarcity of venture funds; the pharmaceutical industry’s reluctance to invest in nanotherapeutics; relative unpredictability of the EMA with respect to a lack of regulatory and safety guidelines pertaining to nanotherapeutics; and the media focus on the negative aspects of nanomaterials, often without clear scientific evidence.41 7

To reach this goal the process of translating research from academic labs to the industry and clinic has to be greatly improved. 1

When nanopharmaceutical products are mentioned in this paper, they concern traditional pharmaceutical substances (active substances – AS) that are design with delivery systems based on nanoparticles/nanomaterials, in other words nanoparticle-based drug delivery systems (NDDSs). This paper does not refer to nanoparticles that have intrinsic pharmaceutical proprieties.

In this review I will focus on the nanopharmaceutical sector, identifying the current regulations available and regulatory needs, which represent the main difficulties during the translation process from lab to industry.

II) Concept Review

In the past few decades, there has been explosive growth in the construction of nanoparticle-based drug delivery systems (NDDSs), namely nanomedicines, owing to their unique properties compared with traditional drug formulations. They offer drug design benefits that can include:

• Prolonged accumulation with passive/active targeting;

• Enhanced penetration in target tissue:

• Prolonged plasma circulation time;

• Increased uptake;

• Controllable release into the cytoplasm;

• Overcome of drug resistance;

• Minimised aggregation and improved stability;

• Improved haemato-compatibility and limit antigenicity;

• Although irrelevant for this paper, the intrinsic therapeutic effects of pure nanoparticles can be regarded as a new therapeutic strategy. 8 9 10 11 12

No medicinal product may be placed on the market of a European Member State unless a marketing authorisation (MA) has been issued by the member state’s or the European union’s competent authority. 13

For its submission there are different processes that are chosen for different situations.

If the medicinal product is only to be available in one Member State market then the MA can be applied by the national procedure through the competent authorities of that Member State.14

In cases where national authorisations are requested for the same medicinal product in more than one Member State and the marketing authorisation holder (MAH) has received a MA in one of them, the applicant/MAH must submit an application in the Member State concerned using the procedure of mutual recognition.14

If no MA has been granted in the European Union (EU), the applicant may make use of a decentralised procedure and submit an application in all the member states where it intends to obtain a MA at the same time, and choose one of them as reference member state. 15

A MA granted under the centralised procedure is valid for the entire EU market, which means the medicinal product may be put on the market in all member states. 14

The centralised procedure is compulsory for:

• Human medicines containing a new active substance to treat: human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions and viral diseases.

• Medicines derived from biotechnology processes;

• Advanced-therapy medicines;

• Orphan medicines; 16

It is optional for other medicines:

• Containing new active substances for indications other than those stated above;

• That are a significant therapeutic, scientific or technical innovation;

• Whose authorisation would be in the interest of public or animal health at EU level.16

Today, the great majority of new, innovative medicines pass through the centralised authorisation procedure in order to be marketed in the EU.16

As NDDSs are still considered innovative products the applicant has the liberty to choose if they submit the MA through the centralised procedure or not

The application data is required to be submitted in the format of Common Technical Document (CTD). The CTD is an internationally agreed format for the preparation of applications to be submitted to regulatory authorities in the three International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) regions of Europe, USA and Japan. It is intended to save time and resources and to facilitate regulatory review and communication.17

The information regarding quality, nonclinical and clinical study results are included in the CTD file.17

The data has included in the CTD file has to be in accordance to the ICH guidelines.

In this review translational science is mentioned as way to better de odds of being successful in achieving approval from the Regulatory Authorities.

The term translational is usually applied as an attempt to bridge a supposed gap between knowledge produced at the lab bench and its use at the clinical bedside. The process requires a collaboration among researchers, clinicians, and pharmaceutical companies conducting clinical trials.

III) Market Assessment

The global market of nanopharmaceuticals was valued by the BCC Research firm at $209 billion in 2014 and is anticipated to expand to $412 billion by 2019. The market share of nanopharmaceuticals represented 15% of the total pharmaceutical market in 2014 and is predicted to increase to 22% in 2019. 2

Despite all difficulties along the development process, a considerable number of nanomedicines are already in the market, approved by the EMA, FDA or a foreign equivalent.18

Also, expected commercialization of products currently in clinical trials is anticipated to drive market growth. Specifically, due to the new generation of NDDSs that includes the delivery of biotherapeutics, polymeric formulations, targeted nanocarriers, and metal-based nanoparticles acting as therapeutic agents under an external stimulus.6

The development of generics of nanoparticle-based drug delivery systems, the so called nanosimilars, is emerging and is anticipated to also contribute significantly to the nanopharmaceutical market growth.6

Geographically, the nanopharmaceutical market is dominant in the USA (35% of the worldwide market share), in Asia (25%), and Europe (25%). 19

Across the world, more than 200 companies are developing nanopharmaceuticals and approximately three quarters of them are start-ups or small and medium enterprises (SME). 20

Doxil was the first nanoscale drug carrier to reach the market in the United States, gaining FDA approval only five years after its development was first reported.21

After 20 years from its approval, it continues to be extensively used and constitutes the pattern of injectable nanopharmaceuticals products and drug delivery systems

Doxil has been used for the treatment of Kaposi sarcoma in HIV patients, ovarian cancer treatment, metastatic breast cancer and multiple myeloma. 22

In Europe, the first approved nanomedicine was AmBisomes, which is based in amphotericin B-loaded liposomes for systemic fungal infections. 22

While there is a large opportunity for future growth, the nanopharmaceutical market is already well-established for several therapeutic indications, the oncology sector being the dominant one, representing approximately 35% of the global market.2

Other important indications are the central nervous system, infections, inflammatory diseases, and cardiovascular diseases. 2

Nowadays, 40% of the nanomedicines in the market are based on protein-polymer conjugates and liposomal formulations.23

Nevertheless, other lipid-based delivery systems are approved such as lipid nanoparticles and nanoemulsions, initially developed for parenteral nutrition.6

In Annex A, table 5 can be consulted for additional data about some of the approved products, the table is a replica of the one that can be found in the revision paper: “Regulatory aspects on nanomedicines”.24

IV) Nanopharmaceuticals: An overview of the current regulatory framework.

a. Current EMA and FDA regulations for nanopharmaceutical products

Identifying the regulatory gap in the area of nanomedicines, EMA and FDA, started to develop some reflection papers that aimed to help nanomedicine product developers to be successful in the approval of the regulatory authorities.

EMA released three reflection papers in 2013, and another one in 2015 through the Committee for Human Medicinal Products (CHMP). Two of them consider important parameters to include in the application of MA for nanoparticle-based drug delivery systems and the other two for nanosimilar products, discussed in chapter 6 of this paper. 9–12. As for FDA, they released a guideline in April 2018. 25

Table 2 – Regulation papers released by the medicinal product authorities.

Release Name

EMA 02/2013 Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product Nanosimilar

EMA 05/2013 Reflection paper on surface coatings: general issues for consideration regarding parenteral administration of coated nanomedicine products Innovator

EMA 12/2013 Joint MHLW*/EMA reflection paper on the development of block copolymer micelle medicinal products Innovator

EMA 03/2015 Reflection paper on the data requirements for intravenous iron-based nano-colloidal products developed with reference to an innovator medicinal product Nanosimilar

FDA 04/2018 Liposome Drug Products Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation: Guidance for Industry Innovator

* MHLW- Ministry of Health, Labour and Welfare (Japan)

Although both EMA and FDA have released papers regarding liposomal products, they are quite different. For once, EMA’s paper is for products developed with a reference to an already existing product, in other words for a nanosimilar liposomal product. And the FDA’s guideline is meant for innovative liposomal products and includes some advice on the labelling of the liposomal products.11 25

In these papers, authorities have defined relevant information related to the nanospecific properties of the medicinal products, which can have an impact on the quality, safety and efficacy.

All of these documents are intended to assist in the generation of relevant quality, non-clinical and clinical data to support a MA and are to be complemented with the information of the appropriate ICH Guidelines when used by product developers.

In contrast to small molecules, these type of medicinal product require additional attention regarding their 26:

 the physicochemical (PC) characteristics;

 the particle interaction with the innate immune system, which influences the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of the drug.

In table 3, there is a compilation of the nanomedicine specific parameters that the medicinal product authorities have included in their papers. These parameters stand out as being the new parameters introduced by regulatory authorities that will help product developers identify critical essays, controls and methods important to these new NDDSs.

Table 3  – Relevant parameters to include in the NDDSs MA applicantion 9,10,25

Parameters regarding Pharmaceutical Quality  Characterization of the nanoparticle’s proprieties;

 Proprieties of the nanomaterial’s manufacturing process and in vivo behaviour

 Validation of the inclusion of the nanoparticle step and its critical attributes

 The nanoparticle potential impact of nanoparticle inclusion heterogeneity on the safety and efficacy of the product

 The nanoparticle potential to have biological activity, its potency and PC proprieties

 Stability of the nanoparticle, the AS and the nanoparticle-AS product

 Identification and control of key intermediates in the manufacturing process.

Parameters regarding Non-Clinical Studies PK

 Cmax*, half-life and AUC* for the total AS and for free AS in blood, plasma or serum measured at different dose levels and appropriate time points

 Distribution of the nanoparticle in organs/tissues

 Compare the PK of the nanoparticle-AS products and the AS administered by itself

 Proteins and cellular interactions with the nanoparticle-AS product administered intravenously

 The nanoparticle’s potential to detach/separate and its degradability, and the potential efficacy and safety consequences of premature detachment or degradation of the nanomaterial

 In vitro determination of the PC stability of the nanoparticle in respect of proposed use

 Bio-distribution of the released nanoparticle and its metabolic fate

 Metabolic and excretion pathway of the nanoparticle constituents and their detailed characterisation

 Study of the possibility that the nanoparticle can cause drug-drug interactions

 In vivo impact of different nanoparticle material on PK and bio-distribution should be considered

PD

 The appropriateness of the pharmacological model should be discussed in respect of the PK of the nanoparticle.

A point to consider: the fate of the AS and of the nanoparticle following administration and cellular entry by endocytosis or other mechanisms.

Parameters regarding Clinical studies  Cmax*, half-life and AUC* for the total AS and for free AS in blood, plasma or serum measured at different dose levels and appropriate time points

 Distribution of the nanoparticle in target lesion/organs/tissues

Other parameters Discuss with the regulators as additional testing may be needed

* Cmax – Maximum plasma concentration

   AUC –  area under curve

b. Decisive factors on the translation from bench to clinic of nanopharmaceuticals and a European Commission Program

To achieve a successful translation to the industry implementation of an improved knowledge and communication between academics, SME, and especially large industry is necessary. Relevant academic departments and individual researchers involved in healthcare should develop an industrial liaison policy to improve their global competitiveness and knowledge.

The understanding of the pharmacology, metabolism, pharmacokinetics, immunology and toxicology of all nanomedicines is an absolute prerequisite.

Some ideas and recommendations are given below as on how the various stakeholders could be able to improve their impact 1, 27:

Table 4 – Recommendations that will lead to improvement of the translational process

Public Authorities

 Improve industrial peer review of applied research proposals;

 Where possible give a tranche of money to universities and ask them to invest it in their research as a portfolio. There would then be an incentive to choose and fund the best projects;

 Request assessment of safety, healthcare impact and industrial relevance in research proposals;

 Strengthen IP protection issues by implementing policies and guidelines that facilitate the interests of both industrial and research partners.

Industry

 Increase the efficiency of industrial contacts with universities;

 Increase involvement of industrialists with the activities of major research departments;

 Promote a higher number of sabbaticals at academic research organisations;

 Create “reverse symposia” on what industry needs or what they are unaware of;

 Provide detailed sources of information on industrial priorities;

 Share specialised industry technologies and expertise;

 Speed up decision making by increasing contact with patients or patient groups.

Academia

 Change the academic culture towards encouraging and rewarding real innovation and entrepreneurship in Europe,

 Involve experienced recently retired industrial experts in evaluation;

 Require both industrial liaison policy and industrial liaison offices as prerequisites to participate in funded programmes;

 Plug in to industry news-flows using widely available internet websites;

 Understand the implications of the “Open Innovation” concept;

 Train academics with an understanding of drug discovery.

Before starting on expensive applied research, it is essential that the safety information, formally acquired in phase one, is seriously considered at the outset and also be certain that analytical methods exist to detect nanomedicine components in vivo or ex vivo. 1

With the intention of supporting SME in the process of getting their product approve several Translational Programs have emerged.

In order to fully exploit the potential of nanomedicines, the European Technology Platform on Nanomedicines (ETPN) as a main structural action introduced a Translation Hub, in 2015, comprised of a set of complementary actions/initiatives such as 28:

– Nanomedicine Translation Advisory Board (TAB), with experienced industrial experts, who will apply horizontal innovation filters on R&D proposals from academics and SMEs to select, guide and push forward the best translatable concepts28;

– European Nano-Characterisation Laboratory (EUNCL) for physical, chemical and biological characterisation of nanomaterials intended for medical use28;

– NanoPilot: Good Manufacturing Practices (GMP) manufacturing pilot lines for clinical batches, which will both assist academic groups and especially SMEs to develop their nanomedical materials for validation in clinical trials, before transfer to Chief marketing officer (CMOs)28;

– NanoFacturing: The objectives of the project consist of scaling up an existing GMP pilot line to a medium-scale sustainable manufacturing process for solid core nanopharmaceuticals and create a large scale process platform that would serve as the basis for GMP compliant industrial manufacture and that will be available as a model for other European companies wishing to develop their own products. 28

– MACIVIVA will pave the path to other large scale thermostable nanopharmaceuticals products for therapeutic and prophylactic vaccines and other potential applications for direct application by non-invasive routes. 28

– a strong link with existing European clinical networks or organisations to help transfer and provide efficient early clinical trials in nanomedicine. 28

After two years of operation, the project has proven its relevance. It has contributed to the development of several start-ups and SMEs on different aspects of their paths to market. The Nanomed Translation Hub is definitely a new approach with tailored services targeted to nanomed start-ups and SMEs.28

V) Nanosimilar Products: Identifying the future need for regulatory growth.

Beyond the development of nanomedicines, the nanopharmaceutical market is already facing the arrival of nanosimilar products.

Nanosimilar or follow-on NDDSs products are similar to an innovator product for which the patent has expired, and they pose an additional upcoming challenge for the regulation of nanomedicines. 27

Their development is necessary to avoid product shortage as well as to make treatment available and more affordable to a larger patient population. 6

Currently, there are only a few nanosimilars requests for MA.27

Aware of the challenges raised by the emergence of generics of new classes of therapeutics the regulatory agencies have elaborated a nomenclature for follow-on versions of non-biological complex drugs (NBCD). Nanoparticle-based drug delivery systems (NBDDSs) fall into the last category of NBCD that are defined as29 30:

– consisting of a complex multitude of closely related structures, the entire multitude is the active pharmaceutical ingredient;

– properties cannot be fully characterized by physicochemical analysis;

– consistent, tightly controlled manufacturing process is fundamental to reproduce the product.

FDA and EMA recognized that nanosimilars needed a case-by-case evaluation due to the complexity of the products, and that safety of nanomedicines may be different from traditional medicines. So they began to release papers on the subject. There are 2 reflection papers by EMA, the first one was release in 2013: “Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product” and the last one in 2015: “Reflection paper on the data requirements for intravenous iron-based nano-colloidal products developed with reference to an innovator medicinal product”.31

The paradigms for abbreviated MA are no longer accepted for complex products and the notion of similarity prevails over equivalence. A crucial question for the developers of generic nanomedicines is how to develop adequate manufacturing and controls to comply with the original product specifications. On the regulatory side: how do we define critical quality attributes for each type of approved nanoparticle-based drug delivery systems in order to develop a regulatory frame to ensure that nanosimilars meet the specifications? 6

Some examples of failed MA applications of nanosimilar products include:

– "Doxorubicin SUN": the nanosimilar drug was accepted as a generic drug of the reference product "Doxil" in the US and when presented in Europe as a generic liposomal formulation of doxorubicin referring to the European innovator product Caelyx®, the assessment report on "Doxorubicin SUN" of the CMPH recommended that: "… is not approvable since there are outstanding major non-clinical and clinical objections which preclude a recommendation for marketing authorisation at the present time …” – Therefore, the product was not recommended to be authorised for the European Market due to major non-clinical and clinical objections. 27

– One claimed copy of Abraxane presented toxicity issues on account of high endotoxin levels and residual solvent. In a different case, the formulation did not meet the requirements of size distribution and stability, impacting the therapeutic efficacy of the product. 6

Since a thorough characterization of the product and a stable manufacturing procedure are crucial for therapeutic performance, production facilities for nanosimilars require the same level of analytical equipment, state-of-the-art manufacturing tools, as well as highly-trained personnel. In the case where additional preclinical and/or extended clinical studies are required, the cost of development would be significantly increased, potentially impacting the final cost of the nanosimilar. 6

Differences between the applicant´s product and innovator product with regard to manufacturing process steps and formulation may not be detectable by conventional bioequivalence testing alone.11,12

Pharmaceutical comparability between the applicant’s product and the innovator product should be established before progressing to non-clinical investigations. Due to the complexity of the nanoparticles, establishing pharmaceutical comparability to the reference product alone cannot replace the need for non-clinical and/or clinical data but may justify reduction in the amount of such studies. The extend and complexity of clinical and non-clinical studies should be driven by the results of the comparability work each stage. 11,12

The complexity of the nanoparticle will determine whether comparative non-clinical studies could be reduced and if appropriate, it may be decided on a case-by-case basis which studies could be waived. 11,12

In table 5, there is a compilation of the nanosimilar specific parameters that the medicinal product authorities have included in their papers. These parameters stand out as being the new parameters introduced by regulatory authorities that will help product developers identify critical essays, controls and methods important to these arriving new products.

Table 5 – Relevant parameters to include in a nanosimilar MA application 11,12

Nanosimilar exclusively Nanosimilar and nano-innovator

Parameters regarding Pharmaceutical Quality  Nanoparticle size and size distribution;

 Nanoparticle and AS morphology/polymorphism, when applicable;

 Surface properties of the nanoparticle-AS complexes

 AS/nanoparticle moiety ratio at relevant manufacturing steps;

 In vitro drug substance release rate in physiologically/clinically relevant media.

 Degradation products of the nanoparticle-AS complex

 Determine safety of intravenous preparations.  Characterization of the nanoparticle’s proprieties;

 Stability of the nanoparticle, the AS and the nanoparticle-AS product

 Identification and control of key intermediates in the manufacturing process.

Comments:

 Determine labile AS in vitro as means to demonstrate similarity, to provide reassurance to batch release and to determine the effect of changes in production processes – this process will lead to assurance of the In-use stability

Parameters regarding Non-Clinical Studies Nanosimilar exclusively

PK

 AS rate release;

 Uptake;

 Distribution, accumulation and retention in at least 3 compartments, (plasma, RES and target tissues/organs). – These studies should provide pivotal evidence of the comparability of the in vivo disposition of nanoparticle-AS products. As sampling in serum alone is insufficient to determine bioequivalence between an originator and a follow-on product

PD

No additional studies/data required than those of the innovator product.

Comments:

 Measurement of the time-dependent overall AS content in different tissues may be sufficient to reflect the degradation profile of the nanoparticle.

Parameters regarding Clinical studies Nanosimilar exclusively Nanosimilar and nano-innovator

 Comparative human studies should demonstrate similarity of exposure of the total, nanoparticle-AS and free AS and demonstrate similar distribution and elimination characteristics

   PK studies: Cmax, half-life and AUC for the total AS and for free AS in blood, plasma or serum measured at different dose levels and appropriate time points

 Distribution of the nanoparticle in target lesion/organs/tissues

For clinical studies: Single dose parallel or crossover study design and baseline correction is recommended to decrease inter-individual variability.

Efficacy and safety studies: Provided that the totality of data demonstrates comparable efficacy and safety it is generally not necessary to perform these studies, otherwise, a therapeutic equivalence study might be necessary to address their impact on efficacy and safety;

When considering a clinical trial to address differences, the applicant is strongly advised to seek advice for the choice of end points and study design.

Other parameters  Nanosimilar exclusively

Qualitative and quantitative composition of the developed product should be identical or closely match the reference product:

 to minimize the possibility of increased frequency of acute infusion reactions, use in vitro and in vivo immune reactogenicity assays (CARPA)

 infusion reactions should be carefully evaluated in bioequivalence studies

In addition to the manufacturing challenges, and contrary to small molecules, the notion of interchangeability of the nanosimilar with the reference product does not exist, since the product is similar but not the same. When we look more closely at the companies involved in the nanosimilar sector (like, TCL, Azaya, Allergan), it is observed that they are developing this activity in parallel to their own proprietary nanoparticle-based products, maximizing in this way their R&D and manufacturing capacities and knowledge. The development of nanosimilar R&D as a distinct branch of the company can be a strategy to drive long-term growth.6

VI) Conclusion

VII) Bibliography

1. EUROPEAN COMMISSION/ETP NANOMEDICINE EXPERT REPORT. Roadmaps in Nanomedicine Towards 2020. in (2009). 58

2. BBC RESEARCH. Nanotechnology in Medical Applications: The Global Market. (2015) Available at: https://www.bccresearch.com/market-research/healthcare/nanotechnology-medical-applications-market-hlc069c.html. (Accessed: 5th April 2018)

3. CHMP. Reflection paper on Nanotechnology-Based Medicinal Products for Human use. (2006).

4. FOOD AND DRUG ADMINISTRATION – COMMISSIONER. Guidance for Industry Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. (2014) 14

5. HEALTH CANADA. Policy Statement on Health Canada’s Working Definition for Nanomaterial. (2011) Available at: https://www.canada.ca/en/health-canada/services/science-research/reports-publications/nanomaterial/policy-statement-health-canada-working-definition.html. (Accessed: 23rd May 2018)

6. RAGELLE, H., DANHIER, F., PRÉAT, V., LANGER, R. & ANDERSON, D. G. Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures. Expert Opin. Drug Deliv. 14, (2017) 851–864

7. HAFNER, A., LOVRIC, J., LAKOS, G. P. & PEPIC, I. Nanotherapeutics in the EU: an overview on current state and future directions. Int. J. Nanomedicine 9, (2014) 1005–23

8. WANG, Y., LIU, L., XUE, X. & LIANG, X.-J. Nanoparticle-based drug delivery systems: What can they really do in vivo? F1000Research 6, (2017) 681

9. EUROPEAN MEDICINES AGENCY – CHMP. Reflection paper on surface coatings: general issues for consideration regarding parenteral administration of coated nanomedicine products. (2013).

10. EUROPEAN MEDICINES AGENCY – CHMP /MINISTRY OF HEALTH LABOUR AND WELFARE (JAPAN). Reflection paper on the development of block copolymer micelle medicinal products. (2013).

11. EUROPEAN MEDICINES AGENCY – CHMP. Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal products. (2013).

12. EUROPEAN MEDICINES AGENCY – CHMP. Reflection paper on the data requirements for intravenous iron-based nano-colloidal products developed with reference to an innovator medicinal product. (2015).

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ANNEXES

ANNEX A – From Market Assessment chapter

Table 6 – Replica of the table in the article “Regulatory aspects on nanomedicines”, describing  somenanomedicine products that are available.

Tradename Nanoplatform and active agent Application Approval (date) Company

Abelcet® Lipid-based non-Liposomal nanoformulation (Amphotericin B) Systemic fungal infections when amphotericin B is not recommended FDA – 1995 Sigma-Tau, Cephalon, Enzon, Elan/Alkermes

Abraxane® Polymeric nanoformulation (Paclitaxel) Metastatic breast cancer, non-small-cell lung CANCER FDA – 2005

EMA – 2008 Abraxis BioScience, AstraZeneca, Celgene

Adagen® PEGylated adenosine deaminase Severe combined immunodeficiency disease FDA FDA – 1990 Sigma-Tau, Enzon

AmBisome® Liposome (Amphotericin B) Fungal infections FDA – 1997

EMA – 1990 Astellas/Gilead

Amphotec® Lipid-based non-liposomal nanoformulation (Amphotericin B) Invasive aspergillosis when amphotericin B is not recommended FDA – 1996 Alkopharma, Three Rivers/Alza

Avinza® Nanocrystal (Morphine sulfate) Moderate/severe pain FDA – 2002 Elan/Alkermes, Pfize

Cimzia® PEGylated antibody (Certolizumab pegol) Crohn's disease, rheumatoid arthritis, psoriaticCrohn's disease, rheumatoid arthritis, psoriatic FDA – 2008 UCB

Copaxone® Polymeric nanoformulation (Glatiramer acetate) Multiple sclerosis

FDA – 1996 Teva

Curosurf® Liposome (Poractant alfa) Respiratory Distress Syndrome (RDS) in premature infants FDA – 1999 Chiesi

DaunoXome® Liposome (Daunorubicin citrate) HIV-related Kaposi's sarcoma FDA – 1996 NeXstar, Gilead Sciences, Galen, Teva

Definity® Liposome (Perflutren) Contrast agent FDA – 2001 Lantheus, Bristol Myers, Squibb

DepoCyt(e) Liposome (Cytarabine) Lymphomatous malignant meningites FDA – 1999

EMA – 2001 Pacira, Sigma-Tau, Skye/Enzon

DepoDur® Liposome (Morphine sulfate) Chronic pain FDA- 2004 Pacira,

Diprivan® Surfactant-based nanoformulation (Propofol) Anesthetic Anesthetic FDA – 1989 Fresenius Kabi, AstraZeneca

Doxil®/Caelyx® Liposome (Doxorubicin hydrochloride) HIV-related Kaposi's sarcoma, ovarian cancer, myeloma, breast cancer FDA – 1995

EMA – 1996 Centocor Ortho Biotech, Janssen

Elestrin® Surfactant-based nanoformulation (Estradiol) Hot flashes during menopause FDA – 2006 Meda, BioSante

Eligard® Polymeric nanoformulation (Leuprolide acetate) Advanced prostate cancer FDA – 2002

Atrix, Tolmar

Emend® Nanocrystal (Aprepitant) Emesis, antiemetic for chemotherapy patients FDA – 2003

EMA – 2003 Merck, Elan Corp

Estrasorb® Surfactant-based nanoformulation (Estradiol hemihydrate) Reduction of vasomotor symptoms during menopause FDA – 2003 Medicis, Novavax/Espirit, Graceway

Feraheme® Metal nanoformulation (Ferumoxytol) Treatment of iron deficiency anemia in adults with chronic kidney disease FDA – 2009 AMAG

Ferrlecit® Metal nanoformulation (Sodium ferric gluconate complex) Iron deficiency anemia FDA – 1999 Sanofi-Aventi

Focalin XR® Nanocrystal (Dexmethylphenidate hydrochloride) Attention deficit hyperactivity disorder FDA – 2005 Novartis/Alkermes

Fosrenol® Metal nanoformulation (Lanthanum carbonate) Fungizones End stage renal disease FDA – 2004 Novartis / Alkermes

Fungizone® Surfactant nanoformulation (Amphotericin B) Systemic fungal infections FDA – 1966 Bristol-Myers Squibb, Apothecon

Invega® Nanocrystal (Paliperidone) Schizophrenia FDA – 2006

EMA – 2007 Janssen

Kadcyla® Protein- grug conjugate (Ado-Trastuzumab Emtansine) Metastatic breast cancer FDA – 2013 Genentech

Macugen® PEGylated anti-VEGF aptamer (Pegaptanib sodium) Neovascular age-related macular degeneration FDA – 2004

EMA – 2006 OSI/Pfizer, Valeant

Marqibo® Liposome (Vincristine sulfate) Philadelphia chromosome and acute lymphoblastic leukemia FDA – 2012 Talon Therapeutics

Megace ES® Nanocrystal (Naproxene sodium) Anorexia, cachexia, breast and endometrial cancer FDA – 2005 Par

Mepact® Liposome (Mifamurtide) Osteosarcoma EMA – 2009 Takeda

Mircera® PEGylated epoetin beta (Methoxy plyethylene glycol-epoetin beta Anemia associated with chronic renal failure FDA – 2007

EMA – 2007 Hoffman–La Roche

Myocet® Liposome (Doxorubicin Metastatic breast cancer EMA – 2000 Cephalon/Zeneus, Elan, Sopherion Therapeutics

Naprelan® Nanocrystal (Naproxen sodium) Rheumatoid arthritis and osteoarthritis, gout FDA – 1996 Almatica, Elan/Alkermes, Wyeth

Neulasta® PEGylated filgrastim Febrile neutropenia FDA – 2002

EMA – 2002 Amgen

Oncaspar® PEGylated L-asparaginase Lymphoblastic leukemia FDA – 1994

Enzon/Schering-Plough, Sigma-Tau

Ontak® Protein-drug conjugate (Denileukin diftitox) Persistent or recurrent cutaneous T-cell lymphoma FDA – 1999 Eisai

Pegasys® PEGylated interferon alfa-2b Hepatitis B and C FDA – 2002

EMA – 2002 Hoffmann-La Roche/Nektar Genentech

PegIntron® PEGylated interferon alfa-2b Hepatitis C in patients with compensated liver disease FDA – 2001

EMA – 2000 Schering-Plough

Merck

Rapamune® Nanocrystal (Sirolimus) Immunosuppressant (kidney transplants) FDA – 2002

EMA – 2001 Wyeth/Alkermes, Elan, Pfizer

Renagel® Polymeric nanoformulation (Sevelamer hydrochloride) Hyperphosphatemia in patients with chronic kidney disease on dialysis FDA – 2000

EMA – 2000 Genzyme

Ritalin LA® Nonocrystal (Methylphenidate hydrochloride) Attention deficit hyperactivity disorder FDA – 2002 Novartis

Somavert® PEGylated human growth hormone receptor agonist (Pegvisomant) Acromegaly FDA – 2003

EMA – 2002 Pharmacia and Upjohn,Nektar, Pfizer

Survanta® Liposome (Beractant) Neonatal respiratory distress in premature infants FDA – 1991 Abbot, Abbvie

Tricor® Nanocrystal (Fenofibrate) Dislipidemias FDA – 2004 Abbot, Abbvie

Triglide® Nanocrystal (Fenofibrate) Dislipidemias FDA – 2005 Skye, First Horizon, Sciele

Venofer® Metal nanoformulation (Iron sucrose (iron (III)-hydroxide sucrose complex) Iron deficienc FDA – 2000 Luitpold, Vifor France

Verelan PM® Multiparticulate system (Verapamil) Hypertension FDA – 1998 Elan/Alkermes

Verelan® Multiparticulate system (Verapamil) Hypertension FDA – 1990 Elan/Alkermes

Visudyne® Liposome (Verteporfin) Photodynamic therapy FDA – 2000 Valeant, QLT Ophtalmics

Zevalin® Antibody-targeted nanoparticle (Ibritumomab tiuxetan) Lymphoma, follicular FDA – 2002

EMA – 2004 Spectrum

Zyprexa® Nanocrystal (Olanzapine) Schizophrenia FDA – 2009 Lilly

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