Biochemical and Biophysical Research Communications 468 (2015) 504–510

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Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc

Review

Regulatory aspects on nanomedicines Vanessa Sainz 1, Joa~ o Conniot 1, Ana I. Matos, Carina Peres, Eva Zupančič, Liane Moura, Liana C. Silva, Helena F. Florindo, Rogério S. Gaspar n Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal

art ic l e i nf o

a b s t r a c t

Article history: Received 3 August 2015 Accepted 5 August 2015 Available online 8 August 2015

Nanomedicines have been in the forefront of pharmaceutical research in the last decades, creating new challenges for research community, industry, and regulators. There is a strong demand for the fast development of scientific and technological tools to address unmet medical needs, thus improving human health care and life quality. Tremendous advances in the biomaterials and nanotechnology fields have prompted their use as promising tools to overcome important drawbacks, mostly associated to the non-specific effects of conventional therapeutic approaches. However, the wide range of application of nanomedicines demands a profound knowledge and characterization of these complex products. Their properties need to be extensively understood to avoid unpredicted effects on patients, such as potential immune reactivity. Research policy and alliances have been bringing together scientists, regulators, industry, and, more frequently in recent years, patient representatives and patient advocacy institutions. In order to successfully enhance the development of new technologies, improved strategies for research-based corporate organizations, more integrated research tools dealing with appropriate translational requirements aiming at clinical development, and proactive regulatory policies are essential in the near future. This review focuses on the most important aspects currently recognized as key factors for the regulation of nanomedicines, discussing the efforts under development by industry and regulatory agencies to promote their translation into the market. Regulatory Science aspects driving a faster and safer development of nanomedicines will be a central issue for the next years. & 2015 Elsevier Inc. All rights reserved.

Keywords: Nanotechnology Regulatory sciences Nanomedicine Biocompatibility ``Quality-by-design'' Manufacturing

Contents 1. Opportunities and challenges of nanotechnology . . . . . . . . . . . . . . 2. Regulatory perspective on the development of nanomedicines . . . 3. Nanomedicines in the market. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Regulatory development for ``next-generation'' of nanomedicines . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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504 505 506 508 509 509 510

1. Opportunities and challenges of nanotechnology

n Corresponding author. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. E-mail address: [email protected] (R.S. Gaspar). 1 Equally contributing authors.

http://dx.doi.org/10.1016/j.bbrc.2015.08.023 0006-291X/& 2015 Elsevier Inc. All rights reserved.

Nanotechnology has been largely explored over the last two decades, emerging as a ``new technological revolution''. The field provides a multitude of possibilities across several traditional research areas, such as physics, chemistry, engineering, biotechnology, and especially in health sciences and biomedicine allowing for integrated platforms focused on solutions for unmet challenges [1–4]. In these areas, nanotechnology is gaining special

V. Sainz et al. / Biochemical and Biophysical Research Communications 468 (2015) 504–510

importance as a strategy to solve in an appropriate manner significant challenges dealing with improved and precision medicine, reduced toxicity and solving previously unmet clinical needs. Important engineered nanodevices and nanomedicines at the atomic, molecular and macromolecular nanoscaled level have been designed and developed in the last decades. The broad field of nanomedicines, which encompasses nanopharmaceuticals, nanoimaging agents and theranostics [5], have led to an improvement of innovation in disease diagnosis and imaging [6,7], prevention and treatment [8]. Both the nanoscale size and the high surface area make these systems adequate platforms to access target locals in the human body and to interact within tissues and cells in a highly specific manner [2–4]. The development of innovative nanomedicines has shown potential impact in global healthcare. More sophisticated and effective nanomedicines such as polymer-conjugates, liposomes and nanoparticles (NPs) has also resulted from increased funding and successful integration of multidisciplinary technologies, both within industry and within academia but also looking at integrated consortia [5]. These have led to a great diversity of strategies, mainly justified by: (i) the versatility of manufacturing processes and materials (i.e., the modification of their surface to overcome formulation stability concerns and/or to include target specific molecules to cell membranes or even intracellular organelles); (ii) their size scale, making it possible to overcome some important physiological barriers, and thus attaining release of the therapeutic drug at the desired target; (iii) the ability to entrap considerable amounts of pharmaceutical active molecules of different nature protecting them from aggressive environment, as well as attaining and targeting specific cells, not only is able to lead to higher therapeutic levels with use of lower therapeutic doses, but also to a significant reduction of pharmacological side effects by avoiding reduced systemic amounts of drugs and reducing their non-specific release from transport systems [5,9–11]. Despite a strong demand for fostering these nanomedicines, their particular properties have raised important challenges for industry and regulatory agencies [12,13]. In fact, there has been a general lack of specific protocols to characterize these nanomedicines at physicochemical, biological and physiological levels, which in a number of cases might have been responsible for their fail in late clinical trial stages. As a consequence, the regulatory environment for those innovative nanomedicines has been increasingly challenged by key issues, which is an opportunity to provide clearer guidance for their development [14].

2. Regulatory perspective on the development of nanomedicines Although a significant number of approved nanomedicines for biomedical applications has appeared in the last decades, the lack of specific general protocols for preclinical development and characterization of these products has hampered their potential for further impact in clinical practice. Global regulatory trends are yet to be defined, despite the several attempts already performed. A closer collaboration between regulatory agencies is still needed but major steps have been taken in last 5 years. As alternative, the strategies used for the development of ``conventional'' medicinal products have been frequently adapted to evaluate the safety/ toxicity and compatibility of nanomedicines [10,15–17]. From regulator's perspective, the active principal ingredient (API) of nanomedicines dictates the specifications to be analyzed within the regulatory context. For biological entities such as proteins, peptides or antibodies, the innovative product has to follow the regulations defined for biological medicinal products and for new chemical entities (NCEs) [13,16].

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In general, one of the hurdles underlying the regulation of nanomedicines is clearly related to their particular characteristics. Following the large scope of evidence assembled for liposomes, polymer therapeutics, and other polymeric systems (including polymeric micelles) and considering the regulatory issues related to their design and development [17], the clinical use of these sophisticated and complex nanoproducts is strongly dependent on extensive assessment, characterization and understanding of crucial properties. Their properties can in fact be easily altered, not only by slight changes in raw materials, but also by small modifications in manufacturing processes. And even though these changes might result in limited alterations in the structure, biological properties and biodistribution patterns may be significantly altered [5]. In addition, as researchers routinely attach drugs and prodrugs, targeting molecules, as well as tracking and imaging entities to nanomedicines, new quality control assays and robust methods have to be developed in order to effectively monitor and characterize not only their physicochemical properties, such as size and size variability, morphology and charge, but also to assess their performance, as drug release, metabolism assessment, protein binding, and specific cellular uptake [18]. These methods would further allow relating the modifications with overall physicochemical alterations and consequent effect on biological properties, biocompatibility, and therapeutic effect [15,17,19]. Depending on size range and physicochemical properties, nanomedicines are known to have the ability to interact with immune cells and to adsorb plasma proteins. Thus, during the preclinical assessment, biocompatibility and immunotoxicity must be taken in consideration (Table 1) [15,20]. An appropriate evaluation of toxicity during the development includes dosage regimen and therapeutic index, administration route and targeted disease environment. Globally, nanomedicines have shown safety, biocompatibility and even ability to decrease the toxicity of conventional drugs as molecules are entrapped and delivered at their targets [5]. However, different classes of proposed nanomedicines such as quantum dots, dendrimers, and carbon nanotubes have brought additional concerns. The clinical use of these new products might be indeed compromised for many years, related to their potential toxicity and immunological deleterious effects [21–26]. Another obstacle in the development and clinical translation of these nanomedicines has been adapting the manufacturing processes. Major questions related with their manufacturing face current pharmaceutical innovation at production facilities, challenging their scale-up potential, mostly due to the extensive diversity of properties of new materials [13]. It is fundamental to identify and control the critical points during each manufacturing process. Applying concepts of ``quality-by-design'', such as process analytical technologies (PAT) will ensure an on-line/at-line quality assessment approach. Knowing and anticipating the most critical points of production, facilitates the implementation of automated procedures to resolve problems as they occur in line [13]. These innovative conceptions have prompted the introduction and implementation of International Conference on Harmonization (ICH) Q8, Q9 and Q10 [27–29] as novel pharmaceutical development regulations. Further than bringing major consequences for established medicinal products, they intend to nurture the future development of nanomedicines and manufacturing processes. Generally, there have been efforts from regulators and industry from the United States of America (US), Europe and Japan in order to develop comprehensive regulatory approaches through the ICH. Even though, some divergent perspectives exist and persist underlying several procedures by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) [12,13]. A number of harmonized strategies and assays is needed looking at aspects known to clearly affect in vivo safety and efficacy of nanomedicines. Main difficulties are related to the

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V. Sainz et al. / Biochemical and Biophysical Research Communications 468 (2015) 504–510

Table 1 Parameters for quality and safety evaluation of nanotechnology-based medicinal products for biomedical use (adapted from [14]). Parameters Physicochemical properties

Production process Microbiology Microbial contamination Endotoxin levels Viral/mycoplasma levels Immunology

Cytokine production Cytotoxicity of Natural Killer (NK) cells Macrophages uptake Complement activation Plasma protein binding Leucocytes proliferation In vivo immune response

Objectives

Assessment

Characterization regarding: Average size, particle size distribution and aggregation; Morphology; Surface charge; Crystallinity; Rigidity/deformability; Chemical and molecular structure and architecture Control of critical points of production

Intermediate product quality

Sterility test To assess the presence of pyrogens Nitron Oxide quantification (indirect evaluation) Sterility test Identification and quantification of induced cytokines Evaluation of:  The effect on NK cell main functions (recognize and destroy).  Phagocytosis of the nanosystem  The effect on complement cascade

     

Surface charge and hydrophobicity effect The influence on leucocyte responses Function of NK cells Production of cytokines Immunoglobulins T (Th1/Th2) and B cells proliferation

Product quality Contamination tests to evaluate product quality & safety

Immunogenicity (immunosuppression or immunostimulation)/ Safety Immunogenicity (/ Safety

Assessment of:

Haematology Coagulation time Platelet aggregation Haemolysis In vivo single dose toxicity study Biodistribution studies

 The effect on coagulation factors  The influence on coagulation cascade  The effect on red blood cells Toxicity to different organs/cells, namely immune cells Pharmacokinetics, pharmacodynamics, metabolism, clearance

implementation of sensitive assays to detect low concentrations of nanocarriers, to differentiate them from formed aggregates or to distinguish intact from metabolized forms [30,31]. Alternative imaging techniques, fluorescence or cellular imaging methods, have been proposed and explored as strategies to overcome these limitations [21,32–34]. Another hurdle behind the regulation of nanomedicines is the nature of data to provide before and during the product life cycle, requiring in vivo animal and clinical studies. In Europe, for Marketing Authorization Applications (MAA) the regulatory system allows the opportunity of ``scientific counselling'' from regulators to applicants, since early stages of R&D [13]. This might rapidly contribute to a harmonized development of advanced nanomedicines, reducing the impact of major avoidable hurdles during the process. This can contribute to an increasingly harmonized development of advanced pharmaceuticals and to reduce the impact of major obstacles during their development process. Recently, EMA has created a working group to specifically address issues of quality, safety and efficacy of nanomedicines. Also, this group has prepared documents – ``orientation documents'' – referring essential aspects to be considered by applicants in the development of nanoproducts. Despite the absence of specific protocols for nanomedicines, since 2009–2010 the regulatory entities from the EU (EMA), USA (the FDA) and Japan (PDMA/ MHLW) have worked together in order to achieve common perspectives in the field of nanomedicines development. Meanwhile, major pharmaceutical companies have also increased their interest on ``proof of concept'' and clinical development of these complex systems. Altogether these aspects will promote clearer procedures for identifying safety and efficacy of innovative nanotechnologybased medicines. Additionally, before commercialization of these nanomedicines, it will be essential to perform pharmacoeconomic

Interaction with blood/Biocompatibility/Safety

Toxicity and prediction of additional toxicity tests/Safety Product safety

studies to demonstrate both social and economic added value of these novel products when compared with established treatments. Important indicators such as increment in QALYs (quality-adjusted life expectancy years) or costs associated to future consecutive hospitalizations shall be considered in the development of these new and sophisticated nanomedicines [14].

3. Nanomedicines in the market The pharmaceutical regulatory environment, the health care strategies, the demographics and the wide economic environment affect the competitive nanomedicine-related drug market approval [35]. Despite all difficulties along the development process, a considerable number of nanomedicines are already in the market, approved by the FDA, EMA or foreign equivalent (Table 2) [36]. Nowadays, regarding nanomedicines in the market, circa 40% of them are based on protein-polymer conjugates and liposomal formulations [14]. The treatment of tumor diseases is one of the major principal therapeutic targets for these nanomedicines. However, many research efforts have been done towards the development of new-generation nanomedicines for specific targeting through the binding of surface ligand and active receptors on the surface of targeted cells [35]. Additionally, novel nanomedicines have difficulties to enter in the market due to the expensive costs in clinical development and regulatory approval process not being compensated by the expected limited sales in niche indications [35,37]. Table 2 lists marketed nanomedicines that have a pharmaceutical and commercial potential role approved by the FDA and/or s EMA. The first FDA-approved nanomedicine was Doxil , a

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Table 2 Nanomedicines in the market approved by the FDA and EMA. Tradename Abelcet

s

s

Abraxane s

Adagen s AmBisome s Amphotec

Nanoplatform and active agent

Application

Approval (date)

Company

Lipid-based non-liposomal nanoformulation (Amphotericin B) Polymeric nanoformulation (Paclitaxel)

Systemic fungal infections when amphotericin B is not recommended Metastatic breast cancer, non-small-cell lung cancer Severe combined immunodeficiency disease Fungal infections Invasive aspergillosis when amphotericin B is not recommended Moderate/severe pain Crohn's disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis Multiple sclerosis

FDA (1995)

FDA (2002) FDA (2008)

Sigma-Tau, Cephalon, Enzon, Elan/Alkermes Abraxis BioScience, AstraZeneca, Celgene Sigma-Tau, Enzon Astellas/Gilead Alkopharma, Three Rivers/Alza Elan/Alkermes, Pfizer UCB

FDA (1996)

Teva

PEGylated adenosine deaminase Liposome (Amphotericin B) Lipid-based non-liposomal nanoformulation (Amphotericin B) Nanocrystal (Morphine sulfate) PEGylated antibody (Certolizumab pegol)

s

Avinza s Cimzia s

Polymeric nanoformulation (Glatiramer acetate) Liposome (Poractant alfa)

Copaxone s

Curosurf

FDA (1999)

Chiesi

FDA (1996)

Liposome (Perflutren)

Contrast agent

FDA (2001)

Liposome (Cytarabine)

Lymphomatous malignant meningites

FDA (1999) and EMA (2001)

Liposome (Morphine sulfate) Surfactant-based nanoformulation (Propofol)

Chronic pain Anesthetic

FDA (2004) FDA (1989)

Liposome (Doxorubicin hydrochloride)

HIV-related Kaposi's sarcoma, ovarian cancer, myeloma, breast cancer Hot flashes during menopause Advanced prostate cancer

FDA (1995) and EMA (1996)

NeXstar, Gilead Sciences, Galen, Teva Lantheus, Bristol Myers Squibb Pacira, Sigma-Tau, Skye/Enzon Pacira Fresenius Kabi, AstraZeneca Centocor Ortho Biotech, Janssen Meda, BioSante Atrix, Tolmar

s

Definity

DepoCyt(e) s

DepoDur s Diprivan s

Doxil / s Caelyx s Elestrin s Eligard s

Emend EstrasorbTM Feraheme Ferrlecit

s

s

Focalin XR

s

s

Fosrenol

s

Fungizone s

Invega s Kadcyla Macugen

s

s

Marqibo

Megace ES

s

MepactTM s Mircera s

s

Naprelan

s

Neulasta s Oncaspar s

Pegasys

Surfactant-based nanoformulation (Estradiol) Polymeric nanoformulation (Leuprolide acetate) Nanocrystal (Aprepitant) Surfactant-based nanoformulation (Estradiol hemihydrate) Metal nanoformulation (Ferumoxytol)

s

FDA (2009) FDA (1999)

Sanofi-Aventis

Attention deficit hyperactivity disorder

FDA (2005)

Novartis/Alkermes

End stage renal disease

FDA (2004)

Shire

Systemic fungal infections

FDA (1966)

Schizophrenia Metastatic breast cancer

FDA (2006) and EMA (2007) FDA (2013)

Bristol-Myers Squibb, Apothecon Janssen Genentech

Neovascular age-related macular degeneration Philadelphia chromosome and acute lymphoblastic leukemia Anorexia, cachexia, breast and endometrial cancer Osteosarcoma Anemia associated with chronic renal failure

FDA (2004) and EMA (2006)

OSI/Pfizer, Valeant

FDA (2012)

Talon Therapeutics

FDA (2005)

Par

EMA (2009) FDA (2007) and EMA (2007)

Takeda Hoffman–La Roche

Metastatic breast cancer

EMA (2000)

Nanocrystal (Naproxene sodium)

Rheumatoid arthritis and osteoarthritis, gout

FDA (1996)

PEGylated filgrastim PEGylated L-asparaginase

Febrile neutropenia Lymphoblastic leukemia

FDA (2002) and EMA (2002) FDA (1994)

Protein-drug conjugate (Denileukin diftitox)

Persistent or recurrent cutaneous T-cell lymphoma Hepatitis B and C

FDA (1999)

Cephalon/Zeneus, Elan, Sopherion Therapeutics Almatica, Elan/Alkermes, Wyeth Amgen Enzon/Schering-Plough, Sigma-Tau Eisai

Metal nanoformulation (Sodium ferric gluconate complex) Nanocrystal (Dexmethylphenidate hydrochloride) Metal nanoformulation (Lanthanum carbonate) Surfactant nanoformulation (Amphotericin B) Nanocrystal (Paliperidone) Protein-drug conjugate (Ado-Trastuzumab Emtansine) PEGylated anti-VEGF aptamer (Pegaptanib sodium) Liposome (Vincristine sulfate) Nanocrystal (Megestrol acetate)

PEGylated interferon alfa-2b

s

PegIntron

Rapamune

s

s

Renagel

s

Ritalin LA s Somavert

FDA (2006) FDA (2002)

Merck, Elan Corp Medicis, Novavax/Espirit, Graceway AMAG

Liposome (Mifamurtide) PEGylated epoetin beta (Methoxy polyethylene glycol-epoetin beta) Liposome (Doxorubicin)

Myocet

Ontak

s

FDA (1990) FDA (1997) and EMA (1990) FDA (1996)

Respiratory Distress Syndrome (RDS) in premature infants HIV-related Kaposi's sarcoma

DaunoXome Liposome (Daunorubicin citrate) s

FDA (2005) and EMA (2008)

PEGylated interferon alfa-2b Nanocrystal (Sirolimus) Polymeric nanoformulation (Sevelamer hydrochloride) Nanocrystal (Methylphenidate hydrochloride) PEGylated human growth hormone receptor agonist (Pegvisomant)

Emesis, antiemetic for chemotherapy patients Reduction of vasomotor symptoms during menopause Treatment of iron deficiency anemia in adults with chronic kidney disease Iron deficiency anemia

FDA (2003) and EMA (2003) FDA (2003)

Hepatitis C in patients with compensated liver disease Immunosuppressant (kidney transplants) Hyperphosphatemia in patients with chronic kidney disease on dialysis Attention deficit hyperactivity disorder Acromegaly

FDA (2002) and EMA (2002)

FDA (2001) and EMA (2000) FDA (2002) and EMA (2001) FDA (2000) and EMA (2000) FDA (2002) FDA (2003) and EMA (2002)

Hoffmann-La Roche/Nektar Genentech Schering-Plough Merck Wyeth/Alkermes, Elan, Pfizer Genzyme Novartis Pharmacia and Upjohn, Nektar, Pfizer

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V. Sainz et al. / Biochemical and Biophysical Research Communications 468 (2015) 504–510

Table 2 (continued ) Tradename Survanta

Nanoplatform and active agent

s

Liposome (Beractant)

s

Tricor s Triglide s Venofer s

Verelan PM s Verelan s Visudyne s Zevalin Zyprexa

s

Application

Neonatal respiratory distress in premature infants Nanocrystal (Fenofibrate) Dislipidemias Nanocrystal (Fenofibrate) Dislipidemias Metal nanoformulation (Iron sucrose (iron (III)- Iron deficiency hydroxide sucrose complex)) Multiparticulate system (Verapamil) Hypertension Multiparticulate system (Verapamil) Hypertension Liposome (Verteporfin) Photodynamic therapy Antibody-targeted nanoparticle (Ibritumomab Lymphoma, follicular tiuxetan) Nanocrystal (Olanzapine) Schizophrenia

doxorubicin-loaded PEGylated liposomal formulation for cancer treatment. After 20 years from its approval, this nanomedicine continue to be extensively used and constitutes the pattern of s injectable nanodrugs and drug delivery systems [14,18]. Doxil has been used for the treatment of Kaposi sarcoma in HIV patients, ovarian cancer treatment, metastatic breast cancer and multiple myeloma [11,35]. In Europe, the first approved nanomedicine was s AmBisome . This product is based in amphotericin B-loaded liposomes for systemic fungal infections [11,14]. However, recent evidences have demonstrated that a nanoparticulate iron oxide formulation for intravenous administration, used since the 1960s, was mistakenly classified as an iron oxide solution [14].

4. Regulatory development for ``next-generation'' of nanomedicines Regulation of medicinal products has been in a changing and evolutive path since ICH started in the early 90s and the regulatory environment around the development of nanomedicines has been under increased challenge (Fig. 1). The anticipated evolution

Approval (date)

Company

FDA (1991)

Abbot, Abbvie

FDA (2004) FDA (2005) FDA (2000)

Abbot, Abbvie Skye, First Horizon, Sciele Luitpold, Vifor France

FDA FDA FDA FDA

Elan/Alkermes Elan/Alkermes Valeant, QLT Ophtalmics Spectrum

(1998) (1990) (2000) (2002) and EMA (2004)

FDA (2009)

Lilly

demands for more and more proof of superiority in clinical efficacy from new innovative approaches, existing as well as an increased pressure for pharmacoeconomic evaluation [13,14]. The historical demonstration of non-inferiority is no longer acceptable in many clinical settings and therefore clinical standards for most applications are under continued revision and updating. Moreover, the new perspectives in healthcare management, incorporating health technologies assessment (HTA), also bring into play the need to integrate different medical interventions complementary to the therapeutic classical oncology setting [38,39]. Major advances in biopharmaceuticals in several clinical areas have also demonstrated their inherent potential for superiority overcoming several of the nanotechnology-based approaches. We have to remember that most of the currently developed systems are based on molecules that were innovative in the late 70s or early 80s but no longer today, like doxorubicin and others [5]. Another critical issue in the current regulatory discussions is the increased focus on nanosimilars, which combine generic drugs and nanocarriers as innovative excipient [40]. In addition, the debate over similar formulations within non-biological complex drugs (NBCDs) brought to the forefront a number of critical issues

Fig. 1. Overview of regulatory presence on the research and development life cycle of any medicinal product. INDA – Investigational New Drug application, NDA – New Drug Application, MA – Marketing Authorization (adapted from Ref. [14]).

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in specific formulations (iron oxide nanoparticles, liposomes, polymeric micelles). Both aspects are now under increased regulatory attention [17,41]. In parallel the ITF (innovation task force) at the EMA had already started to assemble data and, in 2009, the ad hoc expert group in Nanomedicines started a number of activities, including the first global conference on the topic that also mobilised regulators and stakeholders from US and Japan among others [14]. At the same time, different issues have been triggered from the European Union debate on nanomaterials' classification related to the ``similarity'' discussion, namely from a Top Institute Pharma (TI Pharma)-based international expert group in the Netherlands (NBCDs expert group) composed of a number of experts from academia and industry. The FDA and PDMA/MHL, along with Canada, Switzerland, Australia and others also developed their own initiatives, some of them coordinated with the EMA. The major outputs from this burst of new regulatory initiatives include a set of guidance documents from the EMA related to iron-oxide nanoparticles (Reflection Paper on Non-Clinical Studies for Generic Nanoparticle Iron Medicinal Product Applications – Ema/Chmp/ Swp/100094/2011) [42], liposomal similar products (Reflection Paper on the Data Requirements for Intravenous Liposomal Products Developed with Reference to an Innovator Liposomal Product: Ema/Chmp/Swp/100094/2011 2013) [43] and polymeric micelles (Joint MHLW/EMA Reflection Paper on the Development of Block Copolymer Micelle Medicinal Products:Ema/Chmp/13099/ 2013 2013) [44]. The latter can be considered a ``revolutionary'' document in two ways: i) it considers a technology being developed before it comes to market; ii) results from the integrative collaboration of EMA and PDMA/MHLW, being a first example of a ``global'' nanomedicines regulatory guidance document. An integration of the concepts behind those documents has been recently published [16]. Also relevant to the current trends are the documents from the FDA on liposomal products and the scientific discussions about regulatory implications on NBCDs [45]. The latest took place not only at the NBCDs expert group, but also recently in open-fora at FIP (International Pharmaceutical Federation), EUFEPS (European Federation of Pharmaceutical Sciences), AAPS (American Association of Pharmaceutical Scientists), and NYAS (New York Academy of Sciences) [46]. Two relevant papers on NBCDs were also recently published [45,47]. An increased concern both at European and US level has been the question of the harmonization of methodology essential to characterize the quality requirements. The Nanotechnology Characterization Laboratory (NCL) at the National Cancer Institute (NCI) in the US has provided a major contribution to this matter by assembling data with several innovative platforms for the development of nanomedicines in oncology [48,49]. The complexity of integrated platforms of different technologies, from therapeutics to imaging, including cancer therapeutic vaccines and multiplex medical devices, will improve regulation, along with the theranostics and combination products pathways [5,50,51]. A critical role will be played by regulatory authorities through their scientific advice procedures, and an increased pressure will be present to have more cooperative work between different regional regulatory bodies (EMA, FDA, and PDMA/MHL), major academic and industry stakeholders [17]. Current developments in the research landscape of nanomedicines brought the attention to the fact that despite being an already well-established area of clinical practice, it now faces some questions previously addressed by new chemical entities and biologicals. Advances brought by nanomedicines in oncology and infectious diseases are now being expanded both within these

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clinical areas, but also looking at their use to address other less targeted clinical situations [41]. The advances in clinical practice associated to nanomedicines in the last 30 years will in fact allow for significant improvements in the next phase, sustained by both solid basic research and an increased amount of clinical data compiled across different technologies and therapeutic areas. New developments are allowing the introduction of both personalized medicine and combination therapy as drivers for innovation in clinical practice [45]. The innovation in materials science has to meet clinical standards already established for approved medicinal products that went through the challenge of regulatory approval for clinical experiences (under clinical trials), but also for marketing authorization and routine clinical use. Meanwhile, the need for adequate standardization and characterization of nano-based systems has moved the US to a specific platform initiative (NCL at NCI), while Europe is still nanomedicines looking for a more integrated way to address it. Accordingly, new challenges in Regulatory Science will be met by better integration between materials science and solving translational issues, like validation of adequate models (e.g. preclinical human cells and tissues in appropriate setting to foster clinical translation and better outcomes within clinical phase), and targeting an adequate disease stage and disease evolution conditions, within the current setting to address appropriate personalized medicine questions [14,41,45]. Nanomedicine is bringing converging sciences to an adequate platform of technologies, providing better health care, but also enabling the design and clinical use of innovative solutions to unmet clinical needs. The regulatory framework in Europe and elsewhere is currently adjusting to new realities and incorporating the best scientific standards in anticipation of the regulatory needs both to follow-on products, combination products and integrative platforms, bringing together therapy and diagnostics. Innovative Medicines Initiative (IMI) in Europe and National Center for Advancing Translational Sciences (NCTAS/NIH) in the US, are both major platforms that certainly will contribute in the future towards better regulatory science in innovative technologies, as well as in precision medicine, and by default also related to nanomedicines.

Conflict of interest The authors declare no conflicts of interest underlying the content of this manuscript.

Acknowledgments The authors thank to Fundac- a~ o para a Ciê ncia e a Tecnologia, Ministério da Ciê ncia e da Tecnologia, Portugal (PhD Grant SFRH/ BD/87869/2012 to Vanessa Sainz, SFRH/BD/87150/2012 to Joa~ o Conniot, SFRH/BD/87591/2012 to Carina Peres and SFRH/BD/ 78480/2011 to Eva Zupančič; Post Doc research grant SFRH/BPD/ 94111/2013 to Liane Moura; research projects PTDC/SAU-FAR/ 119389/2010 and UTAP-ICDT/DTP-FTO/0016/2014 and iMed.ULisboa grant UID/DTP/04138/2013). J Conniot and V Sainz also acknowledge funding from the UK Engineering & Physical Sciences Research Council (EPSRC) for the EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies.

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