Drug delivery system innovation and Health Technology Assessment: Upgrading from Clinical to Technological Assessment

International Journal of Pharmaceutics 495 (2015) 1005–1018

Contents lists available at ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Drug delivery system innovation and Health Technology Assessment: Upgrading from Clinical to Technological Assessment Michele Panzittaa,b,* , Giorgio Brunob,c, Stefano Giovagnolia , Francesca R. Mendicinod, Maurizio Riccia,d a

Department of Pharmaceutical Sciences Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy AFI—Associazione Farmaceutici dell’Industria, viale Ranzoni 1, 20041 Milano, Italy Recipharm AB, Via Filippo Serpero, 2, Masate (MI), Italy d School of Hospital Pharmacy, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy b c

A R T I C L E I N F O

A B S T R A C T

Article history: Received 25 July 2015 Received in revised form 11 September 2015 Accepted 14 September 2015 Available online 21 September 2015

Health Technology Assessment (HTA) is a multidisciplinary health political instrument that evaluates the consequences, mainly clinical and economical, of a health care technology; the HTA aim is to produce and spread information on scientific and technological innovation for health political decision making process. Drug delivery systems (DDS), such as nanocarriers, are technologically complex but they have pivotal relevance in therapeutic innovation. The HTA process, as commonly applied to conventional drug evaluation, should upgrade to a full pharmaceutical assessment, considering the DDS complexity. This is useful to study more in depth the clinical outcome and to broaden its critical assessment toward pharmaceutical issues affecting the patient and not measured by the current clinical evidence approach. We draw out the expertise necessary to perform the pharmaceutical assessment and we propose a format to evaluate the DDS technological topics such as formulation and mechanism of action, physicochemical characteristics, manufacturing process. We integrated the above-mentioned three points in the Evidence Based Medicine approach, which is data source for any HTA process. In this regard, the introduction of a Pharmaceutics Expert figure in the HTA could be fundamental to grant a more detailed evaluation of medicine product characteristics and performances and to help optimizing DDS features to overcome R&D drawbacks. Some aspects of product development, such as manufacturing processes, should be part of the HTA as innovative manufacturing processes allow new products to reach more effectively patient bedside. HTA so upgraded may encourage resource allocating payers to invest in innovative technologies and providers to focus on innovative material properties and manufacturing processes, thus contributing to bring more medicines in therapy in a sustainable manner. ã 2015 Elsevier B.V. All rights reserved.

Keywords: Health Technology Assessment Nanoparticles Pharmaceutics Drug delivery systems Quality by design Quality risk management Clinical pharmaceutics

1. Introduction Today, there is growing awareness about the importance of balancing all the aspects determining pharmaceutical product impact on the healthcare system. Pharmaceutical products have to

Abbreviations: QbD, quality by design; ICH, International Conference of Harmonization; GMP, good manufacturing practice; EES, efficacy, effectiveness, safety; HTA, Health Technology Assessment; NP, nanoparticles; DDS, drug delivery system; CMA, critical material attributes; CPP, critical process parameters; CQA, critical quality attributes; CTD, common technical document; QP, qualified person; PPQ, pharmaceutical production and quality (skills); PF, pharmaceutical formulation (skills); EBM, evidence based medicine; PE, pharmaceutics expert. * Corresponding author at: Università degli Studi di Perugia, Department of Pharmaceutical Sciences, via del liceo 1, Perugia 06123, Italy. E-mail address: [email protected] (M. Panzitta). http://dx.doi.org/10.1016/j.ijpharm.2015.09.026 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.

be evaluated not only for therapeutic efficacy but more generally in terms of enhanced quality of life, and cost-related implications. The market sustainability of a pharmaceutical product not only hinges on its clinical efficacy, but also on its economic sustainability for payers (i.e., national/regional healthcare systems), providers (i.e., pharmaceutical companies) and availability to patients (Panzitta, 2015). To allow proper intervention, Health Technology Assessment (HTA) is mandatory. The HTA is a complex process that examines the short- and long-term consequences of the application of a healthcare technology (ISPOR). In this paper, we refer to HTA as a body of procedures applied solely to medicinal products, although the methodologies described apply to other healthcare products as well. HTA provides information about policy alternatives, and it includes many assessments such as: technical properties, evidence

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of safety, efficacy, real-world effectiveness, cost and cost-effectiveness, as well as estimated social, legal, ethical, and political impacts (ISPOR). Most regulatory agencies apply HTA to fix price and access of medicines and to assess the innovation level; HTA offers a wide amount of instruments to better manage economic resources of the healthcare system with different results for different stakeholders. In this way, patients can obtain best healthcare solutions and on the other hand the HTA process drives industry R&D and operations because determines return of investment: both, patient and industry, can use at their best the limited resources available. Obviously, technical property assessment is particularly relevant in the case of advanced medicinal products. Evidence Based Medicine (EBM) is the first step and main data source for HTA processes (Eddy, 2009) and it is based on the clinical evaluation of a pharmaceutical product. Anyway, pharmaceutical factor can affect clinical outcome, such us industrial pharmaceutics or clinical pharmaceutical issues ( Florence, 2010); these issues become more relevant as medicinal product complexity increases. In this regard, the continuous progress in the development of more sophisticated DDS (Anselmo and Mitragotri, 2014) requires innovation of the evaluation procedures as well. The HTA process should be upgraded to meet such needs, as non-conventional dosage forms introduce critical factors (technological and economical) which affect patients, payers and providers. Modern DDS are designed to finely-tune drug action through the application of complex technologies, which require specific technical knowledge. Therefore, nowadays implementation of the panel of experts and assessment procedures conventionally adopted for HTA assessment is mandatory. DDS production and evaluation require multidisciplinary sciences, from physical chemistry to biology (Breuer et al., 2009). Such knowledge is crucial to the interpretation of clinical outcomes, as well as the social-economic impact of new pharmaceutical products. In this paper, we will discuss such aspects focusing particularly on nanoparticles (NP) as a paradigm of technologically advanced DDS. In detail, the following tasks will be carried out: 1. Identification of the skills needed to perform a full DDS technological assessment: we will define the “Pharmaceutics Expert” (PE) as the professional who possesses the required knowledge regarding DDS disciplines, classified as Pharmaceutical Formulation (PF) and Pharmaceutical Production and Quality (PPQ). Ideally, the PE should be a player in the HTA process related to DDS and more than one PE may be needed to cover the wide multidisciplinary expertise often required. 2. Identification of DDS critical issues, proposing how these issues and skills can be included in the HTA process: we will build up a “DDS appraisal format” from a pharmaceutical point of view; we will consider integration in the current process to determine the implementation of HTA practices and procedures. A detailed and comprehensive assessment of DDS technical properties can improve HTA usefulness; it may help payers to optimize the pharmaceutical expenditure toward overall assessed medicines. Moreover, it may help providers to design R&D strategic plans to overcome bottlenecks along the difficult path leading medicines to therapy. 2. The proposed approach HTA is a complex process aimed at the evaluation of product performance in terms of theoretical efficacy, typically measured during clinical trials involving a limited number of patients, or the

actual effectiveness that corresponds to the results and performance measured during common clinical practice. (Drummond et al., 2010) From a HTA point of view, effectiveness is more useful but more difficult to obtain, on the other hand, clinical trials can be structured to reduce the gap between efficacy and effectiveness (Drummond et al., 2010). In this paper, we will refer to efficacy, effectiveness and safety with the acronym EES. The assessment of efficacy and effectiveness includes safety appraisal as fundamental issue of clinical trials (European Parliament, 2001a), sometimes in our article we will consider it separately, in order to detail how technological appraisal with specific pharmaceutics expertise on DDS may add valuable data related to safety. The PE must not be the sole protagonist in the HTA process as, during the R&D phase, he/she shares the responsibility with other professionals as member of a multidisciplinary pool of experts, exerting interdisciplinary leadership, (Duncan, 2014; Bertrand et al., 2014) collaborating as equal partners (Barenholz, 2012). HTA is also a multidisciplinary process taking into account the scientific progress of assessed technologies: if technologies change, also HTA skills and methodologies must follow the change and be adapted. The article is not meant to be a scientific guideline but a means to inspire debates on how to adapt HTA processes to scientific progress. 2.1. Nanoparticles as a paradigm of DDS therapeutic innovation 2.1.1. Nanoparticle paradigm: complex research generating knowledge Nanoparticles (NP) refer to a variety of DDS with size 10– 1000 nm (Kreuter, 1994), in pharmaceutics and in medicine NP come as nanocrystals, polymeric NP, liposomes and lipid NP for drug targeting purposes (Wu et al., 2011; Yerlikaya et al., 2013; Schreier, 2001). NP are advanced DDS providing therapeutic benefits as well as outstanding challenges from the product development point of view (Brambilla et al., 2014). In fact, NP technology suffers from several flaws resulting from the sometimes inconsistent and unreliable methods and techniques employed in their preparation. Moreover, the quality assurance of NP products requires advanced technological solutions and adequate funding that need to be accounted in the HTA process. Examples of marketed NP formulations are liposomal doxorubicin (Doxil1) and paclitaxel protein-bound particles (Abraxane1) destined to passive targeting of cancer. Active targeting NP formulations are currently in clinical trial (Bertrand et al., 2014). The NP designed for active targeting need surface affinity ligands granting cell specific uptake. An exciting possibility is coupling two or more API in the same NP, so a timely co-delivery can be achieved simultaneously in the same diseased cell (Zucker et al., 2012). Production of such NP formulations poses tremendous scale up and storage stability challenges (Bertrand et al., 2014). For all these reasons, in this paper we refer to NP as a paradigm of DDS having specific R&D and technical properties, requiring pharmaceutical evaluation in HTA. 2.1.2. ICH Q8: integrated knowledge to support evidence appraisal The development of DDS, in particular NP, requires multidisciplinary skills and expertise ranging from interpretation of biopharmaceutical data to manufacturing process knowledge. These variables are interdependent and indivisible in order to achieve therapeutic EES. To grant product quality, the choice of the production process and suitable materials is of paramount importance. The complexity of NP DDS introduces bottlenecks in the product development stream, they are proportional to the product innovation degree. The Quality by Design (QbD) approach may help in handling such complexity. An accepted definition of QbD is “the systematic, scientific, riskbased, holistic and proactive approach to pharmaceutical

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development that begins with predefined objectives and emphases product and processes understanding and process control. QbD identifies characteristics that are critical to quality from the perspective of patients, translates them into the attributes that the drug product should possess, and establishes how the critical process parameters can be varied to consistently produce a drug product with the desired characteristics” (Yu, 2008) ICH guidelines regard QbD as a tool dedicated to the pharmaceutical development phase; CTD (Common Technical Document) is the document containing all product's information to be submitted to the competent Regulatory Agency in order to achieve the Marketing Authorization. QbD is intended to develop data required to fill the CTD Section 3.2.P.2 “pharmaceutical development” (ICH Q8, 2009). QbD is not just a regulatory requirement, but it allows the mutual connection of process development and R&D phases to product manufacturing. The EU GMP Annex 15 Draft revision deals with process validation (Eudralex GMP, a), the annex remarks the relevance of ICH Q8 and ICH Q9 (Quality Risk Management) as tools to be used coupled with strong process knowledge and product characteristics. Product quality and safety cannot be tested just in the product: they must be built in during the process. Many regulations define data to support marketing authorisations for innovative DDS when developed with reference to an innovator product: the importance of CQA (Critical Quality Attributes) CPP (Critical Process Parameters), CMA (Critical Materials Attributes) and control strategy developed by the QbD approach is stressed in order to ensure similarity (EMA, 2013a,c,d). Above all, QbD serves to translate DDS invention to therapeutic innovation, integrating knowledge from mechanism of action design to DDS production. Generally, a QbD exercise is carried out in 4 phases: (1) design of Quality Target Product Profile (QTPP); (2) design of product and production processes to achieve QTPP; (3) identification of CQA, CPP, CMA and exploration of the design space; (4) establishment of a control strategy to ensure a manufacturing process within the established design space (CMA, CPP). In phase 1, the PE analyzes biopharmaceutical and pharmacokinetic API properties, identifying the limits of current formulations and target properties. The PE also designs a DDS formulation

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exerting a mechanism of action that enhances the API ability to achieve the therapeutic target. In phases 2–4, the PE translates the design into a medicinal product: choosing DDS type, identifying CQA, establishing how and how much CQA affect the patient in terms of EES, identifying a series of CPP and CMA, correlating CPP and CMA to CQA and exploring a design space in which the variability of CPP and CMA is within established limits and able to ensure EES. The ICH Q8 approach can be better understood looking at two examples of NP developed via the QbD approach. Xu et al. (2011) developed a liposomal formulation of Tenofovir, a low permeable antiviral drug, to target lymphatic tissues and macrophages. Two main CQA were identified: liposome particle size (100–200 nm for best macrophage uptake, under 200 nm for manufacturing sterile filtration), liposome drug encapsulation efficiency (increasing patient dosing intervals and exerting better compliance). Risk Analysis (as per ICH Q9) identified eight key factors (CPP, CMA) influencing drug encapsulation and particle size. Yerlikaya et al. (2013) developed Paclitaxel loaded PLGA NP to target cancer. Three CQA were identified: (1) Encapsulation efficiency- higher NP drug loading allows better dosing, extends dosing intervals and decreases toxicity of excipients and residual solvents; (2) Average particle size- <400 nm allows NP to be accumulated in solid tumors by the EPR effect; (3) Zeta potentialaffects physical stability of NP suspensions. CPP and CMA were identified through risk identification steps (via Ishikawa diagram), after which a risk analysis step via Plackett–Burman (statistical experimental design) was performed to study CMA and CPP, relating their influence to the CQA of paclitaxel NP. Then a response surface method (three-factor, three-level Box–Behnken design) was performed for formulation optimization. In such examples, two parameters affected QbD: 1) Physicochemical: amorphous physical states of the API led to a faster release than the crystalline substances. Owing to the very low Paclitaxel solubility, factors inducing a faster release were investigated in vitro. 2) Excipient composition: a residual solvent analysis was performed as per the current guideline (ICH Q3C, 2013), which establishes very low residue limits.

Fig. 1. ICH Q8, development pathway, PE skills and link with clinical outcome.

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About solvents: they are useful and fundamental to achieve best NP characteristics and production performance; this represents a technical challenge bridging research and bedside. In traditional dosage forms, therapeutic innovation relies mainly on the API and the formulation is just useful to allow patient administration and to protect the API. In NP, CQA, CPP and CMA identify the medicinal product characteristics, granting therapeutic EES. From the efficacy point of view, CQA help identifying the formulation features needed to grant therapeutic effect (i.e., particle size), so pharmaceutics knowledge used for designing and engineering CQA may help the HTA evaluation of “efficacy ”. (Refer to formulation appraisal paragraph) Furthermore, CQA identify and prioritize CPP and CMA having an impact on formulation in terms of product quality (i.e., stability), allowing the evaluation of formulation behavior in the “real world”: it may help in the HTA evaluation of “effectiveness”. The reason is that real world variables can have a high impact on CQA (temperature, physicochemical stability, materials compatibility, etc.). (refer to manufacturing appraisal paragraph) The pharmaceutical knowledge gained through QbD (CQA, CPP, CMA) allows the PE to contribute to HTA evaluation with specialist knowledge about critical factors affecting EES. Since many variables contribute to global effect, we must stress the importance of QbD as the paradigm for integrating therapeutic innovation knowledge, research and development in the DDS arena. Fig. 1 shows how PE competences integrate the development stream regulated by ICH Q8. The following paragraphs detail PF and PPQ skills. 2.2. Pharmaceutics Expert (PE) skills The aim of this paragraph is to individuate PE skills necessary to assess DDS. The skills are divided into 2 branches: Pharmaceutical Formulation (PF) and Pharmaceutical Production and Quality (PPQ), in order to separate those necessary for the evaluation of R&D aspects rather than production aspects (Fig. 2); Some application of PF skills in the pharmaceutical practice helps to clarify the proposed definition. The NP design step for solid tumor targeting requires an in depth analysis of the biological barriers (in terms of pathophysiology and natural biological mechanism) in order to overcome bottlenecks preventing local accumulation on the target. This step requires biopharmaceutical skills. Another common fundamental issue is the delivery of poorly water-soluble molecules; use of solvents or surfactants could exert toxic effects so it should be

avoided or allowed within established low and safe limits. This step requires physical pharmacy, biology and chemistry knowledge. Components and characteristics such as: type (i.e., liposome), size, surface characteristics (charge, chemistry, adhesion), steric stabilization, API (type, loading efficiency, kinetics) should be chosen combining their characteristics with the required pharmacological effect. Size is determinant for pharmacokinetic behavior (i.e., size < 20–30 nm led to rapid renal clearance, >400 nm led to hepatic clearance) but also from the manufacturing point of view: size < 220 nm allows sterile filtration. Surface properties influence NP interaction with the organism and on processes like opsonisation, which enables NP clearance by macrophages; formulation strategies using PEG or other polymers giving hydrophilic characteristics to the NP surface protect NP from opsonisation (Desai, 2012). The above-mentioned knowledge is used to ensure efficacy but also safety. From the safety point of view, NP may be antigenic, the API and the delivery system interact increasing this antigenicity and the NP surface characteristics may affect immunological response as well. (Desai, 2012). PE exerts PPQ skills at the production stage (early, clinical trials, or commercial), which are relevant to assess product quality and its impact on the patient, as well as ensuring regulatory compliance and production volume able to satisfy patient needs in terms of quantity. Thus, we consider that the PE's expertise includes the knowledge useful to the research & development and production of DDS. In order to identify PF disciplines, authors consulted books and relevant literature related to DDS and cited skills were extrapolated. Analysis of regulations and legislation identifies PE skills useful to evaluate production and quality aspects (PPQ). 2.3. PF and PPQ: link with HTA Although PF and PPQ aspects overlap along the R&D pathway, their contribution to HTA may be different.  We define as PF the discipline set used to study the DDS mechanism of action leading to therapeutic innovation and which translates it into a pharmaceutical formulation with characteristics allowing administration to patients. Those have main impact to evaluate the efficacy (see Fig. 2).  We define PPQ the disciplines set used to change the pharmaceutical form, through production technologies and quality requirements, in the medicinal product able to exert its therapeutic action in the real life (see Fig. 2). Those have main impact to evaluate effectiveness. Both, PF and PPQ, are relevant to assess safety issues. (see Fig. 2) DDS exert therapeutic effect by means of multifactorial mechanisms of action; the PE is the ideal Pharmaceutical Scientist who possesses the knowledge generating this therapeutic innovation. The expertise necessary to discover and to develop the formulation technology should be directly involved in the assessment of this technology. Since HTA often measures medicinal products innovation level, a DDS appraisal measuring just the clinical outcome is not complete, because clinical outcome evaluates EES on patients but does not in depth evaluates the technology generating it. 2.4. PF and PPQ integrated vision

Fig. 2. PF, PPQ and their link to efficacy, effectiveness and safety (EES).

To split the expertise in PF and PPQ is convenient just to schematize the link to HTA, anyway PF and PPQ should be applied in conjunction. Considering the broad area of skills required, more than one professional (PE) could participate to HTA, each one as per

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proper competences; anyway, their evaluation should be performed integrating PF and PPQ as a whole. PF and PPQ are carried out since early stages of R&D up to patient administration, so knowledge gained throughout the DDS development pathway deals with efficacy and effectiveness issues. PF and PPQ are interdependent and should be applied with an integrated vision during a technology appraisal. For example, the DDS mechanism of action (efficacy evaluation) is strongly dependent on its quality, the quality is built through the production process and by using an appropriate quality system. Risk analysis to evaluate performance of the medicinal product in the real life (effectiveness evaluation) should include situations where an anomaly may occur during use. The PPQ competences assess impact of the anomaly on product quality; the PF skills assess how various features of the anomaly affect DDS, modifying the mechanism of action with potential harm for the patient. (Refers to paragraph physicochemical appraisal and Manufacturing appraisal for examples). Therefore, it is necessary a multidisciplinary and integrated vision to evaluate the mechanism of action, translating quality characteristics into EES potential issues. 2.5. Pharmaceutical appraisal format We suggest three types of appraisal: formulation, manufacturing, physicochemical. In the following paragraphs, we explain how each one links to clinical outcome, improves patient safety and integrates current HTA processes. Each appraisal refers to specific technical and regulatory considerations. The PE applies specific methodological approaches at different times along the DDS life cycle, always evaluating benefits and risks for the patient; it is impossible to identify all the circumstances of its application. Along with pharmaceutical practice, PE expertise stands out in three topics and now we explain:  When it grows up and it is exerted  In which step is critical to understand impact on patient  By which methodology it provides data to support HTA process.

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When: appraisal format refers to activities performed during drug R&D as per inventors, innovators and imitators business model (Venditto and Szoka, 2013). The inventor is the one who creates the technology necessary for drug development, the innovator is who uses the invention to develop the medicinal products (by formulation development phase and subsequent clinical trials), the imitator is who reproduces the medicinal product results by other (similar) DDS (Venditto and Szoka, 2013). Therefore, the PE acts as inventor, innovator, and imitator when he develops a “similar” DDS. The three format appraisals reflect skills and activities used during the DDS life cycle (invention, innovation, imitation), although it is not possible to group uniquely each format to a specific phase. Which step: Horizon 2020 is the EU Research and Innovation program, it recognises nanomedicine as a topic to be developed and the ETPN (The European Technology Platform on Nanomedicine) provides external advice to the European Commission in order to individuate actions improving nanomedicine translation in therapy. ETPN published a white paper outlining an overall strategy, but also providing evaluation in determining if applicants submit to H 2020 projects that can really reach the therapy (European Technology Platform Nanomedicine, 2013). Despite R&D and program funding efforts, nanomedicines effectively reaching therapy have been a few. In order to increase translation, ETPN identifies:  The translational limiting step in the R&D phase (see Fig. 3).  The stakeholders to be involved in the program evaluation process, with the task to individuate which submitted innovation can really reach therapy (NTAB-Nanomedicine Translation Advisory Board) (Table 1).  The topics to be evaluated (Table 1). Furthermore, the white paper recognizes Manufacturing and Physicochemical Characterization as key translational activities to be empowered by knowledge and infrastructure; so a European Nano-Characterisation Laboratory (EU-NCL) and GMP production pilot lines for clinical batches, will both support academics and

Fig. 3. Adapted from ETPN- White Paper to the Horizon 2020 (European Technology Platform Nanomedicine, 2013) EU-NCL: physicochemical characterization; GMP Pilot Lines: manufacturing.

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Table 1 source: ETPN Translational Advisory Board Topics and Expertise (European Technology Platform Nanomedicine, 2013). 3 TAB expertise

Topics to be treated

       

1. 2. 3. 4. 5. 6. 7. 8. 9.

Intellectual Property Market need/market access/reimbursement Manufacturing and Chemistry Manufacturing and Control (CMC) Preclinical and clinical development Regulatory Business development Communication

Small Medium Enterprises to develop their products for validation in clinical trials, prior to Contract Manufacturing Organization transfer. This is an overall picture about competences and limiting step that are critical to develop and bring to therapy nanomedicines, this expertise should be relevant to perform HTA on nanomedicines. Methodology: during invention, innovation and imitation phases the PE uses extensively and systematically QbD (ICH Q8) and QRM (ICH Q9). The PE can contribute to HTA by unbiased, statistically significant and clearly understandable evaluations, so complying with best HTA practice requirements (Drummond et al., 2008) by means of those methodological tools. Fig. 3 shows allocation of format appraisal along key step required for a successful translation in therapy, it also shows their allocation along the invention, innovation and imitation business model. 3. Discussion 3.1. Pharmaceutics Expert (PE) skills 3.1.1. Pharmaceutical formulation skills (PF) The IUPAC glossary defines pharmaceutics as “ the science of preparation of drugs, dosage forms and drug delivery systems, taking into account the pharmacokinetics and pharmacodynamics of the drug as well as its physical and chemical properties” (Breuer et al., 2009). Although an “ultimate” definition of pharmaceutics expertise is not available, certainly proper comprehension about DDS can be achieved by an integrated knowledge of biopharmaceutics, pharmacokinetics, physical pharmacy, pharmaceutical technology (Banker and Rhodes, 2002; Shargel et al., 2005; Krishna and Yu, 2008) and biotechnology (Breuer et al., 2009). Before starting pre-formulation study, API biopharmaceutics and physicochemical characteristics must be in depth evaluated. Biopharmaceutical skills are fundamental in order to study i.e.,: drug dissolution and solubility, physiological aspects of dissolution and solubility test condition, models for studying the absorption potential of drugs and other properties. (Gibson, 2009) The IUPAC glossary provides a clear definition of about 2 key activities- preformulation and formulation: “formulation, intended as summary of operations carried out to convert a pharmacologically active compound into a dosage form suitable for administration”; pre formulation exploratory activity that begins early in pharmaceutics, involving studies designed to determine the compatibility of excipients with the active substance for a biopharmaceutical; physicochemical and bioanalytical investigation in support of promising experimental formulations” (Breuer et al., 2009). The pre-formulation design involves pharmaceutical, technical and regulatory aspects of the product (Gibson, 2009). The PE uses biological and pre-formulation knowledge at formulation stage, added to physiological processes

Safety evaluation Technical evaluation Competitive evaluation Regulatory evaluation Reimbursement evaluation Commercial evaluation Clinical trial design Extent of Paradigm change Societal issues

comprehension that may interact with the biopharmaceutical functions, in order to deploy following activities: (Gibson, 2009)  Characterization of relevant physicochemical, pharmacokinetic/ dynamic API prerequisites.  Identification of relevant biopharmaceutical targets.  Definition of test methods/designs needed to achieve biopharmaceutical targets in the formulation. development and to perform a correct interpretation of study result.s  Design of suitable drug form, excipients, formulation mechanism of action. The subsequent product optimization studies are conducted (Gibson, 2009) in compliance with ICH Q8 and ICH Q9 guidelines. 3.1.2. Pharmaceutical production and quality skills (PPQ) In order to classify expertise necessary for NP production and quality, we refer to two main documents:  CTD Quality sections, as per ICH guideline (ICH M4, 2002).  European Directive 2001/83 EC (European Parliament, 2001b,c). CTD describes how to structure data related to product quality in a format suitable to be submitted to the competent authorities. Several modules compose CTD, module 3 is split in two fields: part S related to API (drug substance), part P related to medicinal product (drug product). In case of DDS, module 3 describes all technical relevant characteristics. Main information reported in part S is: physicochemical and other relevant properties, manufacturing, elucidation of structure and other characte01ristics, specifications and analytical procedures, stability. Main information reported in part P is: pharmaceutical development section containing information on the development studies conducted to establish that dosage form, formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application; manufacturing, controls of excipients, materials, intermediates and drug product; stability data (ICH M4, 2002). In order to perform an in depth technical DDS appraisal, the PE should possess the expertise required to interpret adequately the information provided in the CTD module 3. The European Directive 2001/83 EC establishes the rules governing medicinal products in the EU. All EU Member States adopted the above-mentioned directive: it relies GXP rules to the Member State legislation for manufacturing of medicinal products. Production must be under the “ responsibility of a Qualified Person (QP), he controls and certifies that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that Member State and in accordance with the requirements of the marketing authorization”

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(European Parliament, 2001c). The QP exercises his own role affording to the skills necessary to manage production and analytical methods: i.e., assessing which CQA, CPP, CMA may have an impact on the patient, assessing its impact magnitude, operating in a Pharmaceutical Quality System that protects the patient. National competent authorities must certify the QP status based on specific university degree and professional experience (European Parliament, 2001b). Since QP must have specific knowledge in order to translate GMP rules into a medicinal product with proper quality, which includes being responsible for ICH Q8-Quality By Design and ICH Q9 Quality Risk Management, we can assume those skills as part of the PE expertise. NP technical peculiarity highlights relevance of PPQ skills: physicochemical characterization is critical because excipients and API exert complex interactions, it needs an in depth characterization in terms of their quality, quantity and spatial orientation. (Desai, 2012). It is a technical challenge, in spite of traditional dosage forms many more tests are required, each test is indicative of few quality parameters, analytical tests require complex methodology and advanced instruments. Scale up and manufacturing requires careful development in order to define CPP: little changes in some NP parameters affect dramatically EES, so difficult process step (i.e., sonication, crosslinking, emulsification, evaporation of organic solvents) must carefully scaled up in order to ensure strict quality standard and high batch to batch reproducibility. (Desai, 2012). Lastly, regulations rules: research, development and manufacturing of medicinal products, thus specific regulatory knowledge is common for both PF and PPQ skills. (Table 2) 3.2. Pharmaceutical appraisal format 3.2.1. Formulation appraisal Integration of physicochemistry, nanotechnology and biology makes possible to individuate a specific mechanism of action, to define DDS features able to achieve it, and to correlate it to physicochemical and biophysical properties of DDS. (Barenholz, 2012) At this stage, PE translates an idea into a medicinal products, he makes the invention and starts to bring it to the innovation. It is relevant to characterize fundamental NP properties such us size, surface and three dimensional structures, but also clarify drug loading and drug physical state (i.e., cristallin or amorphous). (Zucker et al., 2012) For example, during Doxil development results of initial clinical trials performed on the first liposomal formulation (OLV-DOX) were inadequate. (Barenholz, 2012) From a clinical point of view, some papers commented in a “ catastrophic” way the liposome ability as drug targeting system in tumors. On the contrary, from a pharmaceutical point of view, clinical trial were just a lightening starting point but it was necessary to analyz;1;e in depth causes of so disappointing clinical evidences. The pharmaceutical analysis of clinical trials results allowed the identification of three connections between mechanism of action, parmacokinetic profile and formulation flaws: (1)

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doxorubicin fast release into plasma related to type of liposome bilayer, (2) quick inactivation by RES related to high fraction of phosphatidylglycerol in bilayer, (3) lack in tumor extravasation related to too big liposome (Barenholz, 2012). Features of the ideal liposome were identified (long plasma circulation, proper drug loading, extravasation into tumour, release into target cells) and related formulative solutions were proposed (lipids composition, pH and drug loading, drug release properties). It is not aim of this paper to deal about just liposome development pathway, anyway above outlined features drove to the invention phase; along it, formulative challenges were overcame creating the liposomal formulation able to exert desired mechanism of action by a suitable manufacturing process. (Barenholz, 2012) During formulation development, PE interprets in vitro release test results, design and interpret in vivo test results, (Zucker et al., 2012) taking into account how and how much selected properties influence pharmacokinetics (Martinez et al., 2008). The in vitro/in vivo correlation is currently an open point, but it is a research phase where PE, collaborating with other scientist, can better understand correlation within biological behavior of NP and their technological properties. (Martinez et al., 2010) Additionally, for DDS in general and for NP in particular, each component matters and contribute to the performances and mechanism of action (Barenholz, 2012; Desai, 2012). At formulation stage, PE chooses excipients and proper strategy to build up desired NP, for exemple currently we have many polymers to be used for several formulation strategy and a lot of polymer therapeutics came into routine clinical use. PEG is a polymer frequently used for conjugation of proteins and peptides. When PE chooses PEG type, he must evaluate a broad band of biopharmaceutical issues because pharmaceutical properties- i.e., molecular weight of the PEG, site of conjugation and linking chemistry—carry out efficacy and safety of medicinal products as well the clinical indication for use. Anyway, also well-known polymer as PEG can led to clinical failure: in these cases, it is essential understand whether it relates to specific design features, quality issues and potential batch to batch variability, biological behavior of the medicine. (Duncan, 2014) NP properties selection in order to exert biological effect, in vitro-in vivo correlation, link between excipients and EES issues, are just some example to clarify how much is relevant PE contribution at HTA process. PE translate the medical need in to a product in the formulation phase: for that reason he possess an in depth knowledge on how and why (or why not) DDS exert the therapeutic effect; due to complexity of NP each excipients (type, physical state, etc.,) is critical to interpret their performance. PE, by proper formulation assessment, could analyze clinical data (which are the basis of EBM) by a specialist point of view, also from the safety side; besides providing a technological description (all excipients matters!), he could highlight pharmaceutical issues modulating mechanism of action helping to understand not explainable clinical outcome. PE links biological behavior with complex technological properties, he could look behind clinical evidence.

Table 2 PF and PPQ skills. Field

Disciplines included

Pharmaceutical formulation (PF)

Physical pharmacy, biopharmaceutics, pharmacokinetics, (Banker and Rhodes, 2002; Shergel et al., 2005; Krishna and Yu, 2008; Benita, 2005) analytics, (Banker and Rhodes, 2002; Shergel et al., 2005) biotechnology (Breuer et al., 2009), pharmaceutical technology (Banker and Rhodes 2002; Shergel et al. 2005; Krishna and Yu, 2008) regulatory (GXP) (Banker and Rhodes, 2002; Shergel et al., 2005), pre formulation sciences (Breuer et al., 2009), formulation sciences (Breuer et al., 2009)

Pharmaceutical production and quality (PPQ)

Pharmaceutical technology, pharmacology-toxicology, Medicinal chemistry, analytical chemistry, formulation sciences, chemistry (organic, inorganic), microbiology, manufacturing process and technology, regulatory (ICH M4, 2002; European Parliament 2001b,c)

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3.2.2. Manufacturing process appraisal Manufacturing is the bridge between research and patient: without product, there is not clinical outcome. For many reasons, product and process complexity and capacity issues are the main challenge for the Pharmaceutical Industry Supply chain (A. T. Kearney, 2014). Dealing about NP, production process is more difficult than traditional formulations; for example, it often requires high pressure or temperature that can lead to crystallinity change of the drug particles. Supply chain conditions (shipping, storage) can lead to sedimentation, agglomeration and crystal growth (Wu et al., 2011). Manufacturing is a challenge for innovation, small medium enterprises that applied for EMA scientific advice had been objections inherent to quality problems related to process validation, specifications and stability of data in the extent of 39% (EMA, 2013b). In oncology, NP complexity is troublesome, active targeted formulations require more components increasing manufacturing complexity in terms of process, equipment and quality system (Bertrand et al., 2014). For approved NP, solving production limits helps overcoming an important limiting step, paving the way for therapeutic use. (Venditto and Szoka, 2013) Relevant regulation as per biotechnology product must apply when manufacturers introduce modification to manufacturing process (in terms of equipment, materials, parameters, ecc.) or when they propose a “generic” version of the nanomedicine (EMA, 2013a,c). NP complexity and process variability does not allow to reproduce “equivalent” products, but it allows to ensure that “similar” products possess quality attributes within a range without impact on efficacy and safety: this similarity is mainly stated characterizing product quality profile (EMA ICH Q5E, 2005). Although HTA normally does not apply to “similar” products, regulations state that manufacturing process and physicochemical characteristics are decisive to determine the medicinal product efficacy and safety and to define the level of the clinical studies required for regulatory application. Correlation between NP and clinical outcome depends heavily on the complexity of production processes (small process variations even with the same qualitative and quantitative composition bring about great changes in the EES) and chemical and physical properties (which cannot be analysed using analytical methods unique and exhaustive) (EMA 2013a,c). Therefore, the PE expertise is useful at the HTA step because he can evaluate how manufacturing and quality attributes affect EES. Above all, the PE expertise could relate safety issues with potential quality problems due to batch to batch reproducibility, which is one of the main NP challenges. HTA process deals often with medicine innovation measurement. Manufacturing appraisal should contain any issues affecting patients and that is relevant to assess process innovation, just to give some example we focus on: shortage risk – patient safety – and cross contamination technology – process innovation. When different products are manufactured at the same facility, cross contamination (intended as undesired contamination of product A with product B) must be carefully evaluated in terms of risk. Recently, regulations strengthen requirements allowing production at same facility for different APIs (EMA, 2014a). In order to reduce risks, technical measures (i.e., insulator) and organizational measures (i.e., production on a campaign basis) take place. The aim is that contamination must not exceed the maximum allowable carryover limit, intended as allowed contamination of product A with the not wanted product B. Recent GMP guideline states that manufacture of different products can take place in the same facility (multishared facility) only when carryover limit is under the Permitted Daily Exposure (PDE), calculated by the formula taking care toxicological evaluation of substances.

When PDE is not available, or when an alternative approach cannot be adequately justified, or when proper technical and organizational measures cannot control cross contamination risk, dedicated facilities are required (Eudralex GMP, b). Materials exerting critical impact on the guideline are often constituents of DDS and NP in particular: excipients, active excipients or API can be sensitizing - i.e. cytotoxic molecules, macromolecules and peptides, which could potentially create conditions requiring dedicated facility (or department or production line) and/or complex and expensive technical and organizational measures (EMA, 2014a). Therefore, manufacturing process needs strong R&D, and high financial investment that is why HTA process should acknowledge manufacture also in terms of innovation. Others manufacturing issues affect the patient: process must reduce risk of shortage but many factors contribute to that: i.e., process and/or facility and/or equipment failure (Barenholz, 2012), supplier failure, and others. Unfortunately, technical or organizational measures cannot mitigate all failure risks. Although drug shortage not directly relates only to DDS, shortage multifactorial causes become more critical in case of complex manufacturing processes, supply chain, raw material type, and many other details handled within tight tolerances in the DDS arena. The ICH Q9 states clearly that a health damage can be caused by loss of product quality or availability, so ensuring the best product quality is not enough to protect the patient (ICH Q9, 2005): a careful shortage risk management must be performed in order to ensure availability to patients. Manufacturing process with mitigated shortage risks requires strong process research and a complex supply chain management by the pharmaceutical industry. HTA based decisions often restrict, or optimize, use of technology making recommendation not for all eligible patients but for patients subgroups, so much effort is exerted to produce appraisal having impact i.e., just on 50% of eligible patients (O’Neill and Devlin, 2010). HTA should consider high complex production as a key factor, because shortage has clinical impact, direct and clearly understandable toward 100% of eligible patients. This is important for life supporting medicines, or when they are life sustaining or intended for use in the prevention or treatment of a debilitating disease or condition: innovative DDS are often included in those conditions. For example, NP for solid tumors often do not have a generic version and even when a generic version is available, therapeutic change should be carefully evaluated because intrinsic complexity of NP cannot allow “equivalent” generic products but “similar” generic products. (EMA, 2013a) Regulatory agencies take care seriously of shortage: FDA is revising this procedure asking the industry to be aware six months before the shortage may occur (FDA, 2014a) EMA published a shortage catalog about product deficiency that affect or are likely to affect more than one European Union member state (EMA, 2014b). EMA does not give a complete overview of all medicine shortages occurring in the EU, as most dealt at a national level: for example in Italy a complete list is steadily monitored by AIFA (AIFA, 2014a). AIFA provides a list of medicinal products under shortage classifying if there is therapeutic alternative and indicating the shortage reasons: 63/195 (33.3%, data referred to August 2014) medicines without therapeutic alternative are on shortage for production problems (AIFA, 2014b). Manufacturing and quality assessment should be a critical HTA analysis point, in terms of product performance analysis and for innovation level measurement. On the other hand, it is possible to evaluate issues having impact on patient (like shortage risk, link between quality defects/process variability and clinical outcome), or issues highlighting process innovation as key step point to bridge DDS in therapy.

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3.2.3. Physicochemical appraisal Defining the DDS physicochemical characterization is an area between on going research and legislation to be adapted. NP can show physical instability (sedimentation, agglomeration, crystal growth and change in crystalline state) or chemical instability strongly related to API characteristics. Physicochemical instability may lead to side effects and should be evaluated for possible risks, due to the intrinsic stability lack of colloidal systems. For example, it is relevant to preserve particle size and size distribution during storage until patient administration, because formation of large particles could result in needle clogging and thromboembolism (Wu et al., 2011). Other links between biological effects and physicochemical properties: cytotoxicity is size, shape, and chemistry dependent; NP (silica, gold, silver) show size-dependent toxicity for small size than big size (approx. more than 100 nm) (Galvin et al., 2012). From the R&D point of view in order to support translation of nanomedicines to therapy, the ETPN enables physicochemical characterization as key knowledge and development step. In order to support this critical step, ETPN creates and coordinates a network of qualified centers able to perform analysis and related development of characterisation parameters (physical, chemical, in vitro and in vivo biological properties) called EU-NCL. EU-NCL should link with the European Medicines Agency (EMA) or other regulatory agencies in order to to facilitate the approval of Nanomedicine (European Technology Platform Nanomedicine, 2013). Due to nanomedicines complexity and due to the fact that experience with such products is limited, companies are recommended to require Authority scientific advice regarding specific questions and data requirements. Anyway, for NP physicochemical properties are critical factors to ensure EES and several guidelines show criteria to determine the physicochemical profile. Tests to determine the physicochemical profile are not unique, but the extent in physicochemical characterization determines clinical trial requirements in terms of breadth, depth and opportunity (EMA, 2013a,c,d). The PE experience in linking physicochemical properties with biological effects can enrich HTA evaluations, i.e., clarifying unexpected side effects due to physicochemical instability seen during clinical trials. Anyway, the PE could help evaluating NP effectiveness, and so to judge how NP work in the real world; in this case PE maximizes its contribution to HTA, because NP complexity combines with the real variables leading to an enormous number of potential situation impacting on EES. When stability related to diluted or reconstituted medicinal products in use is claimed, it should be properly investigated (EMA ICH Q1A, 2003), and from the microbiological point of view it should be precautionary managed (EMEA,1998). Normally, stability in use is performed on medicinal products packed in multidose containers, which can be opened and closed during their use, anyway stability is referred to well defined packaging materials, dilution composition and related standard preparation method (EMEA, 2001; EMEA ICH Q5C,1996). Referring to plastic packaging materials, stability studies should be conducted to characterize stability of medicinal product and plastic materials when in contact during storage time; evaluations comprises extraction studies, interaction studies (migration, sorption), toxicological data for extractable and leachable (EMEA, 2005). Thus, it is critical to understand if materials, environmental condition (i.e., temperature, light, etc.), administration scheme (duration, co-administration, etc.,) are in accordance with everyday conditions in healthcare. Cited factors affect i.e., API concentration and for a selected variable set a safe range for suitable use must be determined (Mollá-Cantavella et al., 2014; EMA, 2012). In this contest, NP are critical because their complexity generates evaluation issues to be analysed in the clinical practice. Reconstitution in situ procedures require high accuracy,

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repeatability and tight tolerances, and validation by proper investigational criteria (i.e., tests to ensure reliability of reconstitution procedure). Furthermore, it should be investigated: stability behavior when in contact with different plastic materials - i.e. device as bags- which may be different from materials tested during approval stability study; effect of mixing with other medicinal products routinely used in clinical practice; impact of any other issues on three dimensional form and size, surface characteristics, and other properties (EMA, 2012). These issues have impact on the patient, because could potentially affect EES of the drugs: some NP require reconstitution in situ, which is a fundamental step to ensure the three dimensional shape and the distribution needed to exert therapeutic effect. Therefore, the hospital pharmacist compounding the DDS, prior to administration, should execute a reliable and easily reproducible procedure. (Desai, 2012). As shown, there are many critical steps between end of production (performed under GMP) and administration to the patient, in this journey any critical event can affect the product but often there are not in place tests to identify it. Hospital organization, co-administration of others medicinal products, hospital logistic (pharmacy- compounding- patient) and many other factors produce heterogeneity and variability in critical events affecting physicochemical characteristics. It is impossible to identify a list of critical events valid in all circumstances, we can only identify and prioritize risks through risk analysis and propose corrective actions. Clinical risk management is a well defined requirement for hospital standards (MIN SAL, 2003, 2006; Joint Commission, 2013). Anyway, risk management on medicinal products requires specific skills and should be based on the expertise gained by GMP, where it is the basis of pharmaceutical quality systems (Eudralex GMP, c) and it is systematically and continuously verified by the regulatory authorities (PICS, 2012). We proposed implementation of quality risk management in clinical phases exploiting PE expertise, identifying PEs as hospital pharmacist and industrial pharmaceutical experts (Panzitta and D’Arpino, 2013; Panzitta et al., 2013; Panzitta and Ricci, 2014), both applying clinical pharmaceutics concepts (Florence, 2010; Florence and Attwood, 2006). As shown in Fig. 4, the rationale is to extend QRM as per ICH Q9 in clinical trials on specific points identified by a list of seven key elements having impact on patient. Analysed point include: physicochemical compatibility with administration device (i.e., bags), physicochemical compatibility with different co administered medicines, posology and logistics (i.e. effect of time, light, temperature), Look Alike Sound Alike risk, physicochemical stability (i.e., stability in use), compounding and preparation standard procedures.

Fig. 4. Extension of Quality Risk Management (ICHQ9) to Clinical Trials, source G.Claycamp, FDA, June 2006, readapted.

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The PE can identify and evaluate by proper methodology critical elements; as results, comparison of those data versus classic clinical trial data could be useful, because could clarify if some unexpected/unexplained therapeutic effect emerging as clinical outcome relates to potential events decreasing i.e., activity of DDS. Authors remarks relevance of this evaluation to interpret completely and correctly clinical outcome used at HTA step: DDS are often complex and susceptible to physicochemical degradation, furthermore already cited regulations recognise to physicochemical characteristics key elements to be more in depth evaluated versus traditional drugs and having impact on clinical outcome (EMA, 2013a,c,d). Thus, physicochemical evaluation, in situ reconstitution methodology and any other clinical pharmacy issues evaluated by Quality Risk management approach, are not just “quality” issue, and so well defined as per part 3CTD “Quality”, but clinical issue to be part of the HTA step. By means of Risk Management approach, PE could provide an effectiveness evaluation related to risk associated in the clinical practice, enriching HTA evaluation. HTA process should acknowledge as innovative properties the DDS characteristics, which decrease risks and implement efficacy, effectiveness and safety, Table 3 shows how the three format appraisal (A,B,C) apply to the HTA process 3.3. PE and format appraisal, link with EBM and HTA As mentioned in the introduction, the PE contribution integrates, enriches and broadens the clinical evaluations that are the basis of EBM. There are several definitions of EBM, commonly it is “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient. It means integrating individual clinical expertise

with the best available external clinical evidence from systematic research." (Sackett et al., 1996). EBM requires some steps in taking clinical decision: defining the clinical question, an in depth search of the literature about the question, review and appraisal of the literature in terms of quality, completeness, adaptability to the clinical contest (Jaeschke and Guyatt, 1999). Schematically, there are six key analysis steps linking EBM with technical assessment, some of them are shared (Table 4) and it is clear how clinical data are the basis for HTA.(Eddy, 2009) The three proposed appraisal formats explain how and where PE evaluation can implement current EBM, in order to extend the appraisal to pharmaceutics factors not measured by EBM but having impact on patients. Fig. 5 shows integration of pharmaceutics expertise in the current EBM-HTA approach highlighting the position of critical factors evaluated out of clinical trials. In the first EBM stages (analysis of clinical evidence, Table 4), mechanism of action strongly relates to the medicinal product physicochemical characteristics, so the PE can increase the knowledge of the critical elements necessary to understand in depth the mechanism of action and the related clinical outcome. In the subsequent outcome analysis, the benefit/risk ratio is performed to understand if the appraised technology is below or under the accepted limits (Eddy, 2009). For example, at this stage evaluation about reconstitution procedure, if executed by a rigorous and standardized QRM approach, helps understanding reproducibility in the clinical practice and it measures the related risks. Therefore, reconstitution procedure assessment increases the scientific relevance of the clinical outcome evaluation because it explores and clarifies the pharmaceutical issues having impact on the patient. Anyway, other factors affecting the patient are not directly measurable by traditional EBM, but they influence the real efficacy

Table 3 Shows how the three format appraisal (A,B,C in the table) apply along the HTA process; A: formulation, mechanism of action appraisal; B: manufacturing process and quality appraisal; C: physicochemical characteristics appraisa l.

A

B

C

Impact Impact on Point of view (skills) on effectiveness efficacy

Assessment example step

Contribution to HTA evaluation

DDS mechanism of action (biopharmaceutics) Active excipients role, criticism, safety Formulation assessment for “similar DDS” Vs originator

DDS mechanism of action, including “potential” innovation QbD/ X QRM QRM X Specialist overview on active excipients Comparison of: formulation, other ingredient’s role, mechanism of action

Tool

QbD

X

Manufacturing technical appraisal Shortage risk assessment Impact on efficacy and safety, relevance for mechanism of action Manufacturing assessment for “similar DDS” Vs originator;

Manufacturing makes available the therapeutic innovation. QbD Its complexity should be recognised as “real” innovation Patient protection in the clinical practice QRM CPP identification and inter relation with mechanism of QbD action and Manufacturing process

X

Comparison of process (CPP) and related controls

QbD

X

Impact on efficacy and safety, relevance for mechanism of action Preparation “in situ” assessment

CQA identification and inter relation with mechanism of action and Manufacturing process

QbD

X

Critical manipulation of the product not conducted under QRM the GMP. It must be reproducible and does not alter the quality of the product in clinical practice. Impact of current practice product’s manipulation QRM

X

QbD

X

Physicochemical interactions: materials, APIs, “current practice” stability in use Physicochemical assessment Comparison in terms of CQA for “similar DDS” Vs originator

Pharmaceutical scientist who formulated the DDS exerting mechanism of action X

X

Pharmaceutical scientist, Pharmacist and QP who developed Manufacturing process and related controls

X

X

Formulation scientist, Pharmacist and QP X

X

X

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Table 4 Link between EBM and Technology assessment (Eddy, 2009). Analysis stage

EBM step

Clinical evidence, individuals Clinical evidence, guideline and policies Outcome Economic Cost effectiveness Ethical/medical

1 2

Technology assessment step 2 3 (based on clinical evidence data) 4 5 6

Fig. 5. Integration between EBM and Pharmaceutical appraisal, numbers in bold refers to key analysis step as shown in Table 4, i.e., 3 refers to outcome analysis.

(effectiveness): for example, shortage risk can affect outcome analysis that is why we consider pharmaceutical appraisal as source of data for outcome analysis. HTA should assess the benefits and risks of the patient, including those that are not directly measurable by clinical trials, so by the proposed approach it could increase the spectrum of evaluated issues. Analysing best practice for HTA (Drummond et al., 2008), the PE involvement as HTA stakeholder can improve many principles. Although we defined just a general picture of PE potential contribution, principle 6 – HTAs should consider a wide range of evidence and outcomes – could be improved widening clinical evaluation with pharmaceutical issues clarifying evidence. Principle 2 and 8 focus on bias; Principle 8 states HTAs should explicitly characterise uncertainty surrounding estimates – because all data are subject to errors in ascertainment, measurement and interpretation; PE appraisal is made by intensive use of QbD and QRM which are highly structured approaches able to decrease (but not to eliminate) bias and subjectivity.

The HTA process often relates to the evaluation of therapeutic innovation of the medicinal product. There are a multitude of approaches and algorithms to determine the therapeutic innovation; they relate to the therapeutic advantage achievable, sometimes accounting the formulation and production process as factors increasing innovation. As shown, likewise other DDS, the NP manufacturing process represents one of the main R&D challenges. So, manufacture is often the critical step to achieve therapeutic effects, this strategic relevance should be accurately evaluated as innovation and acknowledged with high ranking value if decisive to product transfer to therapy. The impact of the development of adequate manufacturing process on the therapeutic progress will increase exponentially: DDS and NP in particular, require complex, expensive, low reproducible processes, critical to be managed under shortage risk. R&D and manufacturing are very challenging, but they bridge DDS from researcher bench to patient bedside, so they should be carefully assessed also in terms of innovation for two main reasons:

4. Conclusions In this paper we have dealt mainly with NP as a paradigm of innovative DDS, anyway the PE contribution and pharmaceutical appraisal formats could be useful also for all other kinds of DDS. Obviously, the more complex the DDS the more relevant is the PE contribution. Furthermore, some explained concept could be applied also to traditional medicinal products, but this will be analysed in further papers.

1) The difficulty to develop “similar” products, and so to technically assess a “similar” version of NP compared to “biosimilar” for biologic products: NP despite biologic products must comply with additional physical and physicochemical requirements, due to their overall relevance for EES (Desai, 2012; EMA, 2013a,c; Barenholz, 2012; FDA, 2014b). 2) Shortage risk management requires strong process innovation, while manufacturing routine is a mix of continuous R&D

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deployed on a quality system able to match regulatory requirements and availability to the patient: without medicinal product, there is not therapeutic effect. In this work, we do not deal with cost analysis and price determination scheme. HTA can account each evidence related to pharmaceutical issues, as per current practice, so the PE evaluation can add further elements to be considered at the cost analysis step (Drummond et al., 2010). The price is generally associated with the therapeutic value: over time, the therapeutic value decreases, and so does the price. Conversely, in the case of DDS the production cost can increase with time, because the regulatory requirements demand more reliable, complex and expensive processes. Production value and clinical value are timely anticyclical: one decreases with time and the other increases. To deal with it is not the subject of this work, but this is an emerging topic to be investigated in further articles. About interaction with EBM and current HTA process, authors proposed an enrichment of the current evaluation pathway: HTA is a multidisciplinary activity and so we proposed profile and methodology to include the PE expertise. Medicinal products are evolving rapidly and DDS represent a large share of therapeutic innovation (Anselmo and Mitragotri, 2014), the HTA should adapt the Technological Appraisal processes by including other relevant disciplines. Data related to stability in use, DDS manufacturing complexity, correlation between physicochemical characteristics and mechanism of action, complete the data set to achieve the best understanding overall impacts on patient. Above mentioned points are necessary to evaluate DDS, which are complex products and require an in depth technological analysis to link clinical evidence with its causes (see Fig. 6). Moreover, HTA can measure the DDS innovation level. Pharmaceutical features generating clinical outcome should be considered as innovative, because they often are the main R&D limiting step. This innovation acknowledgment will enable more medicines to come in therapy. The crucial role of pharmaceutical expertise in R&D is proven by the fact that the “invention” of NP manufacturing process and/or design is the gateway to clinical use.

There is a tremendous lack of available published data of NP formulations before clinical trial phase. (Venditto and Szoka, 2013) It should be useful to include the knowledge “inventing” the therapeutic innovation in the HTA process. In order to stimulate the “invention phase”, Venditto and Szoka proposed to fund the invention and innovation phases separately from clinical trials, this could also stimulate development of standardized approval procedures for NP. (Venditto and Szoka, 2013) Dealing with nanomedicines, regulatory standardization is an open challenge. In order to allow translation of nanomedicine to therapy, the ETPN recognises the manufacturing experts as stakeholders and it supports manufacturing process development and physicochemical characterization through funds and technical activities. (European Technology Platform Nanomedicine, 2013) Simplifying to the extreme, we could use an onomatopoeic criterion to envision a reasonable evolution of HTA: dealing with Pharmaceutical Technology Assessment should require a pharmaceutical technologist. This paper is not a guideline; it has the limitation to deal with very complex issues (DDS and HTA) in a concise way, trying to identify integration points between pharmaceutical assessment and the current practice based on EBM in terms of relevance, expertise and methodologies. Future papers will broaden this limited HTA vision, on the basis of this introductory article. This paper outlines also some critical factors affecting the patient currently not measured by EBM. Integration of the DDS HTA process with Pharmaceutics Expertise (PF and PPQ), may allow a better comprehension and judgment of clinical evidence, resulting in an overall improvement of patient safety and in a more accurate and complete technology assessment (see Fig. 6). The International Network of Agencies for Health Technology Assessment (INAHTA) defines HTA as “the systematic evaluation of the properties and effects of a health technology, addressing the direct and intended effects of this technology, as well as its indirect and unintended consequences, and aimed mainly at informing decision making regarding health technologies. HTA is conducted by interdisciplinary groups that use explicit analytical frameworks drawing on a variety of methods.” (INAHTA). In order to match the above-

Fig. 6. Pharmaceutical factors generating clinical evidence.

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