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Volume 7 Issue 1

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Transparent Regulations for Prescription Medicines The Australian way SUSAR Consolidation New Procurement Approach in Pharmacovigilance Creating A Culture of Trust and Breakthrough Innovation in Pharma Elastomer Gaskets for Injection and Infusion Systems

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Contents 04 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker EDITOR: Orsolya Balogh orsolya@pharmapubs.com EDITORIAL ASSISTANT Olga Henschke olga@pharmapubs.com BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: Paul Beckham paul@ipimedia.com DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks dorothy@pharmapubs.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Heather Bayran Heather@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: info@ipimedia.com www.ipimedia.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in June 2015. ISSN No. International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2015 PHARMA PUBLICATIONS Volume 7 issue 1 - Spring - 2015

06 Transparent Regulations for Prescription Medicines: The Australian Way The drug regulatory approval process is complex and resourceintensive. It must be accountable in terms of the quality, safety and efficacy of drugs. This accountability includes an acceptance of a balance between safety and efficacy. There is no such thing as a totally safe drug, and the approval process must recognise the risk/benefit ratio of any particular drug. The aim of this article is to focus on regulatory requirements and submission process for prescription generic drugs in Australia, written by V. Yugender Reddy, M. P. Venkatesh, and T. M. Pramod Kumar from Pharmacy, JSS University 14 Creating a Culture of Trust and Breakthrough Innovation in Pharma Today’s pharma industry is suffering a crisis of trust. It is grappling with a variety of issues that are affecting the industry’s performance and value and require an adjustment to the traditional business model. Dr Bart Sayle, CEO of The Breakthrough Group explains how to create a culture of trust and breakthrough innovations in pharma. 20 The Growing Prominence and Need of Patient-Reported Outcomes The challenge for pharmaceutical commercialisation no longer ends with regulatory approval; it intensifies after the approval. Today there is greater awareness about the benefit and risk of products, not only among healthcare professionals (HCPs), but also among consumers and the payers. Chitra Lele, Chief Scientific Officer at Sciformix Corporation, shares her thoughts about the need for patient-reported outcomes, and their growing prominence, by submitting a white paper on considerations for measurement, analysis and interpretation of data. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 26 Green Extraction to Development of New Therapeutics in the Pharmaceutical The term “green extraction” was coined to name new green methods, the use of which is more and more applied to processes aimed at preparing bioactive extracts or purified components from plants. Up until relatively recently, two techniques were used to extract bioactive molecules from vegetal resources: the traditional aqueous decoction and techniques using organic solvents are often toxic or expensive. Dr Celine Dejoye Tanzi, PhD, Green Extraction Laboratory Manager at Neuro-Sys, provides this article on the development of new bioactive drugs. 34 FDA Promotes pCR as an Endpoint for Neoadjuvant Breast Cancer Trials Drug sponsors seeking accelerated approval for neoadjuvant treatments of high-risk, early-stage breast cancer should consider using pathological complete response (pCR) as a primary endpoint, according to recent FDA guidance. Released in October 2014, Pathological Complete Response in Neoadjuvant Treatment of HighRisk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval is intended to encourage development of breakthrough therapies for patients with early-stage, invasive breast cancer who are at high risk for distant metastasis and death — an area of “significant unmet medical need,” according to the FDA Margaret Egan-Auderset of ThomsonReuters explains. 38 Producing Colorectal Cancer Vaccine: Combining Forces between Denmark and Estonia Dr Eric Leire, M.D., MBA, Chief Executive Officer, president and director of the board of DanDrit Biotech USA, Inc, and Kairit Tints, Head of Quality and Qualified Person in activities involving handling of cells and tissues at Cellin Technologies LLC. are providing this white paper on producing colorectal cancer vaccine: combining forces between Denmark and Estonia.

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Contents 44 Transparency: Turning Business Constraint into Commercial Advantage The pharmaceutical industry, one of the most crucial in the world in terms of impact on the lives of patients – from relieving pain to conquering disease – is in the midst of significant initiatives to improve transparency and build stronger public trust. In the following Regulatory and Marketplace feature we are going to read about Transparency: Turning business constraint into commercial advantage, by Guillaume Roussel, Director of Strategy, Europe, Veeva Network, Veeva Systems. CLINICAL RESEARCH 46 Remote Diabetes Trial puts Patients at the Heart of Trial Type 2 diabetes might just be the most dangerous non-communicable disease in the history of humankind, but putting patients in charge of their own care could help solve the problem. Zuzanna Fimińska, writer for www.eyeforpharma.com, discusses diabetes trials targeting the patients’ point. 50 SUSAR Consolidation New Procurement Approach in Pharmacovigilance In the past three to five years, pharmacovigilance has witnessed a paradigm shift after release of guidelines by the US Food and Drug Administration (USFDA) and European Medicines Agency (EMA) which has changed the way SUSARs have been managed. Pharmaceutical companies outsource SUSARs under the pharmacovigilance services to various suppliers based upon their geographical, product and service capabilities. Ashwini Tripathi, Senior Research Analyst of Voisin Consulting, explains how Suspected Unexpected Serious Adverse Reactions have become a critical element in analysing the risk and benefit associated with a life cycle of medicinal product either in the market or clinical trials. 52 A Review of Clinical Trial Challenges in Rare CNS Diseases Last year’s ice bucket challenge raised the profile of a rare CNS disease, amyotrophic lateral sclerosis (ALS), a form of motor neuron disease. There is a paucity of treatments for this disease and, like most CNS diseases both common and rare, nothing that alters the exorable progression, which in the case of ALS is likely to prove fatal in three to five years. Susan Mcgoldrick from QCTR provides a review of clinical trial challenges in rare CNS diseases.

resulting in undertreated conditions, increased emergency admissions, and reduced public health outcomes. In the following editorial, David Griffin, Senior Consultant at 42 Technology answers the question: can technology alone tackle the issue of medicine adherence? 74 Elastomer Gaskets for Injection and Infusion Systems Markus Rößler is Product Manager in the Business Team, Marketing and Sales, within the strategic Moulding / Pharma Solution business unit of RAUMEDIC AG. He shares his experiences about sterilisation, and microbiological purity, by presenting a white paper on elastomer gaskets for injection and infusion systems. PACKAGING 78 Predictive Shelf-life Moisture Control Computer Modelling for Ultra-reliable Pharmaceutical and Medical Device Packaging Solutions The new computer model developed by Baltimore Innovations’ R & D Director, Dr Mark Valentine, is a highly detailed evaluation of humidity and desiccant adsorption behaviour within a product’s protective packaging to avoid decomposition, degradation, or other forms of moisture damage. 84 Passive Temperature-controlled Packaging Reuse: Overcoming the Challenges of Quality and Asset Management Temperature-controlled distribution is an expanding market, with an average growth rate of approximately six per cent per year. But as the importance and value of temperature-sensitive pharmaceutical products increases, so does the legislation around how to safely store and distribute them. Stephen Healy, Global Director of Intelsius, provides this article on overcoming the challenges of quality and asset management through the passive temperaturecontrolled packaging reuse. 90 Improving Adherence: Packaging’s Synergistic Role in Delivery, Communication and Education Justin Schroeder, Executive Director, Marketing, Business Development & Design at Packaging Coordinators Inc. (PCI) shares his thoughts about packaging’s synergistic role in delivery, communication and education, by giving some examples on conscious and unconscious patient behavioral considerations.

LOGISTICS

SPECIAL FEATURE

58 Organising the Cool Supply Chain at Airports Stricter requirements for the transportation of pharmaceutical products have an impact on how the cool supply chain at airports should be organized. Despite the complexity of the effort, developing and implementing a global industry certification standard is crucial. Nathan De Valck from Brussels Airport has been working in the aviation industry since 2002. His cargo experience ranges from operational management, legal compliance, business development to commercial key account management at several airports in Europe. He talks about Supply Chain evolution, the work in progress and he explains how to optimise the Supply Chain.

94 Is There a Need for Virtual Pre-clinical CROs (vCRO) to Support the Life Science Industry? Pharma companies need in-vivo pharmacology and toxicology supplied by professionals. Virtual contract research organisations might be the future of drug development partnerships. But what does a vCRO CEO think about this? Is there a need for virtual preclinical CROs to support the life science industry? In the following interview, Urban Hoglund shares his views.

MANUFACTURING 64 When Power Failure is Not an Option Smartphones and portable medical devices are being increasingly used together, raising the eyebrows of many in the industry. Here, Neil Oliver, Technical Marketing Manager at Accutronics, explores the safe transition of medical equipment into the rapidly-changing mobile space. 66 Can Technology Alone Tackle the Issue of Medicine Adherence? Though therapeutic treatments are generally trialled, approved and introduced based on the assumption of correct usage, actual patient adherence has been shown across a range of situations to be less than 50%, 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Editor's Letter IPI has started a new year and we hope that 2015 will serve our readers with many new and informative articles. In this first issue of 2015, we are bringing you another set of exciting articles. JSS College of Pharmacy are always happy to share their innovations and studies with us. In this issue they focus on the regulatory requirements and submission process for prescription generic drugs in Australia. V. Yugender Reddy, M. P. Venkatesh and T. M. Pramod Kumar discuss how products for which therapeutic claims are made must be listed, registered or included in the Australian Register of Therapeutic Goods before they can be marketed in Australia. Another regular contributor, Beroe, wrote many features for us last year. In this issue Ashwini Tripathi of Beroe Inc. deals with Suspected Unexpected Serious Adverse Reactions (SUSARs), and he tell us how they have become a critical element in analysing the risk and benefit associated with a life cycle of medicinal product, either in the market or clinical trials. Today’s pharma industry is suffering a crisis of trust. It is grappling with a variety of issues that are affecting the industry’s performance and value. It requires an

adjustment to the traditional business model. Dr Bart Sayle, CEO of The Breakthrough Group and author of the bestselling book, Riding The Blue Train: A Leadership Plan for Explosive Growth, explains how to create a culture of trust and make breakthrough innovations in pharma. We are happy to welcome Sciformix on board again with their excellent writer, Chitra Lele. She is submitting a white paper on the need for patient-reported outcomes, by considering the measuring, analysis and interpretation of data. This year’s first edition could not exist without clinical research articles. We were pleased to get in touch again with Susan McGoldrick from QCTR, who was happy to create a new white paper for us by continuing her studies of the world of the central nervous system and reviewing the clinical trial challenges in rare CNS diseases.

new therapeutics in the pharmaceutical industry. In ‘Special Features’, we answer the following question: “Is there a need for virtual pre-clinical CROs (vCRO) to support the life science industry?” To do this, we are having a ‘Q&A’ with Urban Höglund, CEO of Adlego, who has a PhD in pharmacology and is assistant professor in laboratory animal medicine. The Pharma Publication team is happy to continue publishing about the pharma industry by commissioning many new and informative papers from and for the industry professionals of 2015. Orsolya Balogh Editor

Development of new bioactive drugs nowadays mainly involves extraction of new compounds from plants. For some years, methods of extraction have tended to become “greener”, solvent-free, energy-efficient, decreasing the amount of non-useful components produced during the extraction process, while ensuring quality, reproducibility and efficiency of finished products. Dr Celine Dejoye Tanzi, PhD, green extraction laboratory manager at Neuro-Sys deals with the green extraction developments of

Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

Jagdish Unni Vice President- Beroe Risk and Industry Delivery Lead- Healthcare, Beroe Inc.

Catherine Lund, Vice Chairman, OnQ Consulting

Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma Jim James DeSantihas, Chief Executive Officer, PharmaVigilant Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP Nermeen Varawalla, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmac Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Spring 2015 Volume 7 Issue 1


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Regulatory & Marketplace

Transparent Regulations for Prescription Medicines: The Australian Way Abstract defines a medicine as “Therapeutic goods The aim of this article is to focus on the that are represented to achieve, or are regulatory requirements and submission likely to achieve, their principal intended process for prescription generic drugs action by pharmacological, chemical, in Australia. A product for which immunological or metabolic means in or therapeutic claims are made must be on the body of a human or animal.”2 listed, registered or included in the Australian Register of Therapeutic Goods Classification of Medicines before it can be marketed in Australia. TGA categorises medicines into The drug regulatory approval process the following groups for regulatory is complex and resource-intensive. It evaluation, as shown in Figure 1. must be accountable in terms of the Medicines quality, safety and efficacy of drugs. This accountability includes an acceptance of Complementary OTC Medicines Prescription Medicines Medicines a balance between safety and efficacy. There is no such thing as a totally safe Figure 1: Classification of medicines in Australia drug, and the approval process must recognise the risk/benefit ratio of any Complementary Medicines particular drug. This requires a detailed Therapeutic goods consisting wholly or evaluation of the data supplied by the principally of one or more designated sponsoring company. In view of this, active ingredients, each of which has a TGA increased the transparency of the clearly established identity of a traditional evaluation process and introduced well- use or any other use prescribed in the defined timelines which benefited the regulations. pharmaceutical companies in obtaining product approvals without any time OTC Medicines delay. An over-the-counter (OTC) medicine is Key words: TGA, ARTG, Prescription, a therapeutic good mentioned in Part 3 Generics. of Schedule 10 of the Therapeutic Goods Act 1989 that does not meet the criteria Introduction for mention in Schedule 4, 8 or 9 of the The apex regulatory body for Australia Poisons Standard. is the Therapeutic Goods Administration (TGA). The Therapeutic Goods Act 1989 Examples include antiseptics, provided a national framework for sunscreens, all other therapeutic goods, the regulation of therapeutic goods in except for a therapeutic device not Australia, so as to ensure their quality, mentioned in another Part of Schedule safety, efficacy and timely availability. 10, an excipient in therapeutic goods TGA ensures that the necessary mentioned in Schedule 10, therapeutic evaluation and assessment procedures goods referred for evaluation to the for medicines are conducted to enable Scheduling and Over the Counter Drug consumer access to the latest treatments, Evaluation Section of the TGA. which are safe and of good quality, in a timely manner. Prescription Medicines3 Prescription medicines are high-risk In Australia, medicines are classified as medicines that contain ingredients that registered medicines or listed medicines, are described in Schedule 4, Schedule depending on their ingredients and 8 or Schedule 9 of the Standard for claims made. Registered medicines can the Uniform Scheduling of Drugs and be further classified as non-prescription Poisons and are available by prescription (low-risk) registered medicines and only. All prescription medicines must be as prescription (high-risk) registered registered. The Drug Safety Evaluation medicines. All medicines which are for Board evaluates the majority of export only are considered as listed prescription medicine applications. medicines1. Examples include all prescription medicines and all injectables. The Therapeutic Goods Act 1989 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

For obtaining an approval, the generic manufacturer should provide quality data and should demonstrate the bioequivalence of the generic drug product with reference to drug product by submitting the dossier in Common Technical Document (CTD/eCTD) format. The newly-introduced “Prescription medicines registration process” improved the transparency of the approval process and timelines. The implementation of this submission process is considered one project within the Business Process Reform (BPR) programme. Each month, the BPR provides information on the progress of pre-submission planning forms (PPF) and submissions under the prescription medicines registration process, and other information to assist sponsors with the new requirements. Types of Applications2, 3 Prescription medicines applications are classified into three categories: Category 1: Applications for new chemical entities, new biological entities, new combination products, extension of indications, major variations, new generics, minor variations etc. fall under the category 1 application. Evaluation time: 255 working days from the date of acceptance. Category 2: Category 2 applications are generally supported by previous approvals and independent evaluation reports, from two acceptable countries. Evaluation time: 175 working days from the date of acceptance. Category 3: Category 3 applications involve changes to the quality data of medicines already included on the Australian Register of Therapeutic Goods (ARTG) which, in the opinion of the TGA, do not need to be supported by clinical, non-clinical or bioequivalence data. Evaluation time: 45 days receipt of the application. The TGA targets the following mean evaluation times, excluding any clock stops to respond to S31 questions (consolidated request by the TGA to provide additional information Spring 2015 Volume 7 Issue 1


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Regulatory & Marketplace or documents), for different types of application: • • • • • •

New chemical entities - 150 working days New generics, other than additional trade names only - 100 working days New indications - 160 working days Product information changes - 90 working days Additional trade names only - 45 working days Other category 1 applications - 130 working days.

The key elements of this submission process are: 33 a pre-submission planning phase, where the sponsor lodges details of a proposed submission at least 2¼ months prior to lodgement of the actual submission and associated dossier 33 use of information submitted in the pre-submission phase to identify evaluation resource requirements, timeframes and key milestones for the assessment and determination of the submission 33 improved quality of submission dossiers (i.e. prepared in CTD format and other TGA requirements) 33 comprehensive process to check the submission dossier prior to commencement of the evaluation process to ensure compliance with TGA regulatory requirements (i.e. submission is effective) 33 implementation of new business processes within the TGA to manage effectively the workflows associated with submission assessment and determination 33 consolidation of regulatory requests issued under S31 of the Therapeutic Goods Act 1989 (the Act) at a single stage in the evaluation process, and a requirement for sponsors to provide information and documents in response within a defined timeframe. Critical Requirements for Compilation A. Quality requirements B. Labelling requirements C. Bioequivalence studies

Dossier

A. Quality Requirements4, 5 With regard to quality (Q) data, the submission should include at least general information and information 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

related to the starting and raw materials, manufacturing process of the active substance(s), data on characterisation of the active substance(s), control of substance(s), and description and composition of the finished medicinal product. The applicant should provide a statement on the components and composition of the product, followed by information on raw materials (active ingredient and inactive ingredients), description of manufacturing facility, manufacturing process and packaging instructions, in-process information, packaging material controls, controls for finished dosage form, analytical methods for the drug substance and drug product, stability of finished dosage form, and availability of samples. If the generic product is a parenteral product, the applicant must provide sterilisation assurance information and data package. B. Labelling Requirements6 The Therapeutic Goods Order 69 general requirements for labels for medicines (TGO 69), sets out the legislative general requirements for labels for medicines. 1. Space for the pharmacist's label There should be a clear space for the pharmacist's dispensing label measuring a minimum of 80 x 40 mm, the size of a commonly-used computer-printed dispensing label. Dispensing label contains batch number, expiry date, storage instructions, product name, strength, name of the active ingredient(s), dose form, barcode (EAN barcode), signal headings, warning statements, AUSTR number. 2. Batch number and expiry date The batch number and expiry date should be positioned together and situated preferably on the end or side panel of the package. For example ink is preferred over embossing. For eye preparations and other topicals, the words "after opening use within [xx] days" should be on the label. 3. Storage conditions Ideally, the storage conditions should be located close to the batch number and expiry date, and preferably on the front or side panels as end panels are already filled with product / active ingredient names and / or batch expiry information.

4. Barcode An EAN barcode can be used to facilitate electronic aids during dispensing. To be effective, it must be easily located so that it will not be covered by the pharmacist's dispensing label and can still be scanned after the pharmacist has affixed the dispensing label. 5. Product name and strength Both the product name and the active ingredient names and strength should be prominently and equally displayed on the packet on at least three sides, including the two end panels. Strength and quantity should also be displayed. 6. Dose form Terminology concerning the long-acting dose forms should be accurate, relate to the product and be clearly specified on the label. For example, extended release, sustained release, controlled release or modified releases are sometimes used. 7. Packaging colour and design The use of colour and design should not unnecessarily clutter or obscure the message of the labels but make them clear and distinguishable. Pictures or graphics should be meaningful and appropriate, represent the use of a medicine, and not suggest an unapproved use. Consideration should be given to including a graphical representation of dosage form on the outer packet. 8. Tamper-evident packaging The tamper-evident packaging should not interfere with the ability of the pharmacist to place the dispensing label. 9. Blister packaging Ideally for blister packaging, each blister cover should include both the active and the product names, and the strength, batch number and expiry date of the medicine. However, this is not always possible. In cases where blisters are small, repetitive diagonal use of product names over the blister covers with expiry date and batch number on the side can assist with identification of partly-used packs. 10. Use of product names in other documents Consumer Medicine Information (CMI) The CMI should contain both active and product names at the beginning of the document. Use of product name is only encouraged where information relates to that product of the medicine. Use of active Spring 2015 Volume 7 Issue 1


Regulatory & Marketplace ingredient name for negative information only is not acceptable. Product Information The product name should not be used only to present positive information in the product labelling, nor the generic name used to present only negative information associated with the product. The product name should only be used where the information only applies to the characteristics of the branded product, for example, the description, form of presentation, strength, method of use and dosage. C. Bioequivalence Requirements7- 11 Two medicinal products containing the same active substance are considered bioequivalent, if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailability (rate and extent) after administration in the same molar dose lie within acceptable predefined limits. The plasma concentration time curve is generally used to assess the rate and extent of absorption. Selected pharmacokinetic parameters and preset acceptance limits allow the final decision on bioequivalence of the tested products. The area under the concentration time curve reflects the extent of exposure. Cmax, the maximum plasma concentration or peak exposure, and the time to maximum plasma concentration, tmax, are parameters that are influenced by absorption rate. Generic medicinal products The purpose of establishing bioequivalence is to demonstrate equivalence in bio pharmaceutics quality between the generic and reference medicinal product. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. Design, conduct and evaluation of bioequivalence studies The number of studies and study design depend on the physico-chemical characteristics of the substance, its pharmacokinetic properties and proportionality in composition, and should be justified accordingly. In particular, it may be necessary to address the linearity of pharmacokinetics, the 9 INTERNATIONAL PHARMACEUTICAL INDUSTRY

need for studies both in fed and fasting state, the need for enantioselective analysis and the possibility of waiver for additional strengths. The study should be designed in such a way that the formulation effect can be distinguished from other effects. Standard design If two formulations are compared, a randomised, two-period, twosequence single-dose crossover design is recommended. The treatment periods should be separated by a wash-out period sufficient to ensure that drug concentrations are below the lower limit of bioanalytical quantification in all subjects at the beginning of the second period. Normally at least five elimination half-lives are necessary to achieve this. Alternative designs Under certain circumstances, provided the study design and the statistical analyses are scientifically sound, alternative well-established designs could be considered, such as parallel designs for substances with very long half-life and replicate designs. E.g.: for substances with highly variable pharmacokinetic characteristics. Test product The test product used in the study should be representative of the product to be marketed and this should be discussed and justified by the applicant. For oral solid forms for systemic action: The test product should usually originate from a batch of at least 1/10th of production scale or 100,000 units, whichever is greater, unless otherwise justified. The production of batches used should provide a high level of assurance that the product and process will be feasible on an industrial scale. In case of a production batch smaller than 100,000 units, a full production batch will be required. The characterisation and specification of critical quality attributes of the drug product, such as dissolution, should be established from the test batch, i.e. the clinical batch for which bioequivalence has been demonstrated. Samples of the product from additional pilot and / or full-scale production batches, submitted to support the application, should be compared with those of the bioequivalence study test batch, and should show similar in

vitro dissolution profiles when employing suitable dissolution test conditions. Comparative dissolution profile testing should be undertaken on the first three production batches. If fullscale production batches are not available at the time of submission, the applicant should not market a batch until comparative dissolution profile testing has been completed. Selection of the reference product The selection of the reference product used in a bioequivalence study should be based on assay content and dissolution data and is the responsibility of the applicant. Unless otherwise justified, the assayed content of the batch used as test product should not differ more than 5% from that of the batch used as reference product determined with the test procedure proposed for routine quality testing of the test product. The applicant should document how a representative batch of the reference product with regard to dissolution and assay content has been selected. It is advisable to investigate more than one single batch of the reference product when selecting reference product batch for the bioequivalence study. Submission Process12 The process of submission is divided into six phases: Phase 1: Pre-submission Sponsors complete and lodge a presubmission planning form. The PPF provides information on the scope and scale of a submission, including details of the quality, non-clinical, and clinical evidence. Based on the PPF information, the TGA assign resources for the evaluation process. PPF should be lodged at least 2Âź months prior to the intended lodgments date for the submission. Within six weeks of receipt of a PPF, the TGA will send the sponsor a TGA planning letter that provides the expected submission date. Phase 2: Submission The planning letter sent by TGA identifies whether the submission is accepted for evaluation. After receipt of the TGA planning letter, lodgment of submission along with supporting data is to be done within a month. Sponsors must lodge well-planned, high-quality, Spring 2015 Volume 7 Issue 1


Regulatory & Marketplace complete submission dossiers. Sponsors must ensure submissions meet the TGA requirements for format and content. Requirements during submission a. Application Fee ($16,600)13: The application fee is a proportion of the evaluation fee that is nonreimbursable from the time of submission. Where submissions are not accepted due to deficiencies in the submission, this amount will be retained by the TGA, covering administrative costs associated with the submission phase. b. Evaluation Fee ($66,000)13: For Category 1 and 2 submissions, payment of 100% of the evaluation fee is required when the submission is lodged.

Table 1: Number of copies of modules required by submission type14

Phase 3: 1st-round assessment The 1st-round assessment will consider all the supporting data provided with the submission. Where there are issues or questions about any component of the submission, a consolidated set of questions from all evaluation areas within the TGA will be developed and sent to the sponsor by a pre-determined date. The default period of the 1st-round assessment is 90 days for completion, with an additional 30 days for the preparation of the consolidated set of questions. Phase 4: 2nd-round assessment Response to questions should be send to the TGA by the sponsor within 30 days. Responses must be provided in electronic text PDF format. Sponsors should also submit a hard copy of their response. Data evaluation15 The data submitted with an application is divided into three types. Quality data • The composition of the drug substance and the drug product • Batch consistency • Stability data • Sterility data (if applicable) • The impurity content

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The data submitted will be evaluated by chemists, biochemists, microbiologists, toxicologists and others working for the TGA.

Non-clinical data • Pharmacology data • Toxicology data Non-clinical data will be evaluated by toxicologists. Clinical data • Mostly results of clinical trials Clinical data are usually evaluated by a medical doctor. Each data set is evaluated Figure 2: Summary of the evaluation process for category 1 and 2 separately by applications three independent DSEB - Drug Safety Evaluation Board e v a l u a t o r s ADEC - Australian Drug Evaluation Committee PSC - Pharmaceutical Subcommittee g e n e r a t i n g Source: http://www.tga.gov.au/pdf/archive/pm-argpm.pdf three evaluation reports. Before sponsor prior to making a decision. the evaluation reports are finalised, the evaluators may ask the sponsor questions about Phase 6: Post-decision the data submitted. Once completed, The Australian public assessment the evaluation reports are reviewed report (AusPAR) provides information internally before they are authorised and about the evaluation of a prescription sent to the sponsor; the sponsor then has medicine and the considerations that the opportunity to make comments. For led the TGA to approve or not approve generic drug products, expert review an application. The AusPAR is drafted during the post-decision phase and may be optional. sent to the applicant for review prior to publication. Any outstanding evaluation Phase 5: Decision The TGA delegate will decide whether payments are finalised (if applicable), the submission is to be approved or relevant documents are published on the rejected. Where any outstanding issues TGA website, and a new or varied entry may affect the decision, the delegate may is made to the ARTG. liaise directly with the sponsor during this When compared to the Australian phase before finalising their decision. The Medicines Streamlined delegate will review all documentation Prescription associated with the submission and will Submission Process (old) the Australian Medicines Registration make an assessment of the risks and Prescription benefits. As part of the review, there may Process (new) is divided into phases be a number of outstanding issues. These which have definite timelines and may relate to suggestions for revision of milestones for each phase. These timelines the product information (PI), CMI or risk are available to the applicant from management plan (RMP), or may be for the planning letter issued by the TGA. general registration details. The delegate may negotiate these issues with the INTERNATIONAL PHARMACEUTICAL INDUSTRY 10


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Regulatory & Marketplace paper_how_to_register_ medicines_australia.pdf 3. Gupta, M.M., Varun Singh Bhati. Dossier submission to TGA for prescription only medicines. International Journal of Pharmaceutical Studies and Research. E-ISSN 22294619. 2010; 1(1):1-10 Available from: http://www. technicaljournalsonline.com/ ijpsr/VOL%20I/IJPSR%20 VOL%20I%20ISSUE%20I%20 J U LY % 2 0 S E P T E M B E R % 2 0 2010/IJPSR%20VOL%20 I%20ISSUE%20I%20 Article%201.pdf [Accessed on 12th Oct 2013] Table 2: Action plan and timelines for generic application 4. Therapeutic Goods Administration, Details Australian Prescription Australian Prescription Medicines quality module [Internet] Medicines Registration Process Streamlined submission Process (old) [Accessed on 17 Jan 2014]. Available from: http://www. (New) tga.gov.au/industr y/pmNot defined Pre-submission Defined and available argpm-ctd.htm#eumod3 planning form 5. Therapeutic Available Pre-submission Available Goods Administration, quality guidelines [Internet] meeting [Accessed on 17 Jan 2014]. Not available Planning letter Defined and available Available from: http://www. by TGA tga.gov.au/industr y/pmNot available Phases of Available euguidelines-adopted-quality. htm#.UwL6tvmSw74 evaluation 6. G e n e r a l Defined and available Not available Notification requirements for labels for letter by TGA medicines. Therapeutic Defined and available Goods Order 69. [Online] Section 31 Defined and available [Accessed on 15 Jan 2014]. (S31) request Available from: http:// Available Only meets the overall evaluation Definite www.tga.gov.au/industry/ timeline timelines for labelling-pm-best-practice. htm each phase 7. U p e n d r a Not available Milestone for Available C. Galgatte, Study evaluation in on requirements of each phase bioequivalence for registration of pharmaceutical products in Committee on Australian Drug Evaluation Committee Expert review Australian USA, Europe and Canada Prescription Medicines (ACPM), (ADEC), Pharmaceutical Subcommittee by [Online] [Accessed on 15 Pharmaceutical Subcommittee (PSC). Jan 2014]. Available from: (PSC). http://www.sciencedirect. com/science/ar ticle/pii/ Defined and available Not defined Australian S1319016413000455 public 8. E u r o p e a n assessment Medicines Agency, Guideline report On The Investigation Of Bioequivalence, (AusPAR) [Online] [Accessed on 12 Jan 2014]. Available Table 3: Comparison of Australian Prescription Medicines Registration Process (New) to Australian from: http://www.ema. Prescription Medicines Streamlined submission Process (old)        e u r o p a . e u / d o c s / e n _ G B / document_library/Scientific_ Conclusion guideline/2009/09/WC500003011.pdf Getting approval for the generic drugs 9. Verbeeck, R.K., Generic substitution: The use of medicinal products containing different was ambiguous and unorganised till salts and implications for safety and efficacy, the initiation of the prescription drug European Journal of Pharmaceutical Sciences, [Online] [Accessed on 10 Jan 2014]. Available submission process. The TGA increased from: http://www.rkv-consultancy.com/docs/ the transparency of evaluation by Alternative%20salts%20-%20EJPS%202006.pdf providing well-defined process timelines 10. Alfredo García-Arieta, Bioequivalence Requirements in the European Union: which benefits the pharmaceutical Critical Discussion, American Association of companies in obtaining approval without Pharmaceutical Scientists [Online] [Accessed on 10 Jan 2014]. Available from: http:// time delay. www2.far.fiocruz.br/farmanguinhos/images/ Bioequivalence%20Requirements%20in%20 References the%20European%20Union%20-%20Critical%20 1. TGA basics. Department of Health and Ageing. Discussion.pdf Therapeutic Goods Administration. [Online] 11. Verbeeck, R.K., Generic drug product development [Accessed on 15 Jan 2014]. Available from: international regulatory requirements for http://www.tga.gov.au/about/tga.htm. bioequivalence, Chapter-5, European Union, 2. How to register medicines in Australia [Online] [Online] [Accessed on 10 Jan 2014]. Available [Accessed on 27 Jan 2014]. Available from: from: http://www.rkv-consultancy.com/docs/ http://www.pharmout.net/downloads/white_ 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

12.

13.

14.

15.

BE%20Regulatory%20Requirements%20EU%20 -%202010.pdf Therapeutic Goods Administration, Prescription Medicines Registration process [Online] [Accessed on 01 Jan 2014]. Available from: http://www. tga.gov.au/industry/pm-argpm-process.htm Therapeutic Goods Administration, Summary of fees and charges [Online] [Accessed on 10 Jan 2014]. Available from: http://www.tga.gov.au/ pdf/fees-130701.pdf Therapeutic Goods Administration, General dossier requirements for prescription medicines [Internet] [Accessed on 10 Jan 2014]. Available from: http://www.tga.gov.au/industry/pmargpm-dossier-requirements-05.htm Therapeutic Goods Administration, Australian regulation of Prescription medicinal products [Internet] [Accessed on 11 Jan 2014]. Available from: http://www.tga.gov.au/industry/pmbasics-regulation.htm#evaluation

Mr. V. Yugender Reddy is currently a post graduate student at JSS College of Pharmacy, Mysore. He is graduated (B. Pharm) from University College of Pharmaceutical Sciences, Kakatiya University, Warangal. Email: yugender. vanavasam@gmail.com Dr. M. P. Venkatesh is an Assistant Professor in Department of Pharmaceutics in JSS College of Pharmacy, Mysore. He has teaching experience of 7 years. He has guided 12 M. Pharm candidates and authored 16 International and National publications in reputed journals. He has attended various national and international conferences and currently he is working on drug regulations in regulated countries. Email: venkateshmpv@gmail.com Dr. T. M. Pramod Kumar is Professor and Head of the Department of Pharmaceutics in JSS College of Pharmacy, Mysore. He has 20 years of teaching experience. He has guided 5 Ph.D. candidates. He has authored 70 International and 50 National publications and has chaired scientific sessions nationally & internationally. Email: tmpramod@yahoo.com Spring 2015 Volume 7 Issue 1


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These customers trust Mikron 3M Health Care, Alere, Aptar Group, Bausch & Lomb, Bespak, B. Braun Medical, Bang & Olufsen Medicom, Eli Lilly and Company, Forteq, Gerresheimer, GlaxoSmithKline, Innovata Biomed, Novo Nordisk, Nypro, Oechsler, Pfizer, Precision Valve, Rexam, Schott, Sanofi, Tech Group, Teva Pharmaceuticals, Vygon, Ypsomed At a glance • Mikron Automation is a leading global manufacturer of automation solutions for cost efficient manufacturing of products in high quantities • Worldwide presence to support our clients locally • Facilities in Boudry (Switzerland, headquarters), Berlin (Germany), Denver (USA), Singapore and Shanghai (China). • 570 employees • CHF 126.8 million in annual sales revenue (2014) • Close to 40 years of experience • 250 customers worldwide • 3000 installed systems • Over 40 projects a year • 4 to 12 months delivery time • Every day 45,000,000 components are assembled on Mikron solutions Company Name: Mikron Automation Address: route du Vignoble 17 / 2017 Boudry / Switzerland Tel: +41 32 843 11 11 Fax: +41 32 843 11 12 Web: www.mikron.com Key Contact: Jean-François Bauer / Head of Marketing & Business Development Mikron Automation Email: mbo@mikron.com


Regulatory & Marketplace

Creating a Culture of Trust and Breakthrough Innovation in Pharma Today’s pharma industry is suffering a crisis of trust. It is grappling with a variety of issues that are affecting the industry’s performance and value and require an adjustment to the traditional business model. To thrive in this new environment, top leaders will not only have to develop innovative patientcentred models, they will also need to achieve enterprise-wide culture change and facilitate breakthrough innovation. There is an urgent need for the pharma industry to redefine itself in the minds of stakeholders following the disappointing business and share price performance of recent years. Pharma companies must also win back trust; they have created the perception that they put their commercial goals above the interests of governments, payers, prescribers and patients. According to PWC’s Report ‘From Vision to Decision Pharma 2020’, the pharma industry faces three fundamental challenges. First, rising customer expectations. The commercial environment is getting harsher. Healthcare payers are imposing new cost constraints on providers and are scrutinising the value of medicines more carefully. They want new therapies that are clinically and economically better than the existing alternatives, together with hard, real-world outcomes data to back any claims about a medicine’s superiority.

problem. “The Big Pharma culture has been homogenised, purified, sterilised, whipped, stirred, filtered, etc. and lost its ability to ferment the good stuff required to innovate. This isn’t covered in most reviews of the productivity challenge facing our industry, because it’s nearly impossible to quantify, but it’s well known and a huge issue.” He cites three hallmark traits of the culture crisis facing pharma from his vantage point: tyranny of the committee, stagnation through risk avoidance and the negative impact of mega-mergers and reorganisations. Booth isn’t alone in blaming the industry’s declining scientific productivity on cultural influences. In a recent survey of 150 R&D executives by Heidrick & Struggles, 54% cited lack of creativity as a key organisational issue, while 53% cited lack of coordination between the R&D and commercial functions. The conclusion from a 2012 Nature article by researcher Jack Scannell: “The number of new drugs approved per billion U.S. dollars spent on research and development has halved roughly every nine years since 1950, falling around 80-fold in inflation-adjusted terms.” It’s a stunning fact. And the pharmaceutical industry has been scrambling for a way to address it ever since.

And thirdly, cultural sclerosis. The prevailing management culture, mental models and strategies on which the industry relies are the same ones it’s traditionally relied on, even though they’ve been eclipsed by new ways of doing business.

Against this background, the results of a recently-published article from PatientView Quarterly entitled ‘The Corporate Reputation of Pharma – The Patient Perspective’, based on a survey of 600 international, national and regional patient groups, cannot be a surprise. Only 34% of respondents gave pharma a “good” or “excellent” rating for reputation. The patient groups listed a number of areas where pharma was rated as having a “poor” record including: a lack of fair pricing policies leading to unseemly profits (50%); a lack of transparency in all corporate activities (48%); management of adverse event news (37%); acting with integrity (32%).

Life sciences venture capitalist Bruce Booth argues that pharma’s performance decline is largely a cultural

There were a number of themes that supported these poor ratings: lack of affordable medicines, a perception that

Secondly, low scientific productivity. Pharma’s output has flatlined for the past decade. Yet the processes it uses to discover and develop new products remain much the same.

14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the industry is preoccupied with drugs that offer only short-term health benefits, inappropriate marketing of drugs, and lack of transparency in reporting results from negative clinical trials. In fairness to pharma, it has been working hard to improve in these areas and there are some great success stories. But it is time for the industry to redouble its efforts. So what can the industry’s senior figures do to rebuild public trust and build healthy, high-performing companies to successfully meet pharma’s fundamental challenges of the future? They would be well advised to start by focusing on their culture as the most critical driver of breakthrough innovation and business success. The Importance of Culture Culture encapsulates your organisation’s self-sustaining patterns of behaving, feeling, thinking, and believing. We are often unaware of it but culture is dominant over innovation, strategy and leadership. No matter how great your strategy, the fact is, your culture and your people always make the difference. The strategy your company employs will only succeed when it is powerfully aligned to your culture. As Peter Drucker so famously stated, “Culture eats strategy for breakfast.” However, it is an area that is often neglected or poorly managed. According to 84% of the more than 2200 global participants in the 2013 Culture and Change Management Survey by Booz & Company, culture is critically important to business success. However, there is a clear disparity between the way companies view culture and the way they treat it. Less than half of participants saw their companies effectively managing culture, and more than half said a major cultural overhaul was needed. Interestingly, 60% of C-suite executives see culture as a bigger success factor than either strategy or operating models. In his latest book, The Culture Cycle, Spring 2015 Volume 7 Issue 1


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Regulatory & Marketplace Professor James L. Heskett of Harvard Business School concludes that effective culture can account for 20-30% of the differential in corporate performance when compared with “culturally unremarkable” competitors. Even more remarkable were the findings of Kotter and Heskett’s landmark study. It documented results for 207 large US companies in 22 different industries over an eleven-year period. They reported that companies that managed their cultures well saw revenue increases of 682% versus 166% for the companies that did not manage their cultures well – stock price increases of 901% versus 74% – and net income increases of 756% versus 1%. These results are staggering and highlight the impact of culture on performance and the bottom-line. Kotter and Heskett found that strong corporate cultures facilitate adaptation to a changing world, highly value employees, customers, and owners, and encourage leadership from everyone in the firm. So if customers need change, a firm’s culture almost forces people to change their practices to meet the new needs. And anyone, not just a few people, is empowered to do just that. Culture, Innovation and Performance Strong cultures don’t happen by accident, or are only achievable by organisations with exceptional leaders or extraordinary products. What many companies don’t realise is that there are a number of practical “tools” (concepts and techniques designed to change the way individuals think and act) and processes that are proven to increase both individuals’ and the company’s future success and levels of innovation and to build and sustain a strong customer-centric culture. Innovation is a by-product of culture. It is not a by-product of organisation. It is not a by-product of how much money you throw at it. It is not a by-product of the processes that you use to run it. Therefore, you need to create a culture that will foster innovation. Apple’s late co-founder, Steve Jobs, sums it up: “Innovation has nothing to do with how many R&D dollars you have. When Apple came up with the Mac, IBM was spending at least 100 times more on R&D. It’s not about money. It’s about the people you have, how you’re led, and how much you get it.” 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Last year’s Global Innovation 1000 study confirms that spending more on R&D is not what drives results. The most crucial factors are strategic alignment and a culture that supports innovation. The elements that make up a truly innovative company include: a focused innovation strategy, a winning overall business strategy, deep customer insight, great talent, and the right set of capabilities to achieve successful execution. More important than any of the individual elements, however, is the role played by corporate culture which can be viewed as the glue that bonds them all together. Yet according to the results of the study, only about half of all companies say their culture robustly supports their innovation strategy. Moreover, about the same proportion say their innovation strategy is inadequately aligned with their overall corporate strategy. The study also found that companies with both highly aligned cultures and highly aligned innovation strategies have 30% higher enterprise value growth and 17% higher profit growth than companies with low degrees of alignment. Underperforming companies have much to gain if they can close these gaps and achieve higher degrees of cultural and strategic alignment. Companies with strong innovation cultures think innovatively in everything they do and are constantly searching for better or more effective ways of doing things. The optimal outcomes are achieved when each person in the organisation channels their creativity and actions toward business growth, people development, an empowering and supportive culture, providing innovative tools and processes for effectiveness and executional excellence. Strengthening consumer and customer focus and trust, accountability for results, teamwork, and sense of urgency along with instilling an entrepreneurial, winning spirit, are the key to achieving success. An innovative culture cultivates engagement and enthusiasm, challenges people to take risks in a safe environment, fosters learning, and encourages independent thinking. Effective innovation means that customers buy your products because they are distinctive and deliver benefits your customers really want. While

many

people

associate

innovation with new products, people are the most important drivers of breakthrough innovation. Great people do great things and build outstanding businesses. That is why your major focus should be on the development of your people. Dr Eirum Chaudhri, Merck’s Global Director of Scientific Affairs, says, “Beyond the compound, it's the people and their passion that actually drive progress and innovation. Whether they are working in R&D, medical affairs, marketing or any other area, there is a culture of focus and commitment to literally making lives better. It is a collective vision, working closely together to cross the finish line, to bring new medicines to market, to make them a reality.” The effectiveness of your people can be exponentially increased as they gain exposure to world-class tools and processes, and selectively incorporate and utilise them. These tools include leadership, management and cultural tools supported by technology. Staff, managers and leaders should be encouraged to create, explore and devise new strategies to further develop leadership and technical skills. It is the leaders’ role to provide people the tools and resources necessary in order to open minds to possibilities of innovation. For innovation to thrive it must exist in a culture that energises and ensures that creative thinking is constantly occurring. Creativity, curiosity and a genuine openness are essential for breakthrough innovation. Creating a culture of trust where risks can be taken without a culture of blame and perceived failure is valuable, as long as the people benefit through learning and discovery. Roche Chief Executive, Severin Schwan, likes to crack open the champagne with his drug research teams at the end of a big project – especially when they are unsuccessful. As the boss of one of the world's most successful pharmaceutical companies, whose leading position in cancer treatments has propelled its market value to more than $250 billion, it might seem a strange response. But a celebration to mark the lessons learned from an unsuccessful experiment are an important component of Schwan's drive to encourage risktaking in an intrinsically risky business, Spring 2015 Volume 7 Issue 1


Regulatory & Marketplace where nine out of 10 potential new drugs turn out to be flops. "We need a culture where people take risks because if you don't take risks, you won't have breakthrough innovation," he says. Schwan likes to empower his people to encourage creativity. “If you continuously tell people what they have to do, there won’t be any innovations. I believe in a decentralised management approach and small headquarters. You have to allow sufficient latitude, especially for creative scientists.” Creating an invigorating sense of purpose that goes beyond profit can have a powerful positive impact on both staff and customers. Profit may motivate senior executives, but it rarely does so for the front-line employees unless they are shareholders. Connecting people to a purpose is an important way of helping them feel good about the company. Why? Because there is a very high correlation between the way your employees feel about the company and the way your customers do.

Culture like the submerged part of an iceberg is often invisible but is dominant over innovation, strategy and leadership

What motivates employees is feeling connected to an authentic company ethos. Creating products or providing services or serving causes that clearly add value in the world, make it possible for employees to derive a sense of meaning from their work, and to feel good about the companies for which they work. A true vision for a business rests on foundations of both purpose and values. The power of vision is at its best when it comes alive in the people of the organisation and they ‘live the vision’. They become passionate about what they do and why they do it. The business goals must then align with this foundation. Without a clear foundation, a business will never be truly strategic. So it is better to stand for something beyond simply increasing profits. www.ipimedia.com

To demonstrate the impact of their work, Astellas invite patients who have undergone transplant surgery to come in to their offices and share their story with employees. Ken Jones, CEO of Astellas Pharma EMEA, recalls: “One patient spoke very movingly about how before surgery she remembers smelling her child’s hair and wondering would that be the last time they'd be together. It’s a powerful medium to demonstrate to people the incredible work that we do and the results of their combined efforts and galvanises their commitment in terms of what we are trying to achieve as a company.” The single most important factor in driving culture, innovation and performance is positive and effective leadership behaviour. Transformational leaders create new futures that are not constrained by past performance, or even current circumstance, and which inspire others to build those futures with them. Former Lilly executive Bernard Munos has analysed industry data to ascertain which pharma R&D operations have been most productive, and why. His analysis confirms Novartis has been one of the best performers over the last 15 years, and he believes that the company’s leadership and culture was instrumental in this success. 2002 was a pivotal year for Novartis. The company’s chief executive at the time, Daniel Vasella, took a handful of bold decisions that helped to shape its approach to R&D over the following decade. Vasella made a multimillion dollar bet by establishing a global research centre in Cambridge, Massachusetts, USA, drawing on the research and academic talent from MIT, Harvard, and other institutions in the area, and internationally. It has become the industry standard for open innovation and developing great people and new compounds. Vasella appointed Mark Fishman, M.D., who came from academic research at Harvard, to run the centre and gave him freedom to determine the R&D strategy. Vasella also insisted that the Novartis Institute for Biomedical Research should have complete independence from the firm’s marketing department. Munos wrote in Forbes: “Ten years

ago, as uninspired CEOs unleashed six sigma onto their scientists, Novartis was the only company to denounce the ineptitude of regimenting science and basing R&D investment on bogus forecasts and NPV calculations. It broke ranks with its peers, and returned to its scientists the freedom to pursue unfettered breakthrough innovation. It is now the company that derives by far the greatest percentage of its sales from new products.” Drawing on the physician role models of his youth and his vision to build a great global healthcare company that could help people through life-saving new drugs, Vasella built a company culture centred on compassion, competence, and competition. He told Fortune: “It may sound trite, but I truly believe my

It is crucial to nurture an innovative spirit among team members. They should exhibit a combination of creative zeal, problem-solving, risk-taking and teamwork

ability to keep shareholders’ faith in our company depends not on whether I make the quarter but on who I am, what my guiding principles in life are, my behaviour.” Vasella’s ethos continues today through the leadership of Novartis’ current CEO, Joseph Jimenez. “At Novartis we are driven by our mission

Joseph Jimenez, CEO of Novartis

of caring and curing. We strive to attract and retain talented associates who are passionate about improving patients’ INTERNATIONAL PHARMACEUTICAL INDUSTRY 17


Regulatory & Marketplace lives," says Jimenez. "Believing in a higher purpose for the organisation builds strong associate engagement, and is critical to building a world-leading culture." He adds, “We try to foster a culture of innovation and creativity, and this includes how we continue to improve as a more responsible and sustainable company.” Another leader who understands

Severin Schwan, CEO of Roche

the impact of culture is Pascal Soriot, who has overseen an increase in AstraZeneca’s share price by nearly 60% since he took over as chief executive. In his words, "We have fostered a culture of innovation where science is at the heart of what we do. We are continuing to create significant shareholder value from our independent strategy.” Susan Galbraith, head of oncology discovery and early development at Astra Zeneca says that the company has become more science-focused since Mr Soriot took over the helm. “There has been a big change of culture,” she says, adding that Mr Soriot’s staunch defence against Pfizer’s takeover approach boosted morale and

increased the sense of urgency within the company. “It had a huge impact.”

understand how their work contributes to the company’s performance.”

Ian Read, Chairman of the Board and Chief Executive Officer at Pfizer believes that, “Shaping and supporting a clearly defined culture is some of the hardest work any organisation can take on, but it’s also the most important. What makes it so tough is that it’s less finite and more subjective than most of the work we do. What makes culture so important is that it’s unique; it’s something that no one can copy.

“By clearly defining the behaviours that comprise the culture you envision, effectively engaging your front-line managers and fostering an environment built on trust, culture can become one of your organisation’s greatest competitive advantages.”

“Your company can have great strategies, ready access to capital and terrific people, but turning these and your other assets into results depends ultimately on a strong culture that enables your employees to perform at their fullest.” He adds, “That’s why when we set the company’s business imperatives a few years ago, we put culture at the core of everything we were doing to transform our approach to research and development, how we used our capital resources and the work we undertook to build our reputation. Since then, we have worked continuously to firmly establish what we call an “ownership” culture across the company. Pfizer colleagues understand that our ownership culture can differentiate us within our industry. They also understand it requires a willingness to take prudent risks, be accountable for their decisions and results, and

The upshot: A culture can make or kill a company. If, as a business leader, managing your culture isn’t already at the top of your priorities, it should be. As Edgar Schein, author of Organizational Culture and Leadership, put it: “The only thing of real importance that leaders do is to create and manage culture. If you do not manage culture it manages you and you may not even be aware of the extent to which this is happening.” Breakthrough discovery comes from a breakthrough culture. Getting the corporate culture right can transform businesses and unleash explosive breakthrough innovation and growth of the enterprise. Dr Bart Sayle, CEO and Nick Hawker, Principal Consultant, The Breakthrough Group. Bart Sayle is the author of Riding the Blue Train: A Leadership Plan for Explosive Growth. The Breakthrough Group unleashes innovation, specialising in accelerated business growth, sustainability and culture transformation, with over 20 years’ experience working with leading brands including Mars, Danone, Unilever, Ferrero, Pepsico, Coca-Cola, Mondelez, British Airways and P&G.

Dr Bart Sayle is CEO of The Breakthrough Group and the author of the best selling book, Riding The Blue Train: A Leadership Plan for Explosive Growth. Bart has 25 years experience working with CEOs and their executive teams in corporations around the world to create high performance cultures and business growth. For further information see www.breakthroughglobal.com or contact Email: nick@breakthroughglobal.com

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Spring 2015 Volume 7 Issue 1


Regulatory & Marketplace

The Growing Prominence and Need of Patient-Reported Outcomes Considerations for Measurement, Analysis and Interpretation of the Data The challenge for pharmaceutical commercialisation no longer ends with regulatory approval; it intensifies after the approval. Today there is greater awareness about the benefit and risk of products, not only among healthcare professionals (HCPs), but also among consumers and payers. All interested parties are demanding more evidence than mere safety and efficacy data from clinical trials. Effectiveness of treatments and comparative effectiveness relative to other therapies are important to measure. This requires real-world data based on longer follow-up and a more representative sample of the patient population than what is typically used in clinical trials. Patientreported outcomes (PROs) can help fill this gap, yet there are challenges that must be addressed. Sources of data can be found in claims databases, disease registries and electronic health records (EHRs), but the quality of readily available real-world data may be poor, due to missing data and inadequate validation. Hence, more outcomes data has to be generated to provide comprehensive evidence of the value of the drug. In addition, patient perspective has become more important to the payers, further supporting the need for outcomes data. PROs and other similar tools are used to capture quality of life (QoL) data along the continuum of clinical development, post-approval studies and patient registries, which are more compelling than, for example, survival or even progression-free survival data. QoL data rose to prominence a couple of decades back with the increase in incidence of oncology indications, high drug prices and small incremental gains in survival rates offered by the new drugs. QoL data is also equally relevant for other lifestyle diseases such as diabetes and asthma. The fundamental premise now is that healthrelated QoL and wellbeing of patients are core co-primary endpoints in clinical research and clinical care. Many companies use PRO data to measure the impact and effectiveness of their drugs, even during Phase II and Phase 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

III clinical trials. In fact, some companies are also using PROs at the very start of the drug development process. Early observational and epidemiology studies can identify unmet clinical needs and potential profitable drug markets. For example, PRO health surveys can be used to quantify the physical health burden of a particular type of disease. The Value of Outcomes Research – Facilitating Better Decision-Making End results of medical treatment and care are available from outcomes research (OR) studies, in terms of the effect on health and wellbeing of patients and the populations. The area of OR encompasses studies that evaluate effectiveness of treatments, development and use of tools to measure health status, and analysis and dissemination of the results. OR evaluates the results of healthcare process in the real world through effectiveness research rather than using efficacy studies, and assesses which treatments for specific problems work best for whom by also factoring in patient preferences and patient satisfaction. Governments, insurance companies, employers and consumers are all looking for OR data for better decision-making. Furthermore, regulators are making approval decisions based on outcomes data. For example, when NICE (National Institute for Health and Care Excellence) reviewed Novartis’ asthma drug Xolair, it considered data from the Asthma QoL questionnaire in observational studies and overturned an earlier decision to reject Xolair1. PRO health surveys have also been used for label claims (e.g., Humira, Allegra, Lyrica)2. PRO data can help influence pharmacy benefit managers and insurers to include a drug in their formularies. Health surveys can also be used to answer any questions regarding comparative effectiveness in order to build an economic basis for formulary inclusion, thus helping to lower claim costs over time. Companies successfully use PROs to prove the positive impact of a product on patient health and ultimately health expenses.

Public and private sector interest in outcomes research has grown dramatically in the past several years, in large part because of its potential to address the interrelated issues of cost and quality of healthcare. Outcomes research touches all aspects of healthcare delivery, from the clinical encounter itself to aspects of the organisation, financing and regulation of the healthcare system. Each of these factors plays a role in the outcome of care, or the ultimate health status of the patient. Understanding how the different factors interact requires collaboration among a broad range of health services researchers, such as physicians and nurses, economists, sociologists, political scientists, operations researchers, biostatisticians and epidemiologists. The Challenges of PROs – Quantifying and Calibrating Patient Perspectives The primary challenges of real-world data are that these data are not controlled, and they may be collected and measured anywhere. The main sources are computerised databases, EHRs and PROs. The PRO data measure health status and consumer preferences and capture the patient perspective of the impact of intervention on quality of life and ability to function. It is a challenge to quantify and calibrate these data. Collection of such data requires tools (PRO instruments) that provide scientifically valid assessments of physical and mental health, to measure health and wellbeing from the patient point of view. There are a few tools that offer a standardised way to measure health outcomes for individuals and large populations, as statistically valid patient-centred measures. Health status is measured as physical functional status, role functioning, social functioning, physical and mental wellbeing, measured in terms of mental health (mood, depression, anxiety), health perceptions (own view of general health), pain and life satisfaction (QoL), all of which require an individual evaluation3. In December 2009, the US FDA released guidance for the industry on Spring 2015 Volume 7 Issue 1


Regulatory & Marketplace

PRO measures4. This guidance reviews and evaluates PRO instruments used to support claims in approved medical product labelling. A PRO instrument (i.e., a questionnaire plus the information and documentation that support its use) is defined as a means to capture PRO data used to measure treatment benefit or risk of medical products. The evaluation of a PRO instrument includes the following considerations: • • • •

The population enrolled in the clinical trial The clinical trial objectives and design The PRO instrument conceptual framework The PRO instrument measurement properties

The adequacy of any PRO instrument, as a measure to support medical product labelling claims, depends on whether its characteristics, conceptual framework, content validity, and other measurement properties are satisfactory. The FDA will review documentation of PRO instrument development and www.ipimedia.com

testing in conjunction with clinical trial results to determine whether a labelling claim is substantiated. The type of PRO information sponsors should provide to the FDA to facilitate instrument review is listed in the guidance document. PRO instruments’ measurement properties included in the review are: • • •

Reliability (intra- and interinterviewer reliability, internal consistency) Validity (content validity and construct validity) Ability to detect change

The use of electronic PRO instruments, however, may pose a problem when direct control over source data has to be maintained by the sponsor or the contract research organisation and not by the clinical investigator. Sponsors need to plan to establish appropriate system and security controls, as well as cyber-security and system maintenance plans that address how to ensure data integrity during network attacks and software updates. Capture of PROs

may also be web-based or through IVRcompatible tools. A commonly-used PRO instrument to measure functional health status is the Short Form (SF) Health Survey (SF-36v2® Health Survey of 36 questions and the shorter SF-12v2® Health Survey of 12 questions). This measures health status across eight domains, summarised into physical and mental health scores. Analysis of PRO Data Involves Substantial Statistically Complexities When PROs are included as endpoints in a study, they may be primary or secondary. It has to be decided a priori whether an endpoint will be analysed as a continuous variable (mean scores), dichotomous variable (success or failure), or some graded response. Multiple comparisons have to be done when PRO endpoints are included. Appropriate statistical methods have to be applied to handle multiplicity and make adjustments to control the overall Type I error rate. Adherence to blinding and randomisation requirements is INTERNATIONAL PHARMACEUTICAL INDUSTRY 21


Regulatory & Marketplace critical in order for analysis of PRO endpoints to be valid, given the subjective nature of measurement. A PRO instrument comprises multiple domains and hence composite endpoints often need to be defined. Analysis of composite endpoints and interpretation of results is challenging, especially when inference has to be made on individual components of the composite endpoint. PRO data is also typically longitudinal in nature and mixed effects models have to be used for statistical analysis of the data. Incomplete data poses an additional challenge in the case of longitudinal data and composite endpoints, thereby increasing the likelihood of bias in the results. Imputation and sensitivity analysis is essential. Moreover, since the PROs measure wellbeing of patients, cross-cultural comparability of data can be a major issue even when validated, translated versions of the PRO instrument are used. Thus, the analysis of PRO data involves substantial statistical complexities. Moreover, clinical interpretation of results and assessment of clinical significance can also be very challenging. It is important to use the right skills to design, analyse and report PRO endpoints. Outcomes research is often a specialised and separate group within the R&D or commercial organisations of pharmaceutical companies. There is increased recognition that PRO data, even when it is collected in the postapproval phase, is challenging to capture, analyse, interpret and report. With the increasing volume of OR data, sponsor organisations often need to outsource some of the analysis. Many CROs (contract research organisations) and other niche providers have been building expertise in handling PRO data to cater to this need. Outsourcing to the right provider will give an edge to the sponsor organisation in this increasingly important and complex area of data analysis and reporting. Market Expansion and Enhanced Consumer Engagement using PROs PRO health surveys generate information that is tailor-made for the marketing of a product. Consumers want to know what a drug does and how well it works. PRO results can be used to convey the value of a drug and encourage patients to ask their doctor about a drug. Marketing professionals can use PRO data to create well-defined marketing communications 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

such as advertising, brochures and educational materials to increase brand awareness and promote sales. Companies are also using online PRO health surveys to generate web traffic in order to engage and educate consumers. Such methods help create ongoing dialogue and relationship with a large number of consumers. They educate consumers on disease and treatments, which in turn leads people to talk about the products to their doctors. Companies try to protect the safety of consumers through post-marketing surveillance, however, once a new drug is made available outside of the controlled environment of clinical trials, it can be difficult to monitor drug response and effects. By using PRO surveys at every stage of the drug development and commercialisation process, a drug company can accumulate an impressive body of data that can enable it to meet the demands of all interested parties, from the FDA and health insurers, to doctors and patients. A company can also solidify its position as an industry leader by consistently finding and cultivating profitable new markets. Through innovative uses of PRO health surveys, drug developers can meet the ever growing challenges created by increased competition and regulatory requirements in a world where the trial never ends. Summary Assessment of QoL and other PROs has become increasingly common in clinical trials and as part of post-approval studies, providing “the patient voice” in evidence on treatment effectiveness. PROs are relevant to many primary care research questions and play a significant role in drug approval and labelling decisions. Hence it is crucial to have a robust plan for capture and analysis of PRO data, which adequately address all challenges of capturing reliable and validated data, as well as statistical complexities involved in analysis of the data and drawing clinically meaningful inferences. Both scientific and logistical issues should be addressed to ensure that the PRO data are of a high quality. PROs are often inadequately reported in trials, thus limiting the value of these data. The CONSORT (Consolidated Standards of Reporting Trials) lacks guidance on the reporting of PROs. This is addressed through development of the

CONSORT PRO extension based on the methodological framework for guideline development proposed by the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network5. Improved reporting of PRO data will facilitate robust interpretation of the results from clinical studies and informed patient care. References 1. Nick Taylor, 2014. Analyzing real-world data for Lifecycle Management. (Internet) http:// www.fiercebiotech.com/of fer/ analyzingdata?source=listing [Accessed 12/01/2015] 2. Gus Gardner, 2009. The Trial Never Ends. (Internet) https:// www.optum.com/content/dam/ optum/resources/articles/ TheTrialNeverEnds08.11.09.pdf [Accessed 15/12/2014] 3. Foundation for Health Services Research, 1994. HEALTH OUTCOMES RESEARCH: A PRIMER. (Internet) http://www. academyhealth.org/files/ publications/healthoutcomes.pdf [Accessed 12/01/2015] 4. US FDA Guidance for Industry on PRO measures, December 2009, http://www.fda.gov/Drugs/ 5. Melanie Calvert, Evaluation of patient reported outcomes in clinical trials: systematic review of trial protocols. (Internet) http://www. spcr.nihr.ac.uk/research/pro-trialdesign [Accessed 12/01/2015]

Chitra Lele is Chief Scientific Officer at Sciformix Corporation, with over 20 years of experience in the healthcare industry. She has been part of the company’s leadership from its inception and has been instrumental in establishing and growing the organisation. Prior to Sciformix, Chitra was Executive Director responsible for Indian operations of Pfizer Global R&D. With a PhD in Statistics from Stanford University, her prior experience includes work as a biostatistician in cancer epidemiology at both Stanford and University of California. Email: chitra.lele@sciformix.com Spring 2015 Volume 7 Issue 1


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Drug Discovery, Development & Delivery

RDD Europe 2015 Scientific Conference Register now to attend the RDD Europe 2015 scientific conference, to be held May 5-8, 2015, in Antibes, France. The Respiratory Drug Delivery (RDD®) Europe 2015 scientific conference will welcome pulmonary and nasal drug delivery experts from around the world to Antibes, France, May 5-8, 2015. The joint organisers of this prestigious event, RDD Online® and Aptar Pharma, invite you to celebrate RDD Europe’s 10th anniversary and announce the opening of registration at www.rddonline.com/ rddeurope2015. Bringing the Respiratory World Together RDD Europe is a major scientific event in the respiratory drug delivery field in 2015 and is widely regarded as the key conference for presentations on the latest pulmonary and nasal drug delivery advances. More than 450 delegates from 29 countries attended the last edition of RDD Europe in May 2013 in Berlin, Germany. RDD Europe 2015 will host high-level academic, industry and government experts who specialise in research, development and marketing in the field of pulmonary and nasal drug delivery. An Outstanding Three-day Interactive Conference The conference will start with a plenary lecture presented by Dr Bruce K. Rubin, Professor and Chair, Department of Pediatrics, Virginia Commonwealth University, entitled “Delivering Drugs to Pediatric Airways: Unhelpful Myths and Future Directions”. The symposium will then focus on: • • • • • • •

Aerosol delivery in paediatrics Personalised medicine Global patent practice Nasal drug delivery Stretching the OINDP boundaries: exploring alternative technologies Particle engineering and QbD Alternative distribution practices for inhalers

24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

As part of the symposium, RDD Europe 2015 will highlight innovative research contributions in podium and scientific poster sessions, and will also host 12 interactive workshops led by device experts and service providers. RDD Europe Celebrates its 10th Anniversary “Presentations this year will address major issues of interest to the industry, from paediatrics and personalised medicine to innovations and research in our field. We are especially excited to invite all of our attendees to help us celebrate the 10th anniversary of RDD Europe, the industry’s leading assembly of drug delivery experts,” said Dr Richard Dalby, one of the organisers from the University of Maryland. “The 10th anniversary of RDD Europe is a perfect occasion to thank our sponsors, exhibitors, all participants and contributors for the great success of this scientific conference, which has rapidly become a major event in Europe,” said Pierre Carlotti, Vice President Marketing and Communication, Aptar Pharma Prescription Division. RDD Europe was launched in 2005 and welcomed 300 delegates. Building on the success of the first edition, RDD Europe has continually improved over the years, attracting world-class speakers and sponsors. RDD Europe 2015 offers numerous opportunities for networking, including a cocktail reception on the evening of May 5th and a gala anniversary celebration dinner on May 7th, sponsored by Aptar Pharma. RDD Europe 2015 also features a comprehensive high-profile exhibition showcasing the latest technologies and devices in this exciting field.

For many years, RDD Europe events have sold out, so early registration is strongly recommended. Further information about RDD Europe 2015, including the detailed programme and registration details, is available now at www.rddonline.com/ rddeurope2015. About RDD Online RDD Online manages the organisation of Respiratory Drug Delivery meetings in the US, and partners with Aptar Pharma to run RDD meetings in Europe. Other RDD Online services available at www. rddonline.com include the provision of scientific and technical publications, aerosol testing equipment including dose collection tubes and mixing inlets, webbased training, textbook publishing, service directories and recruiting services of interest to companies active in pulmonary and nasal drug delivery. For more information, please visit www. rddonline.com. About Aptar Pharma Aptar Pharma is part of the AptarGroup family of companies, along with Aptar Beauty + Home and Aptar Food + Beverage. We create innovative drug delivery systems that meet the evolving needs of biotechnology, healthcare and pharmaceutical companies around the world. We provide our customers with a wide range of delivery technologies and analytical services backed by decades of proven expertise. For more information, visit www.aptar.com/pharma. AptarGroup, Inc. (NYSE: ATR) is headquartered in Crystal Lake, Illinois, United States, with manufacturing facilities in North America, Europe, Asia and South America. For more information, visit www.aptar.com/pharma.

Spring 2015 Volume 7 Issue 1


PLEASE MARK YOUR CALENDARS AND PLAN TO ATTEND!

MAY 5 - 8, 2015 Palais des Congrès d’Antibes Nice, FRANCE

For more information visit www.rddonline.com/rddeurope2015

RDD Europe is a conference jointly organized by


Drug Discovery, Development & Delivery

Green Extraction to Development of New Therapeutics in the Pharmaceutical Industry Abstract: Development of new bioactive drugs nowadays mainly involves extraction of new compounds from plants. For a few years, methods of extraction have tended to become “greener”, solventfree, energy-efficient, and decreasing the amount of non-useful components produced during the extraction process, while ensuring quality, reproducibility and efficiency of finished products. The term “green-extraction” was coined to name new green methods, the use of which is more and more applied to processes aimed at preparing bioactive extracts or purified components from plants. Up until relatively recently, two techniques were used to extract bioactive molecules from vegetal resources: the traditional aqueous decoction and techniques using organic solvents, which are often toxic or expensive. However these methods were shown to be timeand energy-consuming. They have been therefore reconsidered because of their detrimental impact on health and environment. The new methods bypass these problems. They make use of ultrasound- or microwave-assisted extraction, or of alternative green solvent or supercritical dioxide. 1. The Medicinal Plant, an Ancestral History for Drug Discovery For millennia, plants have been used by man for medical purposes. Pollen was found in the grave of a Neanderthal man dating from approximately 60,000 years ago. Its analysis showed that it mainly consisted of pollen from plants endowed with medicinal properties. The earliest medical document is 4000 years old; a Sumerian clay tablet indeed lists a number of plants used to treat various illnesses (Figure 1). The Sumerian pharmacopoeia consisted of about 250 species of plants. Development of writing allowed the scribes to describe their uses in the form of recipes. Old Egyptian civilisation also accumulated a great deal of information on medicinal plants. Ebers Egyptian papyrus, dated 1500 BC, is one of the earliest documents specifically dedicated 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1: Sumerian clay tablet

to medicinal plants. It informs us on the composition of more than 700 preparations made of animal and/or v e g e t a b l e substances (Figure 2). Notable among these are the Figure 2: remedies mentioning Ebers papyrus mandrake to relieve pain, garlic for the treatment of heart and circulatory disorders, and black figs to treat infections of the bronchi and lungs. The famous Greek physician in its corpus lists more than 250 medicinal plants (Figure 3). Ancient China is an invaluable source of knowledge on medicinal of plants. Pun-Tsao, Figure 3: The a pharmacopeia Hippocratic corpus lists dated 1600, contained monographs of thousands of vegetal medicaments. This collection is traditionally attributed to Shen-nung, a mythic emperor of China who would have lived more than 4500 years ago. The first Roman physicians also influenced the development of Western medicine. Dioscorides (1st century AD), for instance, was a Roman military physician who accompanied the

armies during their military campaigns. His work deserves special attention. During his travels, indeed, he observed many useful plants and compiled his observations in the De Materia Medica, an encyclopedia and pharmacopoeia that listed about 600 plant species together with their medicinal properties (Figure 4). Dioscorides included in his opus descriptions and illustrations of plants, as well as instructions on their preparation, uses and side-effects. Thanks to Christopher Columbus and other explorers, the exchange of plants between different countries and regions has developed on an increasingly regular basis. During the XVIth century, a whole medical European or Western system mixing the use of plants and astrology was developed by Paracelsus. For centuries, the western medicaments were Figure 4: De almost exclusively Materia Medica vegetal. Until the Second World War, plants were the primary source of medicinal molecules or medicaments. Since that time, beside the discovery of numerous artificial new molecules, more in-depth and broader researches on natural substances have been successfully developed. They proved that numerous substances found in traditional vegetal medicaments are endowed with high efficiency, and gave rise to a new branch of pharmacology, so-called ethno-pharmacology. 2. Traditional Techniques Used to Extract Bioactive Substances from Plants. Techniques for treating raw vegetal material appeared a long time ago, in various civilisations. Man discovered very soon how beneficial these plants could be for his health. To extract active principles from a plant, several ancestral methods were used which progressively improved their efficiencies.

Spring 2015 Volume 7 Issue 1


Drug Discovery, Development & Delivery Tr a d i t i o n a l l y, plants were dried before the extraction step. In order to speed up the extraction process, the dry plants were often finely crushed using several types of mills or mortars Figure 5: Example of (Figure 5). The several mills first historically identified extracts were obtained by aqueous extraction or alcoholic fermentation. The different extraction techniques made use of distillation, expression, maceration, infusion, percolation and decoction. 2.1. Distillation Distillation is used to extract different volatile substances of plants; a special form is the steam distillation which is used for heat-labile compounds with a low boiling temperature. The dry vegetal powder or the entire plant is put in an alembic. The device consists of a recipient containing heated and vaporised water, a condenser which allows the condensation of vapour, and a receiver which recuperates the drops of liquid enriched in active compounds. Essential oils and other bioactive light components float above the condensed water. 2.2. Expression Expression is still used to extract essential oils from citrus, for example. It involves the application of pressure onto the raw material in order to extract active substances without using heat. This method has been largely used to extract juice from fruits, and essential oils or oil from plants or seeds. 2.3. Maceration Maceration is one of the oldest techniques used by apothecaries; the plant was immersed for various times (hours or days) in a carefully chosen solvent, at ambient temperature. Depending on the active principles to be extracted, the solvent could be water, alcohol, oil, etc. The conventional procedure left the plants in contact with the solvent for several days while shaking the mixture. The plant was then pressed to recover a maximal amount of liquid, which was then filtered. Maceration was used, and is always used in some instances, to extract heat-labile or water solvent-soluble active products. 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

However, maceration is time-consuming and its yields are often low, but it does not alter the structure and properties of the substances of interest. 2.4. Infusion Infusion is always in use today. This mere process is applied to fragile parts of plants such as flowers. Raw material is soaked in water for a given time, determined by experiments. Cold or hot water may be used; the process can also be carried out at room temperature. The temperature range makes it possible to dissolve (sometimes sequentially) different active substances. Sometimes, a solution can be concentrated by boiling water. Alcohol is then added to improve the conservation of the solution. Infusion is a simple and fast process that allows good extraction of heat-labile active principles. 2.5. Percolation Percolation in its primary form is different from the current percolation system used today to prepare a cup of coffee. In the medicinal version, the plant is reduced to powder and placed in a so-called percolator. It is then slowly added to a solvent which fluxes through the powder over a period from one to four days. The matrix is then pressed and the resulting solution is clarified. Percolation respects the integrity of the bioactive substances but requires time and needs to carefully calibrate the size of the powder, which should be neither too coarse (if the extraction time is long) nor too thin, to avoid stagnation of the solvent into the matrix. The hot percolation makes use of Soxhlet which makes it possible to reduce the duration of the process. 2.6. Decoction Decoction is always in use in pharmaceutical researches as a conventional technique. It resembles infusion. It differs from infusion by the use of boiling water all along the process. This method is used for treating compact or hard parts of plants, for instance roots or ligneous stems. It allows a more complete extraction of bioactive principles than infusion. But maintaining raw material at elevated temperature could degrade heat-labile compounds. Improvements in physiology and pharmacology knowledge enabled understanding of the action mechanisms of numerous natural substances. In recent decades, unravelling the relationships existing between the structure of a molecule and its biological activity allowed the design

and manufacture of synthetic drugs endowed with better performance or lesser adverse effects than the natural molecule. But today, suitable materials, advances in engineering processes, phytochemistry and analytical methods or new technologies allow manufacturers to use "greener" extraction methods. Modern expertise in plant extraction relies on associated controlled parameters and traditional use. 3. What is Green Extraction? 3.1. Definition Green extraction methods are based on discovery, design, conception and use of extraction processes allowing noticeable energy consumption savings, as well as making use of alternative solvents and renewable matrix while ensuring production of a safe and high-quality extract. New ways have been opened to imagine and develop green extraction processes. Initially, optimisation improved already existing processes (Soxhlet extraction by alternative solvents for example). Then, new equipment and innovative processes have completed the jump towards novel methods (extraction by microwaves, ultrasounds; use of alternative solvents, etc.). 3.2. Principles of Green Extraction To meet the expectations of professionals in a context of sustainable development, the concept of green extraction has been created; it relies on a few principles designed as a kind of guideline for scientists and industrials. Principle 1: to promote selection of suitable varieties of plants and use of renewable resources. Principle 2: to privilege the use of alternative solvents, especially those originating from agroresources. Principle 3: to reduce energy consumption with the assistance of innovative technologies and to promote energy recycling. Principle 4: to privilege production of co-products instead of waste, in order to integrate bioindustries and agro-refining industries.

Spring 2015 Volume 7 Issue 1


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Drug Discovery, Development & Delivery Principle 5: to reduce unit operations thanks to innovative technologies and to favour safe, robust and controlled processes. Principle 6: to privilege production of non-denatured, biodegradable and uncontaminated extracts and carriers of "eco-extract" values. 4. Modern Extraction Methods. Some more modern extraction methods are primarily used for the development of herbal medicines (capsules, syrup, or tablets). They are referred to as nonconventional extraction techniques. However, in the pharmaceutical industry, the most promising techniques for extracting active substances from plants are ultrasound-assisted extraction, microwave-assisted extraction, accelerated solvent extraction and supercritical fluid extraction (Figure 6). They are named as "green methods". They do not include hazardous chemical synthesis; but make use of safer chemicals and solvents auxiliaries, take into essential consideration optimisation of energy efficiency, treat renewable stocks of raw materials, and reduce useless steps, avoiding or preventing degradation of bioactive products. They also search to prevent or minimise environmental pollution, and to avoid

this phenomenon is called cavitation. Bubbles are produced in the medium where they grow to reach a critical size which is followed by their collapse. Implosion of cavitation bubbles releases very high energy. Each cavitation bubble can be considered as a microreactor in which extreme conditions are reached. The bubbles can reach a temperature of about 4727째 K, and a pressure of about 1013 bars with a heating- and cooling-rate above737째C. Thanks to these properties, ultrasounds have been applied to extraction of natural products from raw vegetal materials. During the impact of cavitation bubbles onto a solid element such as plant tissues, the forces developed are considerable and cause serious damage to the impact point. The cavitation allows, therefore, disruption of the cell walls thanks to the asymmetric implosion of bubbles. Implosion causes bursting of the cells, enabling an improved extraction of bioactive compounds from plants. Ultrasounds can intensify mass transfer and accelerated access of solvent to cells. Two phenomena are here involved; diffusion of solvent across the cell wall, and rinsing of the cell content after disruption of the cell walls. Extraction by ultrasound depends on important factors, namely nature of the solvent, size of particles, moisture content of plant, temperature, pressure, frequency and time of extraction. Advantages of UAE comprise a noticeable reduction of extraction time, of energy consumption and of amount of solvent.

UAE is a very efficient technique to extract bioactive substances from plants. Numerous studies showed its effectiveness in the extraction of very different molecules of pharmaceutical interest: phenolic compounds, alkaloids, anthocyanins or flavonoids. Crocin and crocetin, natural carotenoids found in the Figure 6: Conventional and new extraction techniques from plants for pharmaceuticalsaffron flower which can be used in the Figure 6: Conventional and new extraction industry treatment of neurodegenerative diseases, techniques from plants for pharmaceutical have been extracted from Crocus industry sativus L. using UAE by Lydia Ferrara undesired issues. et al. (2014,1). In 2013, J. Prakash Maran et al. applied an optimised 4.1. Ultrasound-assisted Extraction sonication condition to extract bioactive (UAE) compounds, pigments and polyphenols Ultrasounds are elastic and mechanical from Nephelium lappaceum L. fruit waves, non-audible to the human ear, peel2. They identified optimal conditions whereas they can be perceived by of extraction after a systematic study of some animals. The frequency is usually four factors at three levels. Zu et al. in comprised of between 16 kHz and 10,000 2012 demonstrated extraction efficiency kHz. When crossing liquid medium, it of three polyphenols, phenolcarboxylic generates areas of compression and acid, carnosic acid and rosmarinic decompression and generates bubbles; acid from Rosmarinus officinalis, using 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

ionic liquid-based UAE3. UAE has been proved to be more efficient and less timeconsuming than conventional methods. UAE has been also shown by Yang et al. (2011) as a very efficient technique for extraction of three important alkaloids: vindoline, vinblastine and catharanthine, from Catharanthus roseus4. 4.2. Microwave-assisted Extraction (MAE) Microwaves are electromagnetic waves with a frequency range between 300 MHz and up to 300 GHz (between radio waves and infrared). The frequency 2450 MHz is the most frequently used. Electromagnetic waves are characterised by an electric field E and a magnetic field H, perpendicular to the direction of propagation. The energy is dissipated into heat. The electric field exerts two effects depending on the presence of free charges and/or polar molecules. In the first case, the presence of ions in the medium and the electric field induces conduction current, causing the displacement of ions and production of heat due to shocks with fixed molecules; this phenomenon is named ionic conduction. In the second case, the polar nature of the molecules plays a role in the effect of the applied microwaves. Under the action of an electric field, the dipoles are oriented in the rapidlychanging direction of the field. This results in the collision between molecules and consequently generates heat; this phenomenon is called polarisation by dipole orientation. The MAE involves three effects: increased temperature and pressure into the cells, bursting of cells, and dissolution of solutes from matrix in the solvent. The advantages of MAE comprise quicker heating, reduced equipment size, thermal gradients and increased yield. It is a selective technique to extract organic and organometallic compounds. MAE is qualified as a green technology because of the reduction in the use of organic solvent it provides. As for ultrasound techniques, MAE has been proved to be very efficient in different studies devoted to pharmaceutical applications. Echinacea purpurea, widely used for its immunostimulating properties, contains multiple bioactive substances, including phenolic substances (caffeic acid derivatives), flavonoids, anthocyanins and alkamides. Mona et al. (2014) have compared conventional extraction and MAE for their efficiency to extract the active constituents of Spring 2015 Volume 7 Issue 1


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Drug Discovery, Development & Delivery Echinacea purpurea5. Alupului et al. (2012) extracted flavonoids and phenolic compounds from Cynara scolymus L.6, a plant used for its choleretic and hepatoprotective activities and ability to lower circulating cholesterol in humans. These properties are attributed to cynarin. The authors showed that MAE possessed advantages over other methods, such as higher yields, purity of the molecule, and extractive efficiency. As compared with conventional extraction, MAE has proved to be a simpler and more effective procedure. In 2009, Alipului et al. applied MAE to prepare Stevia rebaudiana extracts. Beside of their ability to reduce cravings for sweet foods, they are also used to treat diabetes, hypoglycemia, candidiasis, hypertension and skin lesions7. MAE is a secure and worthy method to shorten extraction time and can usefully replace conventional energy-consuming processes. 4.3. Accelerated Solvent Extraction (ASE) The abbreviation PLE, for pressurised liquid extraction, appeared in 1996. Today, this method is known under many names, such as ASE for accelerated solvent extraction or PFE for pressurized fluid extraction. This technique aims at heating a liquid (solvent) beyond its boiling point at atmospheric pressure, while maintaining sufficient pressure to maintain the solvent in a liquid state. The ASE technique allows reduced consumption of solvent thanks to the combination of pressure and temperature that allows a fast extraction. The solvent is introduced at high pressure and temperature in the recipient containing the plant. This accelerates the extraction by increasing solubility of active substances and rate of mass transfer. Moreover, it also reduces the viscosity and the surface tension of solvents, which improves the extraction rate. Nowadays, for extraction of polar molecules, ASE competes with supercritical fluid extraction and becomes a potential and credible alternative. Applications of ASE technique for the preparation of bioactive compounds are frequently described in literature. Phenolic compounds such as catechin, caffeic acid, chlorogenic acid, etc. were extracted from various parts of Anatolia propolis using ASE at optimal conditions (40°C, 103 bars, 15 min) by Ergogan et al. (2011;8.) Chen et al. (2007) applied ASE to the preparation of active components from plants traditionally used in Chinese medicine such as Salvia 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

miltiorrhiza and Aucklandia lappa Decne9. Optimal conditions, including extraction temperature, static extraction time, solid/liquid ratio and solvent of ASE for extraction of salvianolic acid B in Salvia miltiorrhiza were determined by orthogonal experiments. Different extraction methods (ASE, steam distillation, ultrasonic wave and Soxhlet extraction) were used to extract volatile oil in Aucklandia lappa Decne. The results indicate that ASE was the most effective method in the case of this plant. Taken together, these studies abundantly prove that ASE is a powerful tool for preparing plant extracts. 4.4. Supercritical Fluid Extraction (SFE) In 1879 and 1880, J.B. Hanny and J. Hogarth presented at the Royal Society results obtained using different pressurised fluids to solubilise at best different substances. They opened the way to the use of “supercritical fluids”. Under normal conditions of pressure and temperature, every earthly substance exists as solid, liquid and gas. The study of phase diagram (pressure, temperature) demonstrated the existence of a limit point defined by Gibbs (1876) as the critical point. The supercritical state is a distinctive state with characteristic parameters such as critical temperature (Tc) and pressure (Pc) and specific physico-chemical properties between liquid and gas phase. A supercritical fluid has a viscosity close to a gas but a density close to a liquid, and it has the same transport properties of a gas. These specific physico-chemical properties allow an adaptation to extraction of natural compounds from raw materials. Carbon dioxide is considered as an ideal solvent for SFE. Extraction by supercritical carbon dioxide is widespread in industry, especially for preparing natural substances. The critical temperature of CO2 (31 °C) is close to room temperature, and the low critical pressure (74 bars) offers the possibility to operate at pressures generally ranging between 100 and 450 bars. The solvation power of supercritical carbon dioxide varied between that of pentane and toluene; it is similar to n-hexane. It is used for extracting natural substances with a molecular weight inferior to 1500. The main drawback of supercritical carbon dioxide is its low polarity, making it ideal for a non-polar substance, but very often unsuitable for most molecules of pharmaceutical interest. In order to modify the polarity

of interesting compounds, it is possible to use a co-solvent to increase extraction yield by increasing solvation power and selectivity. Using SFE for the extraction of bioactive substances has different advantages: the supercritical fluid has a high diffusion coefficient and a low viscosity, which increases mass transfer, and makes use of low amounts of organic solvents; recycling of supercritical fluid, selectivity of supercritical fluid and its solvation power can be modulated by changing temperature and/or pressure; the separation of solute from solvent is realised by simple depressurisation. Wang et al. (2011) extracted flavonoids from Ampelopsis grossedentata stems by supercritical carbon dioxide10. Flavonoids are often known for their antioxidant activity but also play a role in the control and prevention of cancer and tumerogenesis, probably because of their antioxidant activity. The optimal conditions were 250 bars, 40 °C, 50 min, and use of a modifier consisting of methanol/ethanol (1:3, v/v). Furthermore, several unreported flavonoids such as apigenin, vitexin and luteolin have been detected in the extracts from A. grossedentata stems. These results indicate that supercritical carbon dioxide could be a promising alternative for preparing extracts enriched in bioactive compounds from A. grossedentata stems. These extracts have effective antioxidant capacity and could act as agents belonging to several types of natural antioxidant. Liza et al. (2010) applied SFE to Strobilanthes crispus11. This plant is traditionally used as an antidiabetic, diuretic, and laxative, and is endowed with high antioxidant activity; it is also used to fight acquired immunodeficiency syndrome, and has anticancer properties. The bioactive flavonoid compounds of Strobilanthes crispus (Pecah Kaca) leaves were obtained by using supercritical carbon dioxide extraction; the yields of interesting substances in crude extracts were compared under different conditions, in order to select the optimal parameters. Verma et al. (2008) optimised conditions of SFE to extract indole alkaloids from Catharanthus roseus leaves; the best yields in catharanthine were obtained using SFE as compared with other extraction methods, with a pressure of 250 bars and a temperature of 80 °C, using 6.6% methanol as modifier, applied for 40 min12.

Spring 2015 Volume 7 Issue 1


Drug Discovery, Development & Delivery Conclusion Facing the growing demand for bioactive extracts in the field of the pharmaceutical industry, scientific research dedicated to extraction methods is continuously developing and tries to meet the industrial needs. Today, the challenge for chemists is to define a new balance between all the known techniques, to accurately describe new eco-extraction processes and to obtain the highest quality of bioactive substances from plants. Of course, the process should be a viable business model and have a minimum environmental impact. To reach this very desirable aim, it is necessary to understand all the aspects of the extraction processes. The establishment of combined methods must also be developed together with improvement of conventional methods. In addition, the physical characteristics of the raw material have to be taken into account in optimisation of extraction. For instance, enzymatic extraction or application of pulsed electric fields may be effective on plant cells with specific walls (layer of mucilage, wall containing chitin). On

the other hand, the growing economic importance of the bioactive compounds in the pharmaceutical field can lead to more expensive extraction methods in order to meet the market demand. References 1. Ferrara, L., Naviglio, D. and Gallo, M. 2014. Extraction of bioactive compounds of saffron (Crocus sativus L.) by ultrasound assisted (UAE) and by rapid solid-liquid dynamic extraction (RSLDE). Eur. Sci. J. 10:3. 2. Prakash Maran J., Manikandan, S., Vigna Nivetha, C. and Dinesh, R. 2013. Ultrasound assisted extraction of bioactive compounds from Nephelium lappaceum L. fruit peel using central composite face centered response surface design. Arab. J. Chem. in press. 3. Zu, G., Zhang, R., Yang, L., Ma, C., Zu, Y., Wang, W. and Zhao, C. 2012. Ultrasound-Assisted Extraction of Carnosic Acid and Rosmarinic Acid Using Ionic Liquid Solution from Rosmarinus officinalis. Int. J. Mol. Sci. 13:11027-43. 4. Yang, L., Wang, H., Zu, Y.G., Zhao, C., Zhang, L., Chen, X. and Zhang, Z. 2011. Ultrasound-assisted extraction of the three terpenoid indole alkaloids vindoline, catharanthine and vinblastine from Catharanthus roseus using ionic liquid aqueous solutions. Chem. Eng. J. 172:705-712. 5. Mona, A.M. and Nazif, N. 2014. Microwave-assisted extraction of bio-active compounds (phenolics and alkamides) from Echinacea purpurea. Int. J. Pharm. Pharmaceut. Sci. 6: 265-268. 6. Alupului, A., Calinescu, I. and Lavric, V. 2012. Microwave extraction of active principles from medicinal plants. U.P.B. Sci. Bull. 74:129-142. 7. Alupului, A., Calinescu, I. and Lavric, V. 2009. Ultrasonic vs. microwave extraction intensification of active principles from medicinal. Chem. Eng. Trans. 17:1023-1028. 8. Erdogan, S., Ates, B., Durmaz, G., Yilmaz, I., and Seckin, T. 2011. Pressurized liquid extraction of phenolic compounds from Anatolia propolis and their radical scavenging capacities. Food Chem. Toxicol. 49:1592-1597. 9. Chen, J., Yang, B., Li, W., Wang, X., Lee, F.S. and Yang, H. 2007. Application of accelerated solvent extraction technique for analysis of active components in traditional Chinese medicinal herbs. Chin. J. Chromatogr./Zhongguo hua xue hui.

10.

11.

12.

25:628-632. Wang, Y., Ying, L., Sun, D., Zhang, S., Zhu, Y. and Xu, P. 2011. Supercritical carbon dioxide extraction of bioactive compounds from Ampelopsis grossedentata Stems: Process optimization and antioxidant activity. Int. J. Mol. Sci. 12:6856-6870. Liza, M.S., Abdul Rahman, R., Mandana, B., Jinap, S., Rahmat, A., Zaidul, I.S.M. and Hamid, A. 2010. Supercritical carbon dioxide extraction of bioactive flavonoid from Strobilanthes crispus (Pecah Kaca). Food Bioprod. Process. 88:319-326. Verma, A., Hartonen, K., and Riekkola, M.L. 2008. Optimisation of supercritical fluid extraction of indole alkaloids from Catharanthus roseus using experimental design methodology - comparison with other extraction techniques. Phytochem. Anal. 19:52-63.

Dr Celine DEJOYE TANZI, PhD – Green extraction Laboratory Manager at NeuroSys, France. Specialist in Chemistry, her researches are focused on the integration of innovative extraction techniques and analysis of bioactive substances from natural products (herbal plant, microalgae etc.), notably for pharmaceutical applications.

Product News New ambr® bioreactor systems enhanced with software for Design of Experiments (DoE) Robust, Flexible Bioprocess Development in Single-use Bioreactors Sartorius Stedim Biotech (SSB) has announced the 2015 version of the ambr® systems (ambr® 15 and ambr® 250) will be supplied with integrated BioPAT® MODDE Software for Design of Experiments (DoE), powered by Umetrics. This will allow bioprocess scientists to easily implement DoE into their work flow for simpler process optimisation and scale-up to larger single-use BIOSTAT® pilot and manufacturing scale bioreactors, making bioprocess

development faster and more cost-effective. The integrated DoE software will enable scientists to quickly establish a Design Space where relevant bioprocessing conditions are varied simultaneously. Users can rapidly configure DoE experiments via work packets that are exported from the software to the ambr system; configuring each micro bioreactor with its own DoE defined bioprocessing parameters. The data generated from ambr, including offline analytics, is analysed within the software to identify critical process parameters, optimise bioprocessing conditions and define a robust design space for implementation in larger single-use BIOSTAT pilot and manufacturing scale bioreactors. This extended DoE functionality is also available to existing ambr users who can assess the utility of the BioPAT MODDE software via a free 60 day trial, with the option of purchasing the full version if they want to continue to run DoE programmes. Dr Barney Zoro, ambr15 Product Manager at SSB commented: "To facilitate greater implementation of DoE across the industry we have combined the power of ambr with the BioPAT MODDE

www.ipimedia.com

software. These synergistic technologies are ideally suited for media optimisation and process parameter screening applications. Additionally, the software can be used for Monte Carlo Simulations as part of a Quality by Design (QbD) programme to identify the desired operating region for manufacturing scale processes, to make scale-up quicker and simpler.” Mario Becker, Director of Marketing, PAT and Automation at SSB, continued: “Our major goal is to ensure that bioprocess scientists can develop their processes as quickly as possible. Providing a consistent, scalable platform for DoE studies and data analysis which is seamlessly integrated with the full range of ambr and BIOSTAT systems, will help scientists develop robust and flexible manufacturing processes based on single-use bioreactor technology. Ultimately, implementing this approach and extending it with the BioPAT SIMCA MVDA toolkit will contribute to biotech and pharma firms reducing risk in bioprocess development and achieving more rapid, costeffective production of their biologics and vaccines.” Contact: Dominic Grone Corporate Communications, Sartorius Stedim Biotech dominic.grone@sartorius.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 33


Drug Discovery, Development & Delivery

FDA Promotes pCR as an Endpoint for Neoadjuvant Breast Cancer Trials Drug sponsors seeking accelerated approval for neoadjuvant treatments of high-risk, early-stage breast cancer should consider using pathological complete response (pCR) as a primary endpoint, according to recent FDA guidance. Released in October 2014, Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval is intended to encourage development of breakthrough therapies for patients with early-stage, invasive breast cancer who are at high risk for distant metastasis and death — an area of “significant unmet medical need”, according to the FDA. Neoadjuvant chemotherapy treatments are given to patients prior to surgical intervention. While neoadjuvant chemotherapy and postsurgical (adjuvant) chemotherapy are associated with similar survival and relapse outcomes in breast cancer patients, neoadjuvant treatments do offer advantages, according to the American Cancer Society. Preoperative chemotherapy may reduce tumour size, for example, simplifying surgical removal and conserving breast tissue, and potentially improving a patient’s cosmetic outcome. It also gives physicians insight into tumour reactivity and patient prognosis, and may clarify the need for alternative or additional treatments. Accelerated Approval According to Pharmaceutical Research and Manufacturers of America (PhRMA) estimates, from discovery to launch, the research and development process for new drug products typically spans 10 to 15 years. The FDA’s accelerated approval regulations provide a speedier pathway, although products receiving accelerated approval must undergo subsequent confirmatory trials to verify clinical benefit. The FDA considers accelerated approval only for treatments of serious or life-threatening illnesses that provide “meaningful therapeutic benefit” over existing treatments. The accelerated approval regulations allow approval 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

based on a surrogate endpoint that is “reasonably likely to predict clinical benefit.” As used in the new guidance, “clinical benefit” in early-stage breast cancer refers to clinically and statistically significant improvement in event-free survival (EFS), disease-free survival (DFS), or overall survival (OS). Defining pCR for Regulatory Purposes Lack of a uniform definition for pCR has led to difficulties in reporting and interpreting neoadjuvant trial data. The guidance presents two pCR definitions deemed acceptable by the FDA for trials to support US market approval: pCR refers to either the absence of residual invasive cancer or the absence of residual invasive and in situ cancer after neoadjuvant systemic therapy has been completed, as determined by hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes. For accelerated approval of systemic breast cancer treatments in the neoadjuvant setting, a pCR endpoint “reasonably likely to predict clinical benefit” could be evaluated several months after treatment initiation, according to the FDA, potentially resolving unmet medical need in high-risk populations much faster than conventional approaches to drug development. For applicants seeking regular approval in the neoadjuvant setting, the FDA recommends EFS or OS as long-term clinical endpoints. For confirmatory trials in the adjuvant setting, DFS or OS are the recommended long-term clinical endpoints. Support for pCR as a Surrogate Endpoint in Neoadjuvant Trials The guidance cites clinical trial data to support pCR as a predictor of longterm outcome in early-stage breast cancer patients treated with neoadjuvant systemic therapies. Patients who achieved pCR have been associated with reduced risk of death, for example. The guidance stresses, however, that while such data are “informative” at a patient level, a difference in pCR rates between treatment

arms does not necessarily predict longterm outcome at the trial level. Because individual patients who achieve pCR have shown “substantial improvements in survival,” the FDA asserts that a novel agent associated with “marked absolute increase in pCR rate” (versus standard therapy in the intent-to-treat [ITT] population) could be “reasonably likely” to achieve EFS or OS improvement long-term. However, treatments associated with only modest improvements in pCR rate are not likely to improve long-term outcomes in any breast cancer subtype. The agency stresses that analyses of neoadjuvant breast cancer trials for regulatory approval should not be limited to patients who reach pCR, but should use the full ITT population, comparing pCR rates and long-term outcomes between treatment arms. Designing Trials for Accelerated Approval in the Neoadjuvant Setting Trials conducted to support accelerated approval should be randomised and controlled superiority trials. The FDA prefers add-on trials that compare the investigational therapy + standard adjuvant therapy versus standard adjuvant therapy alone. The FDA does not recommend singlearm trials for the neoadjuvant breast cancer setting, since a high pCR rate could be due to biological characteristics of tumours in that particular patient population, the efficacy of the investigational therapy, the efficacy of the conventional therapy, or a combination of these factors. The add-on design ensures that patients “are not denied” effective treatment, while allowing researchers to assess the impact of the added investigational drug. The agency considers non-inferiority (NI) designs to be inappropriate, since they are used to establish similar efficacy between investigational and existing treatments. In recommending the pCR endpoint for the accelerated approval of neoadjuvant breast cancer drugs, the FDA aims to expand therapeutic options for patients who remain high risk despite the best available treatments; treatments Spring 2015 Volume 7 Issue 1


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Drug Discovery, Development & Delivery

that are simply non-inferior are unlikely to improve their long-term outcomes. Assessing Outcomes Pathologists reviewing surgical specimens to assess pCR should always be blinded to subjects’ assigned treatments, according to the guidance. To reduce the chance that pathologists would need to consult patient documents and inadvertently “unblind” themselves, a “summary note” should accompany each specimen. The note should underscore the need for blinding and describe major clinical, radiographic, and operative findings (e.g., the original tumour size and location, whether preoperative lymph nodes were involved, hormone and HER2 receptor status, type of surgery, etc). The FDA stresses that statistical analyses should compare pCR rates and EFS or OS between treatment arms, using the full ITT population. The guidance also recommends: • •

To avoid confounding the primary endpoint, standardise the nature and timing of nodal assessment. For trials intended to support FDA regulatory approval, perform sentinel lymph node biopsy (using dual blue dye and radioisotope tracers) at the time of definitive surgery. Include resection of at least two lymph nodes “whenever possible.” For global trials in regions where sentinel lymph node assessment

36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

• •

typically occurs before systemic therapy, stratify randomisation accordingly. The trial protocol should include guidelines for axillary lymph node dissection for subjects with axillary nodal involvement. The protocol should specify when to perform cytokeratin staining of the axillary nodes. The protocol should specify how to classify patients (with respect to pCR) who have isolated tumor cells.

Confirmatory Trials As noted, products receiving accelerated approval must undergo Phase IV confirmatory trials to verify the clinical benefit achieved; such trials should be underway when accelerated approval is granted. For approvals based on trials using pCR as the primary endpoint, the confirmatory trial should demonstrate a clinically meaningful and statistically significant improvement in EFS, DFS, or OS. The guidance describes two acceptable approaches: the single-trial model and the multiple-trial model. The single-trial model involves following patients from the original randomised neoadjuvant trial until EFS or OS data mature. If the trial is adequately powered and provides compelling results, it could support both accelerated and regular approval. The statistical analysis plan for a single trial intended to demonstrate improvement in both pCR rate and EFS

or OS should include plans for controlling the false-positive rates for both pCR (to support accelerated approval) and for EFS/OS (to support regular approval). The multiple-trial model involves one or more neoadjuvant trials to support accelerated approval and a subsequent larger trial to support regular approval. Trial(s) supporting accelerated approval should be powered to detect “substantial” absolute improvement in pCR rate between arms. The subsequent trial could be conducted in either the neoadjuvant or the adjuvant setting. The FDA recommends an EFS endpoint for the neoadjuvant setting and a DFS endpoint for the adjuvant; an OS endpoint could be suitable for either. The guidance does not favour either model above the other, but describes advantages and disadvantages to each. The single-trial model requires a larger sample size, for example, but saves time and resources, potentially speeding treatment access for high-risk patients. If the therapy proves ineffective or unacceptably toxic, however, a larger number of patients will have been exposed to it. For the multiple-trial model, the FDA cites “feasibility issues” inherent in designing and conducting multiple trials as the “principal disadvantage.” The multiple-trial model enables accelerated approval earlier than the single-trial, however, and efficacy demonstrated in multiple trials is less likely to be due to chance. Spring 2015 Volume 7 Issue 1


Drug Discovery, Development & Delivery The Perjeta Experience The FDA has approved just one drug for the neoadjuvant treatment of early-stage breast cancer: Perjeta (pertuzumab injection), by Genentech, Inc, in September 2013. The neoadjuvant indication specifies use in combination with trastuzumab and docetaxel to treat patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (tumour size exceeding 2 cm in diameter or with positive lymph nodes). The drug was already approved (in June 2012) for patients with HER2positive metastatic breast cancer or locally recurrent, unresectable breast cancer.

trastuzumab + docetaxel; Perjeta + trastuzumab; or Perjeta + docetaxel. Subjects received four cycles (12 weeks) of neoadjuvant treatment.

Perjeta’s accelerated approval was based on a randomised, multi-centre, international Phase II study, Neosphere, which used pCR as the primary endpoint. The trial enrolled 417 subjects with newly diagnosed HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. Participants were randomised to four study arms: trastuzumab + docetaxel; Perjeta +

The confirmatory trial, Aphinity, is a randomised, prospective, double-blind, placebo-controlled, two-arm study. This ongoing Phase III trial enrolled patients with operable HER2-positive primary breast cancer, randomising them to either chemotherapy + one year of trastuzumab + placebo or chemotherapy + one year

Study data demonstrated statistically significant improvements in pCR rates among patients who received Perjeta in addition to trastuzumab + docetaxel. Primary efficacy results showed pCR rates of: • • • •

21.5% for trastuzumab + docetaxel 39.3% for Perjeta + trastuzumab + docetaxel 11.2% for Perjeta + trastuzumab 17.7% for Perjeta + docetaxel

trastuzumab + pertuzumab. The primary

efficacy outcome measure is invasive DFS (IDFS), a composite endpoint defined as the time from randomisation until the date of the first occurrence of one of these events: ipsilateral invasive breast tumour recurrence, ipsilateral local-regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death (attributable to any cause). Aphinity is expected to conclude in December 2023. Meg Egan Auderset is a writer and editor of more than 20 years who has worked in a variety of settings in both the US and Western Europe. Currently a Medical/ Regulatory Writer for Thomson Reuters, her assignments include reporting on FDA advisory committee meetings and drug approvals for the Cortellis Regulatory Intelligence AdComm Bulletin. Email:margaret.egan-auderset@ thomsonreuters.com

Product News In-situ Sterilizable Bioreactor BIOSTAT® D-DCU Further Developed • • •

Standardized modular design accelerates commissioning and training TakeOne® aseptic single-use sampling system for fast and safe sampling Integrated CIP (Clean-in-Place) concept for efficient cleaning

Sartorius Stedim Biotech, a leading supplier to the biopharmaceutical industry, has launched a new version of its proven stainless steel fermentor|bioreactor BIOSTAT® D-DCU. The compact and modular, in-situ sterilizable system is suitable for microbial and cell cultures and is supplied in working volumes of 10 to 200 liters. Typical application areas for the BIOSTAT® D-DCU include the process development and production of small-batch biopharmaceutics, vaccines, enzymes, along with antibiotics and other secondary metabolites. Modular Design Enable Flexible Configuration from Basic Set-Up to Sophisticated Configurations The modular design of the BIOSTAT® D-DCU enables flexible configuration of the bioreactor system to meet individual customer needs. Available options range from a basic batch setup to sophisticated configurations supporting advanced gassing and feeding strategies, WITReady filter housings and automatic transfer of seed to a larger bioreactor or sterile harvest into a stainless steel vessel or single-use bag. Thanks to its standardized components and functions, design lead times are abbreviated, www.ipimedia.com

which results in faster system deliveries to our customers. Furthermore, standardization simplifies operator training and process transfers to other departments and locations, and finally, speedy availability of spare parts is achieved wherever needed to keep operations running smoothly. The bioreactor's control unit is available in a single- or twin version and can drive one or two culture vessels simultaneously and independently of each other. Their 19'' touch screen is easy to use and intuitive, which shortens training of new operators. In addition to controlling relevant process parameters like temperature, agitator speed and pressure, pH and DO (pO2), optical density etc., the system features fully automatic sterilization and cleaning functions. The novel mobile CIP unit completes the fully automatic cleaning concept of the BIOSTAT® D-DCU. Hybrid Solutions for the Entire Upstream Process It's not only easy to connect the stainless steel bioreactor to single-use filters or bags, but also to single-use systems for media preparation or cell harvesting. What's new to the product portfolio is the TakeOne® aseptic single-use sampling system that ensures safe and contamination-

free sampling. This avoids complicated and time-consuming cleaning and sterilization of the sampling valve and bottle. That means that SSB can equip the entire upstream process of its customers with hybrid, perfectly matched solutions. The customer enjoys the advantages of a proven stainless steel fermenter, while benefiting from the low initial investment costs and the flexibility and speed of innovative singleuse solutions.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 37


Drug Discovery, Development & Delivery Producing Colorectal Cancer Vaccine: Combining Forces between Denmark and Estonia DanDrit Biotech is a US biotechnology company developing a drug candidate that could become the world’s first vaccine for the treatment of colorectal cancer. Springing from academic roots in Denmark, they have built and patented immunotherapies, targeting advanced non-small cell lung cancer and colorectal cancer. Their lead compound, MelCancerVac™ (MCV), is a dendritic cell immunotherapy vaccine that aims at preventing relapses of advanced colorectal cancer after resection and chemotherapy. Three single-arm Phase II clinical trials were conducted in Europe and Asia in cancer where MCV demonstrated efficacy. Based on the promising results from these clinical trials, the developer needed to confirm the efficacy of MCV in a larger, comparative randomised clinical trial. As a result, with the assistance of experienced practitioners in colorectal cancer treatment and Cellin Technologies LLC, a contract manufacturing organization, a randomised Phase III trial (VIVA) with stage IV colorectal cancer patients with no evidence of disease after resection and chemotherapy is carried out. Developers believe that MCV has the potential to solve the problem of the high rate of relapses that dominates stage IV colorectal cancer patients with no evidence of disease. MelCancerVac™ MelCancerVac™ (MCV) is a vaccine composed of the patient’s dendritic cells (DC) generated from peripheral blood primary monocytes loaded with a lysate from an allogeneic melanoma cell clone with low expression of melanocytespecific differentiation antigens1. For MCV to work as a therapeutic cancer vaccine the injected DCs need to be able to activate appropriate T cells in the draining lymph nodes and to generate effector T cells that are ultimately capable of destroying tumour cells. The dose of each vaccination is 3-5 x 106 DCs pulsed with allogeneic tumour cell lysate. The vaccine is administered intra-dermally in the upper front thigh (trigonum femorale). The developers believe that the next generation dendritic cell vaccine, MCV, benefits from technological competitive advantages over other cancer vaccines, including: 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The vaccine is manufactured within eight days from a patient’s peripheral blood. The producer will be able to generate the vaccine with only 250mL of blood. Leukapheresis, which is used in Dendreon's Provenge™ cancer vaccine preparation, is not required. The vaccine uses an allogenic (using cells, tissues, or organs, sourced from a genetically non-identical member of the same species as the recipient) tumour lysate as opposed to inconvenient autologous (from the patient) tumour lysate. The cancerspecific antigens are “off-the-shelf” and therefore patient’s tumour cells are not needed to manufacture the vaccine. The vaccine is polytopic (targets several cancer-specific antigens). As a result, the risk of the tumour escaping is more limited and more T cells can be activated than if the vaccine was targetting one antigen only. However, MCV keeps a focus on melanoma-associated antigens (MAGE-A) that are only expressed by tumours and absent in normal tissues.

MCV Could Prevent Relapse of Advanced Colorectal Cancer MCV demonstrated efficacy in three separate Phase IIa clinical trials in colorectal and non-small cell lung cancer2. Even if MCV can be used for various cancers, the developers decided to focus MCV’s clinical development specifically on the prevention of relapses of advanced colorectal cancer (CRC). CRC is the second most frequent cause of cancer-related mortality in both Europe and the United States. The problem of the high rate of relapses dominates the stage IV patients with no evidence of disease (IV NED) condition. Despite the improved possibility of reaching the NED state in metastatic CRC, 90% of these patients eventually recur and die of their disease. Therefore, any systemic treatment aimed at reducing the chances of recurrence of stage IV patients who have reached the NED state should be considered. The classical paradigm of cancer treatment is that whatever works in the

advanced setting, like useful clinical responses, prolonged progression-free survival (PFS) or overall survival (OS), should work with curative intent when used as adjuvant therapy. This paradigm has held up in CRC: Fluoropyrimidines (FU) affording a six-month gain in the advanced setting produce an additional cure rate of about 10% when used as adjuvant therapy in stage III. Based upon this paradigm, the benefit of adjuvant chemotherapy (CT) in the setting of stage IV NED should be even higher, considering the 90% chances of relapsing of these patients. But, unfortunately, adjuvant therapies of stage IV do not work too well. The efficacy of pure adjuvant CT is debatable: FU affords a borderline significant benefit in OS compared to surgery alone (absolute delta 7% at five years) and FOLFIRI produced a numerically better OS that was not statistically significant compared to FU alone3. FOLFOX has not been studied (the NSABP trial C09 was discontinued for lack of accrual), although FOLFOX remains the most commonly employed regimen in clinical practice around the world. In the light of these marginal results obtained by the adjuvant strategies, “neo-adjuvant CT” of resectable metastases has been investigated within the frame of a “perioperative strategy” i.e., preoperative CT, then surgery, then CT after surgery. The EORTC produced the only randomised Phase III study available, that failed to demonstrate an OS advantage of the interventional strategy as compared to surgery alone4,5. The developers of the MCV believe that an immunotherapy with a good safety profile such as MCV may be the perfect adjuvant therapy for CRC. Immunotherapy has gained substantial interest in cancer therapy lately. Since the early steps taken in this field in the 1980s, and after a lag phase of decades during which much effort has been put into basic research, in the last few years several new immune modulatory agents showed activity in a number of solid tumours, both as single agents and in combination with other anti-cancer therapies (chemotherapy, radiotherapy, vaccines). Strategies designed for “removing brakes” from the Spring 2015 Volume 7 Issue 1


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Drug Discovery, Development & Delivery antigen-mediated immune response, for example anti-CTL4 and anti-PD-1/PDL-1 antibodies, have proven effective against cancer 6. An alternative approach involves stimulation of innate immunity, based on the rationale that activation of this system may have both direct anti-tumour effects and a role in enhancing tumour antigen presentation. In particular, agonists of Toll receptor 9 have shown promising antitumour activity by enhancing the clinical outcomes from cancer vaccination, conventional chemotherapy and other therapeutic modalities7. The knowledge of a growing number of tumour-associated antigens has provided a major stimulus for the development of cancer vaccines, i.e. active immunisations designed to treat growing tumours. In this context, recent studies have shown that high infiltration of primary CRC by CD3(+) and CD8(+) lymphocytes are associated with a better prognosis 8 independently from the CRC TNM classification. This finding suggests that the immune response plays an important role in CRC natural history and that boosting this response by vaccination may lead to clinical benefit. Currently, the use of dendritic cells pulsed with tumour lysate, such as MCV, for anti-cancer immunotherapy vaccines is of great interest, and the vaccines have been investigated in more than 150 clinical trials to date. The results demonstrate that these vaccinations are safe and in some cases can increase anti-tumour immunity in cancer patients and eventually induce clinical response in some patients. Although surgery is the primary effective treatment for CRC, combination regimens with conventional oncological therapy and new immunotherapeutic treatments can improve CRC treatment efficacy, resulting in reduced relapses and improved overall survival. The early experience in patients with progressive stage IV CRC treated with MCV showed 4/17 SD with 2 of these 4 lasting more than 27 and 37 months. Because the refractory, advanced setting is worse for vaccine therapy, these results, although very limited and preliminary, constitute a hint of activity for running this randomised trial. Moreover, the evidence available from pre-clinical and early-phase clinical trials justifies the study of the effect of dendritic cell-based vaccine on stage IV CRC patients in formal, controlled, randomised studies.

40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

VIVA: Phase III Clinical Trial The development programme is centred on VIVA, a randomised, open label, multicentre Phase III clinical trial in stage IV colorectal cancer patients with no evidence of disease after standard of the care (SoC). VIVA will be conducted in Italy in collaboration with GISCAD (Group for the Study of Digestive Tract Cancer). VIVA’s principal investigator is Prof Alberto Sobrero at IRCCS AOU San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy. The primary objective of this study is to investigate the efficacy of MCV in stage IV CRC patients rendered disease-free after completion of standard treatment according to local practices. The primary endpoint is Relapse Free Survival (RFS). Prior to randomisation, patients will have completed all treatment for colorectal cancer (CRC), including complete resection of the primary CRC tumour and any liver metastases and all SoC including chemotherapy (neo-adjuvant/ adjuvant). VIVA will enrol 174 patients with stage IV CRC and no evidence of disease within two years. 87 patients will be randomised to active treatment with MCV; 87 patients will be randomised to no further treatment (control group). Eligible patients randomised to active treatment will be vaccinated with MCV and receive a total of 15 vaccinations. Patients randomised to no further treatment (control) will receive SoC. Vaccine group patients will have three blood draws for the production of the vaccine. The first blood draw for vaccine production will be after randomisation. Patients will be followed for RFS and OS for five years after randomisation. For active treatment patients, plasma samples obtained from blood collected for vaccine production will be frozen and stored for possible analysis of immunological response at a later date, given that a specific informed consent form has been signed by patients. Response will be assessed according to Response Evaluation Criteria in Solid Tumours (RECIST). At the discretion of the investigator, patients with confirmed relapse during the treatment early phase and before receiving all the 15 planned vaccinations may continue to receive treatment and undergo all scheduled assessments, unless clinically indicated. Adverse events (AEs) will be assessed according to the National Cancer Institute’s Common Terminology Criteria for adverse events.

MCV is Produced by Estonian Company MCV manufacturing for the VIVA trial is outsourced from a contract manufacturing organisation under a pharmaceutical agreement, namely from Cellin Technologies LLC (CT), based in Tallinn, Estonia. CT will manufacture the MCV for the whole clinical trial program for up to 174 patients in their licenced GMP facility. Moreover, CT is also responsible for manufacturing the melanoma cell lysate (MCL), a critical raw material used for MCV production, and preparing and storage of melanoma working cell bank cells needed for MCL production. CT uses the state-of-theart GMP cleanroom facilities dedicated and equipped for the production of cell therapy medicinal products. They hold a manufacturer’s authorisation for preparing of sterile products and an activity licence for handling cells, tissues and organs, issued by the Estonian State Agency of Medicines (SAM). The collaboration of the two organisations began in January 2014, with the MCV technology transfer to CT’s GMP facility. The process to get the manufacturer’s authorisation for MCV production started in March 2014 and was successfully evaluated by the Estonian competent authority (SAM) in June 2014. Due to Estonian innovative e-services, the processes with government organizations are fast and efficient compared to many other countries nearby, without losing the compliance to high quality demands. In addition to GMP contract manufacturing services, CT is also actively involved in an EU-funded research and development project, which studies the use of regenerative cells from human adipose tissue in the creation of new blood vessels, directed by Dr Andrus Loog. Furthermore, the company's own research focus is to investigate the molecular mechanism of stem cells proliferation and differentiation, with a main emphasis on development of techniques to manipulate homing, differentiation and integration of cells following transplantation9–10. Benefits of e-Estonia The term “e-Estonia” is often used to describe Estonia’s emergence as one of the most advanced e-countries in the world. For the citizens of Estonia, e-services have become routine: e-voting, e-taxes, e-police, e-banking, and e-school11. In addition, there are Spring 2015 Volume 7 Issue 1


Drug Discovery, Development & Delivery tasks: the common understanding of the work ethics, and the sense of mission.

some e-services in healthcare that are widely used in Estonia, e.g. the digital prescription system and e-Health record – a medical information system with which people can view their own digital medical history11. Recently this year, Estonia announced the e-residency that has gained popularity worldwide, giving the opportunity to others than Estonians to use secure e-services that have been accessible to Estonians for years already12. Based on Estonian outstanding e-capability and the high quality of the state-of-the-art GMP laboratory and competent personnel, the Estonian company has become a partner enterprise, in which to develop an innovative personal medicine. Furthermore, never should anybody underestimate two very important assumptions, when starting to solve great 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

References 1. Kvistborg P, Boegh M, Pedersen a. W, Claesson MH, Zocca MB. Fast generation of dendritic cells. Cell Immunol [Internet]. Elsevier Inc.; 2009;260(1):56–62. Available from: http://dx.doi.org/10.1016/j. cellimm.2009.09.003 2. Kvistborg P, Bechmann CM, Pedersen a. W, Toh HC, Claesson MH, Zocca MB. Comparison of monocyte-derived dendritic cells from colorectal cancer patients, non-small-cell-lungcancer patients and healthy donors. Vaccine. 2009;28:542–7. 3. Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/ folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009;20(June):1964– 70. 4. Bernard Nordlinger, Halfdan Sorbye, Bengt Glimelius, Graeme J Poston, Peter M Schlag, Philippe Rougier, Wolf O Bechstein, John N Primrose, Euan T Walpole, Meg Finch-Jones, Daniel Jaeck, Darius Mirza, Rowan W Parks L. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371(9617):1007–16. 5. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14:1208–15. 6. Callahan MK, Wolchok JD. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol [Internet]. 2013;94(1):41–53. Available from: http://www.pubmedcentral. nih.gov/ar ticlerender.fcgi?ar tid=4051187&tool=pmcentrez&rendertype=abstract 7. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. The New

England journal of medicine. 2010 Aug p. 711–23. 8. Pagès F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009 Dec;27(35):5944–51. 9. Kauts ML, Pihelgas S, Orro K, Neuman T, Piirsoo A. CCL5/CCR1 axis regulates multipotency of human adipose tissue derived stromal cells. Stem Cell Res [Internet]. Elsevier B.V.; 2013;10(2):166–78. Available from: http://dx.doi.org/10.1016/j. scr.2012.11.004 10. Jääger K, Islam S, Zajac P, Linnarsson S, Neuman T. RNA-seq analysis reveals different dynamics of differentiation of human dermisand adipose-derived stromal stem cells. PLoS One. 2012;7. 11. http://estonia.eu/about-estonia/ economy-a-it/e-estonia.html, visited on 4 Feb 2015 12. https://e-estonia.com/e-residents/ about/, visited on 4 Feb 2015

Dr Eric Leire, M.D., MBA is the Chief Executive Officer, president and director of the board of DanDrit Biotech USA, Inc. (DDRT;OTCQB). Dr Leire has a solid background in oncology, immunotherapies, and clinical research. E-mail: epl@dandrit.com Kairit Tints is the Head of Quality and Qualified Person in activities involving handling of cells and tissues at Cellin Technologies LLC. Kairit Tints holds a master’s degree in molecular diagnostics from University of Tartu and has long-term experience as molecular and cell biologist. She is specialized in cell biology and has extensive experience in human stem cells. E-mail:kairit.tints@cellintechnologies. com Spring 2015 Volume 7 Issue 1


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Drug Discovery, Development & Delivery

Transparency: Turning Business Constraint into Commercial Advantage The pharmaceutical industry, one of the most crucial in the world in terms of impact on the lives of patients – from relieving pain to conquering disease – is in the midst of significant initiatives to improve transparency and build stronger public trust. To ensure ethical practice in the promotion of new therapies to healthcare professionals (HCPs), governments in the US and now Europe have tightened regulations to ensure that companies foster a culture of compliance and transparency.

data collection for reporting across 33 European countries. Differences in language, local regulation, and even alphabet put new demands on the IT infrastructure supporting data collection and reporting in Europe.

At its recent European Commercial Summit, Veeva Systems hosted a panel of pharmaceutical strategists, IT specialists, and compliance experts to share perspectives on the challenges and opportunities that lie ahead as the European pharmaceutical industry prepares to provide full transparency of HCP interactions. There was sweeping consensus that complying with EFPIA disclosure rules would not only help refocus sales and marketing activities, but also restore and strengthen relationships with healthcare stakeholders. However, to do so successfully, companies must first overcome the technical and cultural challenges of full disclosure.

Those companies still operating disparate legacy systems across their European businesses will struggle to streamline payment-tracking processes and deliver accurate reporting of total payments made to HCPs. Storing and reporting cross-border speaking fees, for example, will require interoperability and easy, agile information sharing between local databases to meet regulatory expectations. Increasingly, pharmaceutical organisations are looking to the cloud to store, integrate, and manage all this disparate payment data, and centralising on master data management solutions that enable the capture of large, complex volumes of HCP and HCO expenditure data across multiple source systems and countries. But integrating payment data for record keeping is just the first step. With 33 sets of transparency rules, reporting software will allow companies to be fully transparent, which, in turn, will help them regain the trust of the public. The need for a central reporting engine that allows regulatory affairs managers to produce and send tailored spend publications to multiple recipients based on local disclosure requirements is critical. Robust integration between a cloud-based master customer database and a central compliance solution allows for seamless exchange of information between the field, corporate home office, and regulatory bodies. This ensures accurate and consistent spend transparency and the opportunity to regain public trust.

Harmonising Transparency Reporting Across the Continent Since 2010, the US Physician Payment Sunshine Act has required pharmaceutical companies across the Atlantic to also disclose all payments to HCPs. However, organisations operating in Europe face a much bigger challenge in collecting payment data centrally, and in harmonising and preparing that

Creating Cultural Change If the changes in the transparency codes are to rebuild public trust in the pharmaceutical industry, companies must first ensure that they are adhering to both the spirit and letter of the law. Francis Geysermans, co-founder at life sciences compliance software provider BMI SYSTEM, believes that these regulations represent a major shift that

The European Federation of Pharmaceutical Industries and Associations (EFPIA) Disclosure Code came into effect in 2015, requiring pharmaceutical companies in 33 European member states to keep records of every speaker fee, travel expense, and sponsorship paid to a healthcare organisation or professional. By 2016, pharmaceutical companies in Europe must publish these records, either on their own websites or through reporting on a centralised database.

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is just beginning to take hold in this industry. “Currently, just 25 per cent of companies have grasped the importance of this change.” As the industry works to build public confidence and get life-saving drugs to market with a rapidly declining window of opportunity to meet face to face with physicians, transparency reporting presents both opportunities and obstacles. Pharmaceutical companies’ reputations are not the only ones called into question. Physicians are also in the spotlight, and will be sensitive to how their relationships with drug makers are documented in the public view. Rais Amils, a Barcelonabased lawyer with Clifford Chance, says, “Because the EPFIA code is voluntary in nature, data privacy regulations are especially important, and will prevail. The implication is that it will be necessary to request express consent from doctors for data disclosure, and it is likely that, at first, doctors will be reluctant to reveal personal data.” In this environment, trust between the sales representative and HCP will be crucial to maintaining relationships, and may drive new forms of communication between the physician and the brand. Training the sales force on the processes and protocols for tracking their transactions with physicians is necessary, but many in the industry think transparency requirements could usher in a larger change in how drug makers market to physicians. Further, Pascale Paimbault, chief executive and founder of compliance specialists Consulting Alley, believes the success of a company’s EFPIA reporting will rely on how the compliance officer is positioned within the company. This person needs to be seen as more than just a trouble-shooter for when something goes wrong. “The compliance officer needs to carve out a proactive role and take the lead in making sure the company has its own business ethics and puts those ethics into practice,” says Paimbault. “All pharmaceutical companies are ultimately Spring 2015 Volume 7 Issue 1


Drug Discovery, Development & Delivery

geared to producing medicines for the benefit of patients – a very ethical goal – so the company’s behaviour needs to reflect that. “Making compliance valued in an organisation is not just an obligation, but an opportunity – having collected all this data on whom you are paying, and for what, compliance officers can work with sales and marketing to analyse that data to correct inappropriate spending, analyse risks, and judge upon future relationships.” A New Era in Customer Data Analytics A look at countries where payment transparency has already come into effect indicates that payment data may trigger a cultural shift in how pharmaceutical sales representatives serve their customers. The bulk of transactions made by drug makers in the US and the Netherlands are to healthcare organisations, patient groups, and university researchers. Payments to individual HCPs are far lower, fewer, and less consistently applied. Now that these payment records are centrally stored, drug makers can begin to dig into the data and see which payments are creating value, and whether conference tickets and complimentary meals are really what healthcare professionals are looking for from their sales representatives. When records are publicly reported next year, drug makers will have access to even more information about HCPs’ preferences, including whether they are www.ipimedia.com

receiving payments from other brands, and the return on investment to particular brands. Customer analytics have come a long way in telling drug makers what information physicians want and what channels they use to research new therapies. Aggregating customer insight with payment data will help sales and marketing paint a more complete picture of what the customer needs, and what type of interactions they prefer, with the brands they value. This new information avalanche will transform brand marketing from the traditional supply-driven model to a more inclusive and responsive demanddriven sales and marketing approach. Rather than showing all of a company’s new therapies to a physician, in three to five years sales representatives will first download the latest holistic insight on a specific physician, and then prepare for the visit by arming themselves with the information and therapies that an individual HCP most needs to solve his or her current patient case load. Looking Forward Alexandre Regniault, life sciences legal expert at Simmons & Simmons, has observed how France’s transparency regulation has helped the industry rebuild its reputation and modernise its sales model. “Everybody accepts that there is no going back,” Regniault says.

“Companies will have to live with the new rules, and must learn to make the most of them. That includes seeing them as an opportunity to understand their business and relationships better, and using them as a means of competitive advantage.” These regulations will introduce a new era to the progress of the pharmaceutical industry. Companies can see the requirement as a threat – or they can embrace it, using the codes as a launch pad to improve compliance and transform their customer engagement strategies. Open disclosure shows that companies have nothing to hide, and this can be a step toward building patient and caregiver trust.

Guillaume Roussel is Director of Strategy for Veeva's data solutions in Europe. Over the course of 13 years at Cegedim, Roussel launched technology solutions designed to support the unique sales, marketing, and compliance needs of life sciences companies. With his unique experience, Roussel is set to drive the industry toward greater transparency, agility, and global harmonisation by delivering a world-class master data solution in the cloud. Email: guillaume.roussel@veeva.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 45


Clinical Research

Remote Diabetes Trial puts Patients at the Heart of Trial Type 2 diabetes might just be the most dangerous non-communicable disease in the history of humankind, but putting patients in charge of their own care could help solve the problem. “As a doctor, I would rather have HIV than diabetes,” Max Pemberton, a UKbased medic wrote in The Spectator in April 20141. “The prognosis for those with type 2 diabetes is much worse than for those with HIV,” he argued, listing increased risk of stroke, cardiovascular disease, and kidney failure, all complications of diabetes, as evidence. Reporting that most people consider it an “irritant,” Pemberton pointed out that, no matter how well-controlled, diabetes is a “progressive disease, which results in the need to increase pharmacological therapies over time.” While most people start with a tablet, after six years, 44% of patients no longer respond to oral medication and require insulin injections2. Furthermore, Pemberton noted, “many people are complacent about diabetes in a way that would seem reckless with HIV.” He might have had a point. According to a report from the London School of Economics3, treating diabetes, which was diagnosed in 3.2 million people in the UK in 2013 alone, cost £13.750 billion in 2012, including treatment of the primary problem as well as complications, and the spending associated with social care. Medication for cardiovascular disease constituted the largest proportion of prescription costs for people with diabetes. In addition, Diabetes UK reported4 that over 100 amputations are carried out every week on people with glucose control problems because of complications associated with the condition; up to 80% of these procedures are preventable. In addition, the Health and Social Care Information Centre5 reported that in 2012/13 only 46% of patients under 40 were given a full range of NICErecommended screening tests (e.g. BMI checks), while only 24% of under-40s met suggested targets for cholesterol, blood pressure, and glucose levels. Adherence to treatment was also poor. 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A cross-sectional study using face-toface or telephone interviews conducted on 5104 adults across 13 countries in 2005 and published in Diabetic Medicine6 revealed that medical regimen compliance is deficient among diabetic patients, particularly when it comes to diet and exercise. “Diabetes is badly controlled. Treatment is often based on poor data and outcomes are not tracked properly. Patients have no idea how controlled their diabetes is and doctors have very little structured data to support the management of an individual patient’s condition. Pharma companies lack scalable and efficient mechanisms to evaluate how their drugs are performing in a real-world setting in different countries.” said Kai Langel, Director at eClinicalHealth Ltd, a company which, in partnership with Langland, Mendor, and Sanofi launched a remote trial for diabetes. “This initiative is important because there are no patient-friendly or effective tools to track the condition, and doctors have to make treatment decisions based on scarce information.” In contrast to diabetes, Pemberton continued in his editorial, HIV patients take multiple antiretroviral drugs in a single tablet for the rest of their lives, which is much easier than injecting insulin. “To put it starkly,” Pemberton wrote, “the latest statistics show that because of Haart [antiretrovirals], HIV now no longer reduces life expectancy, while type 2 diabetes typically reduces it by ten years.” In 2013, there were 6000 people diagnosed with HIV, according to the National Aids Trust7, and less than 1% of all people living with the virus died. The average annual cost of treating HIV in the UK was estimated at £1bn in 2013 by PLoS One8.

enable them to know what their sugars are up to on a weekly or monthly basis, so they can start planning for that. It’s putting the power back into patients’ hands.” Empower the Patient! Changing the way diabetes is dealt with requires giving patients control over their condition, which the remote trial aims to do. The European Network on Patient Empowerment (ENOPE)9 defines patient empowerment as “putting the patient at the heart of services” and designing and delivering health services in a way which is “inclusive and enables citizens to take control of their healthcare needs.” It requires a revolution in thinking about patients within healthcare, but is vital to prevent an irrecoverable crash of the system. By the year 2050, when the number of people over the age of 65 will have tripled across the world, one in three Americans will have diabetes, according to the Centre for Disease Control and Prevention. This state of affairs, combined with increasing prevalence of other chronic conditions, can ruin the healthcare system. But it doesn’t have to be this way, as patients with chronic conditions and their families are both willing and able to cooperate with their healthcare providers, reducing the overall burden of disease. Creating a culture of empowerment within the system would allow patients

What’s the problem? Why do medics say that they’d rather have HIV than diabetes? “Diabetic patients can struggle with knowing when their sugar levels are dipping too low and when they’re going up too high,” explained Olivia Hunt, Account Manager, Langland, a leading advertising agency in healthcare. “[Our] idea was to give them a tool that will Spring 2015 Volume 7 Issue 1


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Clinical Research to understand what is happening to their bodies, enable them to make informed choices about lifestyle and treatment, and equip them with knowledge and confidence to challenge and ask questions of the healthcare professionals providing their care. Ultimately, it would allow individuals to actively seek out, evaluate, and make use of the provided information. “Patient empowerment means providing patients with the data to make their own lifestyle and treatment decisions,” Langel said. “Patients need to see how interventions are affecting them, so they can adjust their way of living. They need access to data on their own health status, so they can effectively consult with their physicians for data-driven treatment decisions,” Langel pointed out. But collecting data on patient performance also allows payers to assess interventions and reallocate resources as appropriate. “Diabetes is a big problem in the world and various stakeholders within healthcare are interested in improving the situation. We already have data that some of the interventions are not doing what they are supposed to be doing, despite costing hundreds of millions [of pounds], but it has been difficult to evaluate them because there were no feasible solutions available to help gather reliable data. It’s mind-

boggling!” Langel said. The remote diabetes trial was created with both those aims in mind. “Our belief [at Langland] is that patients should be at the heart of all our thinking. Whatever service is being rolled out, we always think of how to make it easiest for the patient. After all, a happy patient, is a compliant patient, which, in turn, creates good quality data, and helps drive medicine forward,” Hunt added. Patient-centric Trial Nominated for the eyeforpharma Barcelona Awards in Most Valuable Patient Initiative category, The VERKKO Trial is powered by Clinpal – a cloudbased platform from eClinicalHealth that allows patients to track their glucose levels in a very patient-friendly way. Patients give their consent to participate in the study online, they have access to a patient’s portal that allows them to manage their activity within the trial, and they can track their glucose measurements. Enrolled for five days to eight weeks, patients check their glucose levels on their own (e.g. before and after a meal) at their convenience, and have access to precise and easy-toread graphs that show them how they’re doing. “I was thinking about this challenge when I was still working for a different company,” Langel recalled. “At the time, the gold standard solution for capturing blood glucose data was a smartphone connected to a Bluetooth-enabled glucose meter, a rather clunky and expensive solution, but I didn’t have anything better to offer back then.” The VERKKO trial is a collaboration between Langel’s company eClinicalHealth; Langland, a leading advertising agency in the healthcare sector; Mendor, a developer of “disruptive diabetes management solutions;” and Sanofi, a global healthcare leader. Described by one of the eyeforpharma judges as “every patient’s dream trial,” VERKKO plays into people’s key drivers to participate in studies, and eliminates nearly all the obstacles, like time commitment, travel issues, and lack of information. “Everything is online. Information is available 24/7 in one click. Plus, there is no need to travel to the site, [participants] save time, it’s not disruptive

48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to [participants’] work schedule, and [patients] can do their [glucose] readings whenever it’s convenient for them,” Langel described. “A completely remote, online trial is not a model that would apply to every trial, but in this case it’s perfect as there is no study drug and the risks are very low. We’re testing the entire methodology and workflow with VERKKO, and it is likely that many of the concepts from this study are very suitable for any trial in any study phase. For example, electronic informed consent, patient portal, online recruitment are all applicable across all study phases,” Langel said. Hunt elaborated: “For a patient, being a part of a clinical study can be a daunting process. Taking them out of the clinical setting, which is what this trial does, allows them to feel more at ease. They don’t have to go to any visits, they don’t have to be interviewed by doctors about their medical history; they can do it all online.” Spring 2015 Volume 7 Issue 1


Clinical Research We created sugar cubes that are up to various activities, e.g. skiing, being at the beach having an ice cream,” Hunt described. But it’s probably Sanofi’s participation that is most noteworthy. After all, although the fact that pharma companies need to start offering a service instead of just pushing drugs is an industry platitude, not everyone is embracing that piece of advice. “When I went to Sanofi with this idea [for a remote trial],” Langel began, “they were keen to collaborate. The idea was very well received and they turned out to be eager to fund a trial that would test the concept of conducting remote trials,” Langel remembered.

The trial has been recruiting patients for about a month now, with very limited budget on media advertising. “Most of our recruitment is done through social media,” Langel explained. “Yesterday 16 patients were enrolled. So far we’re having a better conversion rate between traffic and enrolment than traditional studies. We will also be measuring patient satisfaction with their trial participation at the end of the study using an online questionnaire that’s part of the Clinpal system.” Both Langel and Hunt were pleased about their eyeforpharma nomination. “It’s amazing to get this external validation. We as a team thought the platform would serve the patients and to have this confirmed is really satisfying,” Hunt said. Collaboration Key to Disease Management VERKKO is a product of interdisciplinary efforts of four companies, each of which contributed their experience and knowledge to one of the most forwardthinking initiatives in the industry. “Langland developed the creative idea of ‘do you know what your sugars are up to,’ which is the visual identity that we hoped would resonate with patients. www.ipimedia.com

Sanofi saw an opportunity to engage their customers and took it. “This concept of providing patients with the right intervention and then providing them with a tool to see what the outcomes are [is] exactly what many companies are after. It’s a change in the pharma business model,” Langel said. Many companies are also interested in rethinking the way patients interact with clinical trials and this is something new. After all, having all the trial process on an online platform is an uncharted territory. “For a big pharma company to be involved in a remote clinical study like this is brave. Online consent is something people in the industry have been stressing about, and the early adopters are now taking action,” Hunt explained. And the payoff can be great. Since all pharma are competing for the same patients, the company that can make trials simpler and more user-friendly will be able to enrol more patients and complete a trial sooner, which will give it an edge. Despite diabetes being a pressing 21stcentury epidemic, affected patients rarely have access to tools that allow them to effectively manage their condition. The results are often catastrophic, leading to cardiovascular complications, kidney failure, and amputations. The VERKKO trial is aiming to change this by equipping patients with data that enables them to take charge over their disease progression. By putting the patients at the centre of their care, the thinking goes, complications can be averted, and treatment can once again become sustainable for the healthcare system, hopefully leading physicians like Max Pemberton to change their minds about manageability of diabetes.

References 1. h t t p : / / w w w. s p e c t a t o r. c o . u k / features/9185591/why-id-ratherhave-hiv-than-diabetes/, visited on 31 Jan 2015. 2. http://www.australianprescriber. com/magazine/27/4/93/6, visited on 31 Jan 2015. 3. http://www.diabetes.co.uk/costof-diabetes.html, visited on 31 Jan 2015. 4. https://www.diabetes.org.uk/ Documents/About%20Us/Statistics/ Diabetes-key-stats-guidelinesApril2014.pdf, visited on 31 Jan 2015. 5. http://www.pulsetoday.co.uk/ clinical/type-2-diabetes-less-wellmanaged-in-the-under-40s-findsaudit/20008094.article, visited on 31 Jan 2015. 6. Peyrot M., Rubin R.R., Lauritzen T., Snoek F.J., Matthews D.R. & Skovlund S.E. Psychosocial problems and barriers to improved diabetes management: results of the CrossNational Diabetes Attitudes, Wishes and Needs (DAWN) Study. Diabetic Medicine.22(10), 1379-85 (2005). 7. http://www.nat.org.uk/HIV-inthe-UK/HIV-Statistics/Latest-UKstatistics.aspx, visited on 31 Jan 2015. 8. Mandalia S., Mandalia R., Lo G., Chadborn T., Sharott P., Youle M., Anderson J., Baily G., Brettle R., Fisher M., Gomples M., Kinghorn G., Johnson M., McCarron B., Pozniak A., Tang A., Walsh J., White D., Williams I., Gazzard B., Beck E.J. Rising population cost for treating people living with HIV in the UK, 1997-2013. PLoS One. DOI: 10.1371/journal.pone.0015677. Visited on 2 Feb 2015. 9. http://www.enope.eu/patientempowerment.aspx, visited on 31 Jan 2015.

Zuzanna Fimińska is a writer for www. eyeforpharma.com, a hub for seniorlevel pharma executives, patient advocacy groups and other health experts to exchange ideas and stay upto-date with shifting trends and practices within the pharmaceutical industry. INTERNATIONAL PHARMACEUTICAL INDUSTRY 49


Clinical Research

SUSAR Consolidation - New Procurement Approach in Pharmacovigilance Abstract Suspected Unexpected Serious Adverse Reactions (SUSARs) have become a critical element in analyzing the risk and benefit associated with the life cycle of a medicinal product, either in the market or undergoing clinical trial. It has been a dynamic and swiftly changing area of the pharmaceutical industry and has become one of the concerns as well. In the past three to five years, pharmacovigilance (PV) services have witnessed a paradigm shift. The release of guidelines by the US Food and Drug Administration (USFDA) and European Medicines Agency (EMA has changed the way of managing SUSARs. Stringent guidelines, patient awareness, and pharmaceutical companies’ interest in drug safety data has given rise to intense patient safety monitoring. Today, the pharmaceutical industry is facing challenges due to changed reporting requirements to manage volume of SUSARs reported. Pharmaceutical companies outsource SUSARs under their PV services to various suppliers based upon their geography, product and service capabilities. The pharmaceutical companies maintain inhouse resources to ensure the quality of services for SUSAR reporting and maintenance. The volume of SUSARs reported in the USA has amplified by 20-25% year on year. At present, pharmaceutical companies are exploring various opportunities to bring down the ascending cost of SUSAR reporting by harmonizing service line, supplier base and the technology platform. SUSAR consolidation to a few suppliers can serve the purpose of supplier consolidation; service consolidation is related to drug safety, technology platform and reduced headcount to manage the service. In a nutshell, pharmaceutical companies can save significant costs, and enhance productivity, integrated communication with suppliers and quality of services. 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Recommendations • SUSAR consolidation to best fit suppliers based upon large product portfolio management • SUSAR consolidation based upon product life cycle – clinical trial or post-market Ascending SUSARs - concern for pharmaceutical companies The past couple of years have been overwhelming for pharmaceutical companies due to increase in numbers of SUSARs being reported in developed nations. Due to rise in case process workload, the large pharmaceutical companies started to outsource SUSAR processing to pharmacovigilance suppliers to meet the resource requirements, significant cost savings and improving the operational efficiencies without trading the quality of work. In the USA, more than 770,000 people are injured or die every year in hospitals from adverse drug events (ADEs). This may cost them up to USD 5.6 million per year. The treatment expenditures of patients who suffer ADEs during hospitalization at national hospitals are estimated between USD 1.56 and USD 5.6 billion per year. The patients who had ADEs spent close to 8-12 days more than patients who did not have ADEs, and their hospitalization cost is USD 16,000 to 24,000 or even more. These figures worked as a catalyst and pushed the US government, USFDA and pharmaceutical companies to brainstorm, resulting in increasing the drug monitoring to evaluate the benefit or the risk associated with a drug.

Source: USFDA; Beroe Analysis

As per FAERS Statistics (FDA Adverse Event Reporting System) the adverse reactions rise by 17-22% year on year. It clearly indicates the ascending workload of pharmaceutical companies.

The European Union, one of the most regulated markets, is no different compared to the USA, especially after July 2012, when the PV legislation announced direct case reporting of ADRs by patients, which further increased PV workload.

EMA, EudraVigilance Annual Report, 2013

Traditionally, pharmaceutical companies engage with suppliers based upon study, product or geographical expertise, due to the regional preferences in terms of local regulatory knowledge. In its current state, SUSAR reporting services across the value chain are not outsourced to a single vendor but distributed in sections among different suppliers. Now, an increased number of suppliers in different locations performing similar tasks indirectly elevate the cost. Even internally, the pharmaceutical companies need in-house resources to keep an eye on the process, which makes it complex and cost-intensive. SUSARs Consolidation Engagement between pharmaceutical companies and suppliers has been strategic. Most of the sourcing categories have not witnessed much consolidation of suppliers relating to SUSAR processing services. In the past years, due to rising Spring 2015 Volume 7 Issue 1


Clinical Research operational costs, pharmaceutical companies have been trying to recognise effective approaches to descend the spending. In current culture of supplier management, the pressure due to rise in workload and decrease in spending pushes pharmaceutical companies to assess their current suppliers, evaluate and shape the number of total suppliers to a selected few best-fit suppliers or “partners”. Keeping the nature of services under consideration, pharmaceutical companies can consolidate SUSARs to a few best-fit suppliers, especially in low-cost destinations. Consolidation of SUSARs will lead to a volume of cases on a global level which can be leveraged for price negotiations for case processing services. If we look into the market dynamics we should not be surprised by the fact that the few global, full-service CROs – large IT/BPO companies – are aiming to expand their services with niche knowledge, geographical coverage, technology capability and workforce to meet the demand of the pharmaceutical companies, and indirectly consolidating in terms of adding services to the value chain of a category or a new service along with other services to the portfolio. The Low-hanging Fruits of SUSAR Consolidation The SUSAR consolidation would be an overall reduction in the various aspects of procurement and sourcing management between the pharmaceutical companies and their pharmacovigilance partners performing case processing of SUSARs.

Reduced costs: SUSAR consolidation to a few suppliers will bring an opportunity for financial benefits. As the number of suppliers reduces to a few, the buying power of pharmaceutical companies will arise. Further to this, it will boost the competition among the suppliers to www.ipimedia.com

provide the services at a lower cost. Ease of supplier management: Roughly it costs between USD500 and USD1500 for resources, technology, outsourcing and overheads to manage each supplier. After SUSAR consolidation to a few suppliers, the number of separate transactions will drop, as will the amount of time to manage them. At the same time, the overall risk associated with transactions will condense. As a result, fewer suppliers mean lower collaboration costs with reduced FTEs effort than required. It will create a closer association with the supplier. Reduced headcount and increased productivity: Relatively, the procurement professionals required in-house will fall in number, which will give them an opportunity to handle more strategic roles and responsibilities. Increased negotiation: Based upon the volume of work due to SUSAR consolidation, the bargaining power of pharmaceutical companies will rise up, which will definitely help in reducing the cost while at the same time aligning the suppliers according to their needs. How to Go Forward with SUSARs Consolidation? Various large suppliers are enhancing their competences to meet the volumebased requirement of pharmaceutical companies. It has been observed that these service providers are raising the headcount in low-cost countries like India, which has been providing drug safety services for the past decade and has been able to match the quality standards to handle serious cases and various drug safety services as well.

Source: Beroe Analysis Note: LCC: India (Contribution: 70-75%) China, the Philippines, Turkey, Brazil, Argentina; PVO: Pharmacovigilance Organisations Source: Beroe Analysis EU Big 5: UK, France, Germany, Italy, Spain; CH: Switzerland; LCC: Low cost country

In addition to this, a few large suppliers

have identified the Philippines as the next strategic destination to provide costeffective services, as it contributes close to 3-5% of total outsourcing to large IT suppliers. The intense competition among suppliers has improved operational capability to handle the large volume of cases, which can be leveraged through consolidation in low-cost country locations. Conclusion Consolidation of SUSARs can yield various significant benefits and efficiencies. Opportunity costs, collaborations, enhanced communication between buyer and supplier and the development of niche capability to serve the buyer will shrink cost and surge quality of services. Consolidating SUSARs to a few suppliers will enable pharmaceutical companies to recover significant value in opportunity costs of in-house resources, infrastructure, duplicate work between the different suppliers for the same services and time investments. The pharmaceutical companies will be able to reap the low-hanging fruits of consolidation through various operational efficiencies like better programme management, enhanced communication and training, standardized processes, and technology setup costs. References 1. USFDA, FAERS Patient Outcomes by Year 2. EMA, 2013 Annual Report on EudraVigilance for the European Parliament, the Council and the Commission 3. http://www.manufacturingchemist.com/ news/article_page/Sciformix_expands_ into_the_Philippines_and_opens_office_in_ Manila/90714 4. AHC Pharmacovigilance Workshop, 2013

Ashwini Tripathi is a dynamic and passionate procurement professional with experience in delivering various sourcing solutions to Fortune 500 pharmaceutical clients and interpreting procurement solutions to the key industry concerns for various pharmaceutical services. His expertise and knowledge encompass industry best practices, best cost sourcing, supplier mapping and building negotiation parameters based upon supplier capabilities. He is currently working as a Senior Research Analyst at Beroe. INTERNATIONAL PHARMACEUTICAL INDUSTRY 51


Clinical Research

A Review of Clinical Trial Challenges in Rare CNS Diseases Last year’s ice bucket challenge raised the profile of a rare CNS disease, amyotrophic lateral sclerosis (ALS), a form of motor neuron disease. There is a paucity of treatments for this disease and, like most CNS disorders, both common and rare, there is no cure or treatment that will alter the inexorable progression which, in the case of ALS is likely to prove fatal in three to five years. It could be argued that a diagnosis of ALS is worse than a cancer diagnosis. So with the increasing awareness of the need for new treatments, there should be an increase in the number of clinical trials in this area. This article reviews the challenges of designing and conducting late-stage clinical trials in three rare CNS diseases: ALS, Huntington’s disease (HD) and progressive supranuclear palsy (PSP). Amyotrophic Lateral Sclerosis/Motor Neuron Disease Motor neuron disease (MND) is the overarching description of the devastating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) that attack motor neurons. ALS is the most common form of MND and is known as Lou Gehrig’s disease in the US, after the great American baseball player whose career was ended by the disease. It affects both upper and lower motor neurons, and limb weakness and wasting is a key symptom. Other types of MND that have recently been characterised are • • •

Progressive bulbar palsy Progressive muscular atrophy Primary lateral sclerosis (PLS, subtypes being ascending, multifocal, and sporadic paraparesis (PLS-A, PLS-M or PLS-SP)) Kennedy’s disease

These MND disorders are rare, and treatments even rarer. There is one drug approved for the treatment of ALS – Riluzole (trade name Rilutek), developed by Rhone Poulec Rore (now Sanofi) and approved in 1995. It was shown to delay disease progression in clinical studies and in 2012 sales reached $64 million before generics were introduced in 2013. A Health Technology Assessment1 of the effectiveness of Riluzole concluded 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

‘There is limited evidence of a modest increase in tracheostomy-free survival for patients taking riluzole. However, the evidence is restricted and uncertainty remains as to the true size of any effect due to riluzole.’ The prevalence of MND is around seven in 100,000, and ALS constitutes around 65% - 85% of these. Age of onset is generally in late middle-age, but in rare cases it can affect people in their early twenties. Progression varies, with ALS generally leading to death in three to five years, although a small number of ALS cases have had an essentially normal lifespan albeit with severe disability. The eminent British scientist, Stephen Hawking, was diagnosed in his twenties with ALS and he is now in his seventies, although completely paralysed. With PLS the lifespan is also essentially normal but with severe disability. What is known about the causes of MND? As with most neurodegenerative disorders the cause is unknown. There is increasing work looking at the role of genetics in ALS02 . It has also been noticed that MND seems to affect more male, fit sportsmen, such as Lou Gehrig and more recently the Dutch footballer Fernando Ricksen. Various reviews have investigated this, but no definitive conclusions have been reached3, 4. So what are the major challenges faced by drug developers when they are planning their Phase II and, crucially, the Phase III trials in ALS or other motor neuron disease types? •

Patient selection. There are many types of MND and the knowledge of each type is evolving. It is crucial that the correct patients are included from what is a very heterogeneous disease. It is also crucial to ensure that the patient population is at the same stage in their disease in order to get close to a homogenous study population. The inclusion/exclusion criteria may need to go beyond the typical diagnosis in order to achieve this. Endpoint

selection

-

The

gold

standard is the ALS functional rating scale- Revised (ALSFRS-R)5 . The advantage of this scale is that it measures the progression of disability and, therefore, meets the clinically relevant hurdle. The disadvantage is that it is a composite score covering multiple symptoms and domains, such as limb and bulbar dysfunction as well as dyspnea, orthopnea, and the need for ventilatory support. As such, the slope of decline is not consistently linear and statistical assumptions based on a linear model may be incorrect. Other endpoints have been the traditional survival time to death, meaning that patients are included in the study whilst in the midst of a rapid decline in their condition. This is a highly clinically relevant endpoint but presents a challenge for clinical trial design. The primary endpoint in Biogen’s recent 973-patient Phase III ALS study, Empower, used a combined assessment of function and survival, based on changes in ALSFRS-R total scores and time to death up to 12 months. Sadly this showed no difference from placebo. Top Tips in Planning Efficacy Clinical Trials in ALS/MND In aiming for a homogenous population, additional inclusion/exclusion criteria could be used to supplement the traditional diagnosis (e.g. the revised El Escorial criteria6). This can also help ensure you have a study population as close as possible in the stage of their disease progression, another important feature to ensure a homogenous population. Cognitive and behavioural impairment are now recognised features of ALS, however, they are often not measured in clinical trials and are not part of the ALSFRS. Importantly, cognitive dysfunction particularly in executive function may predict those patients with reduced survival7, 8. Additional outcome measures such as the Neurophysiological Index (NI) could be included. The NI has good intra-rater reliability and has been shown to be Spring 2015 Volume 7 Issue 1


Corporate Profile Neuro-Sys, the preclinical CRO with a different approach Age-related neurodegenerative disorders currently affect millions of people worldwide and their prevalence is increasing at an alarming rate. Elucidating the basic biology and physiopathological mechanisms leading to neurodegeneration and treatments is a key challenge. Neurodegenerative disease research that blossomed in the last 40 to 50 years brought new technics and innovative methods in research. Based on these new technics, in-house automatized platforms and with the serious experience of its researchers and scientists, NeuroSys has standardized models of CNS diseases specifically on: • • • •

Alzheimer disease (AD); Parkinson disease (PD); Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig's disease); and Demyelinating diseases.

What we do Neuro-Sys is an innovative company that provides the pharmaceutical and biotech industry with efficient and highly skilled cell-based preclinical modeling services: • • • • • • • • • •

Cortical neurons; Glial cells (astrocytes, oligodendrocytes); Hippocampal neurons; Mesencephalic neurons (dopa-, gabaergic neurons); Models of central and peripheral myelination; Motor neurons; Muscle cells; Nerve-muscle co-culture; Schwann cells; Sensitive neurons.

With a strong expertize and a hi-end laboratory equipment, Neuro-Sys develops and uses specific preclinical models of CNS diseases to achieve high-quality efficacy pharmacology and mode of action studies. We are dedicated to provide high-level technical expertise and preclinical services in a collaborative relationship with our clients.

provide the best results, faster. We have selected some of the best automation providers capable to design and setup such platforms. The starting point Standard screening platforms on the market generally accept molecular compounds coming from the chemical industry that we also do perfectly. Uncommonly, our processes and platforms have been designed to be capable to receive other entities such as: • • •

natural products (plants, seaweed…); extracts from natural source; compounds from natural or chemical source.

Hence, before providing a full pharmacological and analytical profile of the initial entity, we apply a specific standardized process depending on the input source. The pharmaceutical and biotech industry as well as Governments are now really interested in this approach and the extended service coming from natural sources (more generally from plants) we propose to seize the potential on neurodegenerative diseases of natural products. Green-Extraction Natural products are processed into our “Green-extraction” laboratory where “green” stands for ecology. Extraction of natural products using standard methods is a truly polluting activity. Because reducing carbon footprint is important to us, Neuro-Sys also has a strong green policy regarding its activities and extraction which is a major activity. Our green-extraction laboratory composed of brand new extraction technologies (micro waves, ultrasounds, alternative solvents…) is handled by scientists, experts in eco-extraction technics and methods that provides similar or even better results than conventional extraction methods. Drug discovery programs Neuro-Sys also develops and uses its platforms to perform proper dedicated drug discovery programs. Sharing the same vision and determination, the IDVP (Institut de Développement Vietnam Pacifique) and Neuro-Sys setup an exclusive partnership to bring a new dynamic to neurodegenerative disease drug discovery researches. The IDVP was founded in 1989 in Nouméa, New Caledonia, to survey the medicinal flora of this rich archipelago, kept intact for 350 millions of years. From this privileged base, IDVP jumped to Vietnam and focused on medicinal plants with a traditional reputation for enhancing graceful aging. Such prevention derives from stimulating the immune system of natural defenses against oxidative stress created by free radicals. We are then proposing our clients brand new compounds with a proven efficacy and mode of action coming from medicinal plants selected by our scientific board.

A team of experts Our operational and scientific team is composed of highlyskilled and experienced specialists such as pharmacologists, neuroscientists, neurologists, cell-biologists and phytochemists. Innovative models and automatized screening platforms Neuro-Sys invests a lot in R&D to continuously enhance its models of CNS bringing then the most advanced solutions to clients. Our high-content imaging platforms composed of the last cuttingedge equipment allows the highest screening quality. Moreover, assisted with a fully robotized system, our platforms including efficacy and mode of action testing can run on a 24/7 basis to www.ipimedia.com

Key contact Yann Jaudouin, CEO Neuro-Sys 410 Chemin Departemental 60 13120 Gardanne France Email: yann.jaudouin@neuro-sys.fr Tel/Fax +33 4 13 41 51 71 / 72 Website: www.neuro-sys.fr

INTERNATIONAL PHARMACEUTICAL INDUSTRY 53


Clinical Research sensitive to change in ALS; its inclusion may allow for shorter studies9. Try to measure the biological activity of your drug in the disease. Look at imaging, blood plasma, CSF or PK sampling as ways to measure whether your drug is meeting its target. Without this then it has to be faced that you are effectively working in the dark. This is also where the crucial role of the drug’s mechanism of action meets the proof of the drug’s concept and leads onto the proof of the drug’s efficacy. Inclusion of biomarkers in clinical trials of MND. Work is ongoing in this area, such as the NIH/NINDS and ALS Association-funded study of validation of biomarkers in ALS, and the NINDSfunded study of screening and natural history of PLS and related disorders . It is clear that future trials must routinely incorporate candidate biomarkers if the historical reliance on survival as the primary outcome measure is to be overcome. Ideally we would all like to see patients being offered, as soon as they are diagnosed, immediate entry into a short clinical trial, with a biomarker outcome, modelling the clinical trial pathway of people with a cancer diagnosis. With the increased research and increased funds raised by initiatives such as the ice bucket challenge, this may just be possible. Huntington’s Disease Having worked on clinical trials of new treatments for Huntington’s disease since 1999, I have followed this area with intense interest. So what has changed over the last 15 years? One drug for the treatment of Huntington’s chorea (a motor symptom of HD) was approved by the FDA in 2008. The drug is Tetrabenazine and it was a new drug for US patients only; it was already available in most EU countries and Canada and had been so for many years. Tetrabenazine is a classic case of drug repositioning and also demonstrates the value in obtaining an orphan drug designation for a drug well outwith its patent life. Tetrabenazine is a very old drug and its development was a tale of twists and turns. However, the end result is a product earning yearly revenues in 2011 of over $150Million for Lundbeck . For a drug discovered in the late 1950s, that is quite staggering. The prevalence of HD is around three to seven in 100,000 and it has a higher 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

prevalence in Europe, America and Australia than in Asia. Symptoms usually occur in middle age (35 – 55 years of age) and progressively worsen over 15 – 20 years. HD is a genetic disorder, caused by a mutation in the HTT gene. The HTT mutation that causes Huntington’s disease involves a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Everyone has a CAG segment and in normal circumstances, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington’s disease, however, the CAG segment is repeated 36 to more than 120 times. People with 36 or more CAG repeats will be diagnosed with HD. A genetic test has been available since the early 1990s, however the uptake is low, possibly because of the lack of treatments. It is a dominantly inherited gene, so the child of an affected parent has a 50/50 chance of being affected. In very severe cases, with very long CAG repeat lengths, the age of onset is younger, and in extreme cases this causes juvenile HD where people in their late teens have symptom onset. The symptoms expressed by HD include gaining involuntary movements (chorea, dystonia) as well as problems with controlling voluntary movements (i.e., gait and balance, speech, swallowing, and hand and eye control). Cognitive decline presents early and progresses through to severe dementia. There are also behavioural and psychiatric disturbances although these tend to follow a non-linear progression, showing much variability over time. At end stages patients are severely functionally impaired, often bedridden with severe motor problems, either hyperkinetic or rigid and severely cognitively disturbance. Causes of death are usually related to the symptoms of having HD, such as pneumonia as a result of being bedridden or choking caused by the lack of control over swallowing. As with so many rare CNS disorders, the majority of clinical trials in HD over the last 15 years have been negative. So what are the issues? Endpoint selection: • The Unified Huntington’s disease rating scale UHDRS is the gold standard. It measures four domains: motor, cognition, behaviour and

• •

function. Each domain is scored separately by separate scales, and it is important to note that some domains such as motor can contain compensatory symptoms, making it difficult to interpret the change in a total score. Cognitive tests may be difficult to administer if motor disturbance is manifest. The domains may take years to show a change, so designing disease-modifying trials is extremely challenging.

Patient selection: • Design your study to aim for a homogeneous population. This can be tricky, and the genotyping of patients has only added another variable to consider. As with ALS (discussed above) it can be important to include patients that are at a similar stage in their disease progression, and for HD that has typically a 10-20-year disease course, this is more of a challenge. What About HD Patients – Any Cause for Optimism? The number of clinical trials in HD is growing. Drug developers need to be aware of the pitfalls when designing their pivotal clinical trials, and have strategies to avoid them. I am sure that the future offers hope for HD patients and their families, and that the tide will eventually turn in their favour. Progressive Supranuclear Palsy Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease, often confused with Parkinson’s disease. The cause is unknown, diagnosis is difficult and there is no cure and once again, no effective treatments. It gets its name from the effects of the disease: progressive – because it gets worse over time; supranuclear – because it damages parts of the brain above the pea-sized ‘nuclei’ that control eye movements; palsy - because it causes weakness The average age at symptom onset is 63 although there are instances of people in their 40s with a diagnosis. Mean survival is 5-7 years from symptom onset. There are three man categories of symptoms: facial, postural and cognitive. The early symptoms are eye problems, including difficulties looking up or down Spring 2015 Volume 7 Issue 1


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Clinical Research or focussing, double or tunnel vision, and often an aversion to bright lights. Problematic symptoms appear, such as loss of balance and unexpected falls, usually backwards. There is also dysarthria, dysphagia, rigidity, and frontal cognitive disturbance. As with HD, the most common cause of death is pneumonia. The condition is rare, first described in 1964 by Steele, Richardson, and Olszewski , in their seminal work on nine cases with autopsy confirmation. PSP has an estimated prevalence of 1.4 per 100,000 in the US and three to six per 100,000 in the UK . There is a similar incidence between males and females. Macroscopic abnormality is severe pigment depletion in the substantia nigra, which becomes orange, discoloured and shrunken. PSP affects neurons and glial cells. Structurally, the principal areas affected are the basal ganglia, brainstem, cerebral cortex, especially the frontal lobes, dentate nucleus of cerebellum, and the spinal cord, which can cause problems with bladder and bowel control. Investigations have identified the neurotransmitter abnormalities with dopamine, acetylcholine, gamma aminobutyric acid and noradrenaline.

There is no cure and no effective treatment for the symptoms The first clinical rating scale for PSP was published in 2007. The "PSP Rating Scale" rates 28 items, with a total score range of 100 points, and requires about 10 minutes to administer. No floor or ceiling effects occur and patients progress an average of 11.3 points per year. Validated by its ability to track and predict clinical decline, the scale is clinically relevant and easy to administer. It has been adopted internationally in interventional and observational studies. There have been an increasing number of clinical trials in PSP, especially as more companies look at Tau as a target. Being a pure tauopathy, PSP offers the chance for both target therapeutics and also diagnosis such as CSF marker. Clinical trial challenges remain and include: • • • •

How to ensure a homogenous population with such an inaccurate diagnosis Can you include a population close to the same stage in their disease progression Study duration in a relatively rapidly progressing disease Measuring response of the target

Figure 1 With imaging, PSP had been characterised with MRI by the structural similarity to the morning glory flower (A) and hummingbird (B). Image (C) shows asymmetrical atrophy of the frontal lobes. As these structural changes are manifest in the late stages of the disease, MRI is unfortunately not useful for the initial diagnosis. In the early stages, MRI is more often used to rule out other possible explanations for the symptoms such as a brain tumour or stroke. As with ALS, the diagnosis of PSP is clinical and is made on a possible, probable or definite basis depending on the presence of the range of symptoms. 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A recent large clinical trial of Davinutide in PSP, conducted by Allon Therapeutics, used the commercial strategy of working in a rare disease rather than the more common Alzheimer’s disease for their Tau drug. Sadly the study was negative and the development of the compound has been discontinued. Summary In conclusion, there are common challenges in the rare CNS disorders related to patient selection, diagnosis, staging, endpoints for clinical trials and a lack of biomarkers. These can all be traced back to the lack of knowledge of the biology of the disease, a problem

resulting from the historical lack of research in the diseases of the brain. Fundraising initiatives such as the ice bucket challenge have been subjected to criticism, including that it is selfcongratulatory and put its emphasis on fun rather than raising money for research. However, even the most hardened critics could not doubt the effect it had on the amount of funds raised. The monthly donation to the ALS charity in the US went from $2.7m to $98.2m. In the UK, the MND Association would receive on average £200,000 a week in donations pre-ice bucket challenge. In one week in from 22 to 29 August 2014, it received £2.7m. With these charities’ commitment to research this surely means that advances in diagnosis, treatment and ultimately a cure are becoming closer. With so many common themes to these neurodegenerative disorders, then advances in one area will add to the sum of knowledge in other areas. Here is hoping the ice bucket challenge becomes a regular fundraising event for research into neurodegenerative disorders. References 1. h t t p : / / w w w. j o u r n a l s l i b r a r y. nihr.ac.uk/__data/assets/pdf_ file/0018/65052/FullReporthta5020.pdf 2. Gijselinck I. et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study Lancet Neurology 2012; 11: 54–65 3. Harwood CA, McDermott CJ, Shaw PJ. Physical activity as an exogenous risk factor in motor neuron disease (MND): a review of the evidence. Amyotroph Lateral Scler. 2009; 10: 191-204 4. Chio A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. 2005; 128: 472-6. 5. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III) J Neurol Science 1999, Oct 31, 169 13-21 6. Brooks BR, Miller RG, Swash M, Munsat TL. World Federation of Spring 2015 Volume 7 Issue 1


Clinical Research Neurology Research Group on Motor Neuron Diseases. Amyotrophic Lateral Scler Other Motor Neuron Disorder 2000 Dec 1(5) 293-9 7. Elamin M, Phukan J, Bede P, Jordan N, Byrne S, Pender N et al. Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia. Neurology. 2011; 76: 1263-9 8. Turner MR, Hardiman O, Benatar M, Brooks BR, Chio A, de Carvalho M et al. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 2013; 12: 310-22. 9. Swash M, de Carvalho M. The Neurophysiological Index in ALS. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004; 5 Suppl 1: 108-10 10. http://1.usa.gov/1mdA9yA 11. http://www.ihs.com/products/ global-insight/industry-economicreport.aspx?id=1065932287 12. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disorder 2012 Aug:27(9):1083-91

13. http://www.movementdisorders. org/MDS-Files1/PDFs/RatingScales/uhdrs.pdf 14. Steele JC (1994) Progressive supranuclear palsy. Historical notes. J Neural Transm 42 (suppl) 3–14. 15. Steele J, Richardson JC, Olszewski J (1964) Progressive supranuclear palsy. A heterogeneous system degeneration involving brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 10:333–359. 16. Golbe LI, Davis PH, Schoenberg BS, Duvoisin RC. Prevalence and natural history of progressive supranuclear palsy. Neurology 1988; 38:1031 17. Schrag A, Ben-Shlomo Y, Quinn NP, Prevalence of progressive supranuclear palsy and muscular system atrophy: a cross sectional study. Lancet 1999; 354:1771 18. Hawley JS et al. Neurology 2011;76:S67-S68 19. Golbe LI, Ohman-Strickland PA. A clinical rating scale for progressive supranuclear palsy. Brain 2007; 130: 1552-1565. 20. http://en.wikipedia.org/wiki/Ice_

Contract Manufacturing Excellence Cobra invites you to visit our modern, purpose built, aseptic manufacturing facility in Matfors, Sweden. Please visit our website to arrange a tour: www.cobrabio.com

Bucket_Challenge#Criticism 21. h t t p : / / w w w. b b c . c o . u k / n e w s / magazine-29013707 22. http://www.alsa.org/research/

Susan McGoldrick is an e x p e r i e n c e d pharmaceutical executive having worked in various roles within the pharma industry including a small pharma company developing a treatment for Huntington’s disease and founding and running a CRO specialising in CNS disorders. Susan now advises The CNS Company on clinical trial issues in CNS disorders, particularly in rare CNS disorders. Email:susan_k_mcgoldrick@ thecnscompany.com


Logistics

Organising the Cool Supply Chain at Airports Stricter requirements for the transportation of pharmaceutical products have an impact on how the cool supply chain at airports should be organised. Despite the complexity of the effort, developing and implementing a global industry certification standard is crucial. Supply Chain Evolution Shippers and forwarders stress the importance of time- and temperaturesensitive products in pharma as well as their trend to grow in the short term. Since more countries are enforcing GDP-type (good distribution practices) guidelines, this will likely lead to an increase of pharma shipped via air cargo, due to stricter requirements. The consensus and understanding in the logistics air cargo community are growing that shippers will increasingly look for reliable and transparent temperature-controlled solutions. The global sourcing and distribution model of the pharma industry favours air cargo. The current major production

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locations in Europe and the US are expected to grow, with new production sites being developed in India and Latin America. This explains the big differences in pharma volumes between regions. As an example, looking at the European average, pharma represents 3.3% of air cargo volumes. Looking at Belgium, being in the middle of one of the European pharma clusters, pharma represents 5.7% of total air cargo volumes in Belgium. As a result, the logistical service providers based at Brussels Airport are investing more than the European average on dedicated pharma infrastructure and specific pharma handling know-how.

We also see this evolution taking place at Brussels Airport, developing into a preferred pharma gateway in the region. Local logistical suppliers are taking steps to increase the quality of their services in the air freight supply chain for pharmaceutical products. It consists of a diverse range of commodities with different handling and storage requirements. This drives the diversification of specific handling services offered for pharma products. Based on pharma volumes handled at our airport, estimates indicate that about 75% require passive cooling solutions and about 25% require active temperature control.

Since the average market share of the pharma segment in the total air cargo volume is limited, specialisation is only possible in an exclusive number of international logistical platforms. A clear trend is emerging where airports close to pharma clusters are specialising in offering reliable and transparent temperature-controlled handling of pharmaceutical products.

Due to the complex supply chain requirements, active temperature control solutions demand a premium handling. Passive solutions, on the other hand, are less costly to implement and drive the biggest part of the pharma volumes in air freight. The global pharmaceutical industry will spend $8.36 billion on cold chain

Spring 2015 Volume 7 Issue 1


Chapter Title

Complete peace of mind for your pharmaceutical and healthcare shipments

Flying with care It is essential that the quality and integrity of your high value and temperature sensitive pharmaceutical and healthcare products is protected throughout the entire transportation cycle. Backed by our fleet of advanced Boeing 747-8 and 747-400 freighter aircraft and a brand-new purposebuilt 3,000 m2 warehouse facility with temperature- and humidity-controlled environments at our Luxembourg hub, we offer you speedy, reliable and tailored solutions to meet your sophisticated needs. On and off ground, your pharmaceutical products are in the best hands with our dedicated team of highly trained and experienced professionals. And, as you would expect from true pioneers, we are the first GDP certified airline in the world.

+2°C to +8°C

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 59


Logistics audits by various pharmaceutical companies and freight forwarders, with different sets of standards. This is not contributing to a smooth effective change in the cool supply chain, which is required by pharmaceutical shippers. Optimising the Supply Chain Logistical service providers must adopt a more aligned supply chain model. This means working collectively with all business partners and service providers to craft supply chains for optimal end-toend visibility and reliability.

logistics in 2014 and is expected to expand to more than $10 billion by 20181. A recent IATA study has shown that the mode shift from air to ocean has occurred, also applying for pharmaceutical shipments2. However if we take a closer look, differences exist based on the value density of the products. The more valuable the commodity, the more likely it is to fly by air. The air freight transport mode has seen higher growth rates for the segment with high-value density pharma products. A good example of this trend is the biopharmaceutical products, which are often extremely highly valued. Protecting and certifying the integrity of these costly biopharmaceutical shipments requires a significant additional investment in cold chain capabilities. Close and careful temperature and humidity management during transport is essential, but has significant supply chain implications. Effective cold chain management with a risk-based approach has to be introduced by logistics managers, in order to handle these products within very specific parameters. This carries significant specialist storage and transportation capabilities which are not limited to pharmaceuticals; some medical devices and diagnostics products are also condition-sensitive. Work in Progress The pharmaceutical industry relies on air transport for its speed, reliability and efficiency in delivering high-value, timesensitive, temperature-controlled cargo. 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Air carriers, freight forwarders, ground handlers and airports provide quality services, but many challenges remain. Regulations are increasing around the world, processes and specialised equipment are becoming more complex, specific training is required to ensure the staff handling the products have a good pharma awareness, and multiple audits are imposed by pharmaceutical companies and regulators. Historically, there have been an enormous number of different regionally-based regulations for the industry, like airlines, handlers and forwarders, to comply with. More recently, various countries and the European Union (EU) have introduced good distribution practice (GDP) guidelines to ensure the product integrity is maintained throughout the supply chain. However, until this year, there were no global certification standards that could be internationally recognised and implemented. As a result, in many cases a mismatch remains between expectations and service offered. We see a lack of uniform implementation through the entire supply chain at the airports globally. Not all stakeholders in the cool chain at origin or at distination of the route are properly equipped to handle temperaturecontrolled products. There is no common global certification for handling of pharmaceutical cargo in line with existing regulations and standards. And finally a common audit format is lacking, leading to a lower audit effectiveness; ground handlers and airlines are being subjected to multiple

So what exactly constitutes an optimal cool supply chain? Firstly, from an infrastructure perspective, any operator participating in the cool chain – be it a trucker, a forwarder, a handling agent or an airline – must have the right temperature control technology and process in place to keep the pharma products at the correct temperature. This often requires investments in temperature-controlled warehouses with a variety of temperature zones. 15-25°C; 2-8°C; and cold storage at -20°C are the temperature zones that are commonly used as standards in pharma air freight. As an alternative to temperaturecontrolled warehouses, high-level passive solutions or specific active containers can be used to protect the temperaturesensitive cargo during transport on the ground and in the air. Regardless of the type of packaging or cool room, the quality of the handling is primarily impacted by the expertise of staff. Specific and rigorous training has to be put in place in order to make the people handling the shipments understand the specific transport and storage requirements. Staff need to develop a pharma-awareness. Every operator should make a selection of its suppliers based on this pharma awareness, ensuring correct handling in every step of the supply chain. Training of every person involved in the handling, supervision or processing of pharma is key, in order to make them understand the impact on their job of good distribution practice guidelines. Managing the Complexity The biggest challenge, however, lies in the complexity and number of handovers from the moment the goods Spring 2015 Volume 7 Issue 1


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61 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2015 Volume 7 Issue 1


Logistics by IATA, ultimately assuring that coldchain pharmaceutical products can be transported in a standardised, sanitary and secure way throughout the world. IATA is now in the process of rolling out this certification programme for pharmaceutical handling on a global scale. Airlines, handling agents, forwarders and truckers at various airports around the world are joining the programme, in order to align their training, processes and infrastructure to this new air cargo standard. As a result the transport of pharmaceutical shipments via air freight will be managed as a transparent and reliable cold chain, which will improve the risk profile of these certified lanes compared to uncontrolled routes. are transported to the airport, to the point at which they are handed over to the customer at the destination. If not all the different steps in the logistical process are up to standard, the integrity of the product cannot be maintained. Aligning and standardising the pharma handling processes between the supply chain partners, as well as to train all industry stakeholders through the entire supply chain on and around the airport is the only effective way to guarantee the correct handling of pharmaceutical cargo. Instead of local regulations and standards, the focus should be on a global standard. This will lead to an endto-end integrated cool chain. Instead of individual local heroes upgrading their operations to a toplevel performance, the focus should be on a community approach where all the partners in the supply chain apply the same high standards for temperature control. IATA is best placed to take the initiative to develop a global air cargo industry certification standard. Brussels Airport worked collaboratively with IATA, in order to develop and implement such a standard in the framework of the IATA Center of Excellence for Independent Validators in Pharmaceutical Handling programme, or CEIV Pharma. The CEIV Pharma certification programme provides participants in the air cargo value chain with the tools to ensure that they are operating to the highest standards for the transport of what in many cases are life-saving drugs and medicines. And

it will give pharmaceutical companies confidence and assurance that their coldchain logistics requirements are being met through an independent certification process. IATA and Brussels Airport have successfully tested the pilot concept by developing the programme and certifying an entire airport community covering the entire cool chain through the airport. The Belgian regulator (FAGG) and Belgian Customs, as well as the pharma shipper community, are actively involved in the project. This highlights the intention to build a broad consensus on the subject by bringing together all stakeholders. Brussels Airport is working with a group of twenty local stakeholders (ground handlers, freight forwarders, truckers and airlines) to undergo the CEIV Pharma training, bringing the cargo community together for the common goal of becoming certified. This will allow those Brussels-based stakeholders to offer pharmaceutical companies the competitive advantage of assuring coldchain integrity to their clients for all pharmaceutical shipments handled at the airport. We see a positive impact on the risk profile of the cold chain through Brussels Airport, in the sense that all the steps and handover points are now aligned, trained and up to GDP standard. We hope that our leadership in being recognised as a CEIV Pharma-certified community will persuade other airports to do the same. Step-by-step routes will be certified when airport communities at origin and destination are aligning to the clear set of guidelines created

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References 1. Pharmaceutical Commerce, 29 April 2014 2. IATA World Cargo Symposium, 11 March 2014

Nathan De Valck, Cargo Account Manager, Brussels Airport Company has been working in the aviation industry since 2002. His cargo experience ranges from operational management, legal compliance, business development to commercial key account management at several airports in Europe. Nathan has joined Brussels Airport Company on July 1st, 2012 as Cargo Key Account Manager. Nathan’s main responsibilities include business development with the forwarders, shippers and other stakeholders at BRUcargo. In his role of resident pharma and lifescience logistics expert, he is also in charge of the pharma and perishables projects at Brussels Airport. Nathan managed the CEIV pharma certification program at BRUcargo making Brussels Airport the first cargo community in the world to be CEIV pharma certified. Nathan is a member of the Cool Chain Association and the IATA Time and Temperature Taskforce. Email: nathan.de.valck@brusselsairport. be Spring 2015 Volume 7 Issue 1


Manufacturing

When Power Failure is Not an Option Smartphones and portable medical devices are being increasingly used together, raising the eyebrows of many in the industry. Here Neil Oliver, Technical Marketing Manager at Accutronics, explores the safe transition of medical equipment into the rapidly changing mobile space. There was a time when, for common ailments, no matter how big or small, most people would head to their local GP. If a sample of any kind was required, this would be sent away to a lab, often taking weeks to return and enlighten a potentially anxious patient. They say necessity is the mother of invention, and the intervening years have certainly seen rapid development in testing and sample analysis. Further advancements have also been made in medical diagnosis technology. Part of this progress can be attributed to improvements in rechargeable lithiumion batteries, which have allowed medical devices to cross the chasm into the portable and wearable sector. Doctors, emergency services and patients have benefitted, and countless lives have been saved or improved, but a recent consumer trend has raised concerns. Our pocket pal, the mobile phone, has experienced even faster product development lifecycles, with new iterations available every six to ten months. This increased dependency on our smartphones has resulted in a wave of portable medical devices which can connect directly to the phone, with an app relaying an on-the-spot diagnosis. Heart rate and blood pressure monitors are already extensively used in tandem with mobiles and tablets. More complex devices for patients with chronic diseases, such as glucose meters for diabetics, pulse oximetry and kidney infection machines, as well as ultrasound wands and smart fitness monitors, are all flooding the market. Vital Reliability At first glance, this seems like a great innovation. However, on deeper inspection, problems arise. In isolation, the emergence of new technologies empowers consumers with increased transparency in health monitoring. In reality, however, the convergence of 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

professional portable equipment used by doctors, and cheap consumer devices used by hobbyists, poses the possibility of an unregulated self-diagnosis society. We could see potentially unsafe and unreliable devices being used to selfdiagnose and self-treat. Any trend in the consumer market would inevitably have a competitive knock-on effect on professional use and the proliferation of sub-par devices could put lives at risk. At the heart of the issue lies the power supply. On a typical day, a paramedic may report for a 24-hour shift, and ensure the equipment is charged and ready to use before undertaking emergency calls. Throughout the day, a device may be turned on and off multiple times and withstand the bumps and knocks inherent in a pressurised urban environment. The effect is multiplied for medical personnel in emerging and developing countries such as rural Malawi and Sudan. Roaming doctors use an eRanger portable trike to get from one village to the next. The supply of electricity is unreliable, the roads are underdeveloped, and temperatures fluctuate rapidly, all placing extra strain on the battery's ability to power the device. The consequences of a battery failing during medical use could, quite literally, be life-threatening. A failing lithium-ion battery may not be immediately noticeable but may become unreliable over time as overcharging and overheating could lead to a risk of failure or even combustion. This is relatively common in poorly-tested, often consumer-focussed, batteries, but extremely unlikely in professionallydesigned smart batteries. OEM Battery Solution Luckily, some battery manufacturers now offer a range of highly-tested, but off-the-shelf portable smart batteries. This includes a series of slim credit-cardsized smart Li-ion batteries, boasting high gravimetric and volumetric energy density, which means longer run times, supported by intelligent monitoring. In contrast to the short product lifecycles of smartphones, medical devices can be expected to endure periods of up to a decade without redevelopment. The stark reality is that the cell technology used

in such devices will become obsolete long before the product is discontinued. If we are to eliminate the medical risk, it is essential that battery solutions are designed into the product at the conceptual stages, rather than being relegated as an afterthought. Manufacturers can work with battery manufacturers from concept to the design and production stages. Implementing a holistic development philosophy means that OEMs can benefit from application support and design advice to achieve shorter development times and better cost savings. Accutronics' customers can also benefit from unique labelling and firmware support as well as applicationspecific testing and regulatory approval. Manufacturers can rest assured that custom battery designs will not be changed, unlike mass-produced, consumer batteries which quickly become obsolete. The rise of portable medical devices also raises concerns within regulatory circles. There are strict testing requirements for lithium-ion batteries to ensure that they remain safe whilst being transported, stored, charged, discharged and even when electrically or mechanically abused. A good lithium-ion battery should meet or exceed required standards which are set out by the IEC and UN. Smartphone use isn't going to go away, and portable medical use is becoming an increasingly serious proposition, so why inhibit either? Rather, use the benefits of both and minimise the burdens and shortcomings of each. An effective solution in which the two areas can co-exist is using the smartphone to complement the medical technology. This could be to log and share data over our improving cellular networks. Similarly, they could be used as a secondary monitor to give additional information, and utilise their increasingly powerful processors to perform non-vital diagnoses, supporting medical staff. So the next time your doctor starts playing with their mobile phone in an emergency, don't panic! They are probably checking your vitals and not Facebook ... probably.

Spring 2015 Volume 7 Issue 1


Advertorial

A CLOUD SOLUTION INDEPENDENT OF THE LOGGER DEVICE

The data retrieved from data loggers contains vital information for pharmaceutical companies, as they all face rigorous regulations ensuring patient safety. However, recognizing that all loggers, no matter what supplier, more or less record the same set of data implies that the value provided to pharmaceutical companies lies in the information rather than in the logger device. As information is the crucial factor, there is a need for temperature monitoring solutions supporting any logging device, no matter its technical capabilities. Through their cloud information service, TSS moves beyond the traditional approach, announcing that the time has come for a change; focus must be shifted from the device to how data can be captured, analyzed, and presented most efficiently and intuitively. This allows pharmaceutical companies to make more profound decisions for their supply chain operations, for example through a more time and cost effective excursion management process. The idea behind integrating devices from various vendors into one single system is rather simple; As in most industries, different pharmaceutical companies have different needs, stemming from different business requirements and strategies. Providing these companies with a one-stop-shop for temperature monitoring will therefore save them both time and money. In doing this, it is crucial to first identify and comprehend what information is needed for the purpose at hand, i.e. to not merely look at a logger’s technical specifications. To maintain high reliability and compliance with GDP regulations, all loggers are qualified through TSS partner program before they are being integrated.

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A solution independent of the logger device makes you flexible and open for emerging technologies. You do not risk being locked into one specific technology, but you are able to make strategic changes relying on proven know-how and established processes. >>

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What the future holds is uncertain. What we do know is that change is the only constant. Technology will evolve, and new software will be developed. Make sure to choose a solution that allows you to evolve with the flow of the market. At the end of the day, it all comes down to how to handle the information.

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Contact us: Sanna Persson Email: sanna.persson@tss.se Phone: +46 8 630 06 06 or visit: www.tss.se INTERNATIONAL PHARMACEUTICAL INDUSTRY 65


Manufacturing

Can Technology Alone Tackle the Issue of Medicine Adherence? Though therapeutic treatments are generally trialled, approved and introduced based on the assumption of correct usage, actual patient adherence has been shown across a range of situations to be less than 50%, resulting in undertreated conditions, increased emergency admissions, and reduced public health outcomes. The issue applies not just to taking medication but also to correct and timely use of medical devices. Technological developments aimed at addressing aspects of the problem range from standalone smartphone apps to intelligent medical devices and fully integrated telehealth systems. But can this problem be solved by technology? The Scale of the Problem There is no doubt that medicine adherence is a significant problem. Various studies have shown that in developed countries the adherence to long-term therapy for chronic illnesses is less than 50%, and worse in developing countries. It is estimated that the cost of non-adherence in the USA is between $100 and $250 billion1. Non-adherence to prescribed therapy will in most situations result in a worse outcome, and often leads to the need for more expensive interventions. One study2 estimated that non-adherence accounts for 10% to 25% of hospital and nursing home admissions in the USA. Furthermore, the percentage of the burden on healthcare systems represented by chronic diseases is set to rise, making the cost of associated nonadherence more significant. Yet rates of adherence have not changed noticeably in the last three decades, despite World Health Organisation (WHO) and Institute of Medicine (IOM) improvement goals and an increased focus on implementing solutions. Making the Business Case There are clearly benefits to the overall healthcare system to addressing nonadherence. 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

For the vendor of a specific device or therapeutic agent, better patient compliance should lead to better outcomes, which (if demonstrable in a formal trial) should confer a competitive advantage. For technology that purports to work across a number of different therapeutic areas, the savings in reduced interventions and improved outcomes must justify the overall investment, but are hard to prove in the general case by trials. For a successful business case, the savings must accrue to the same budget holders who invest in the technology, not to another part of the organisation (which is not always the case). In some healthcare systems where the financial incentives are skewed towards billable treatment, improved adherence may even run counter to commercial interests. Defining the Problem In the past, adherence has been defined in many ways, such as “the extent to which a patient follows medical instructions”, but that style of wording has been criticised because “instructions” implies a completely passive patient and such an attitude to treatment may form part of the problem. Though the question of nonadherence is generally framed as “Why doesn’t the patient follow prescribed treatment?” it is also more broadly applicable in public health situations, such as, “Why do x% of parents not vaccinate their children against various diseases?” or, “Why do y% of adults fail to take sufficient exercise?” There are multiple causes for non-adherence, and therefore no single solution. As a result, there are a number of technological innovations which have been developed to address the various different aspects of the problem, which are all present to a greater or lesser extent in different patient groups. The Centers for Disease Control and Prevention (CDC) in the USA lists five areas in which contributory factors to non-adherence can be found.

­“Social and Economic” factors including, among others: • Health literacy • Cost or lack of insurance coverage ­“Healthcare System” such as: • Provider / patient relationship • Patient education programmes • Continuity of care ­“Condition-related” such as: • Lack of symptoms • Depression caused by condition ­“Therapy-related” such as: • Complexity of treatment • No immediate benefit of (or immediate deterioration after discontinuing) treatment • Actual or perceived unpleasantness in the treatment or its side-effects ­“Patient-related” including: • Physical factors, such as sensory, motor or cognitive impairments • Motivation No single solution will address all of these in all groups, but there are certainly some obvious areas to target. For example, an estimated 25 to 30% of prescriptions are never dispensed. The leading reason for this is cost, but patients not understanding the rationale behind their treatment is also a significant factor. Though solving the problem of unfilled prescriptions may not be easy, monitoring it should be. A nationwide integrated system could track undispensed prescriptions and enable intervention by Healthcare Providers (HCPs). Though technically feasible, however, this would not be cheap, and the benefits don’t necessarily flow to those who incur the costs. Where the treatment presents patients in the target group with a significant physical or cognitive difficulty, it can be expected to lessen adherence. A 2002 study of 325 older people (average age 78 years) reported that 39% were unable to read the prescription labels. It may be clear what to fix in this case (even if the solution is not necessarily easy).

Spring 2015 Volume 7 Issue 1


www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 67


Manufacturing However, the same study of older patients showed that 67% in all did not fully understand the information given to them, and as a result 45% were nonadherent. There is a bigger problem than just label legibility. Technological developments which make self-administered therapy easier (less complex, less painful, more discreet) show benefits in areas where these are identified as major issues. But often just making the patient’s regimen of treatment less confusing can make a significant difference. According to one study3, 29% of adults aged 57 to 85 were taking five or more prescription drugs. Combining an individual’s medications into daylabelled packs at dispensing time can help. And simply simply changing the appearance of a medication can result in a decrease in compliance4; when a pill looks different, patients often simply stop taking them as prescribed. There have even been proposals from regulators to mandate that generic drugs look like the branded originals to address this issue. Young patients with certain conditions also show low compliance, but for different reasons to seniors. Teenagers are frequently reported by clinicians as “thinking they are immortal” when it comes to compliance with long-term drug regimens, and may require regular testing to confirm "correct drug function" (and hence compliance). Achieving optimal compliance may be the result of many interventions, each addressing different parts of the overall problem. The Role of the Healthcare Provider The extent to which the HCP accurately communicates the particulars of the disease and the therapy has a significant effect on adherence, as evidenced by some of the factors which are shown to be associated with poor adherence (health literacy, quality of provider/ patient relationship). Adherence is lower in diseases where the symptoms respond slowly to the treatment, implying that the patients don’t have faith in the treatment. Anecdotal evidence from doctors indicates that many patients may stop treatment once they are feeling better, regardless of instructions to the contrary. Guidelines have been developed for HCPs for improvement of compliance, which encourage better communication 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

about the therapy, modification of patient beliefs and behaviour, and continual monitoring of adherence. In the absence of automatic measurement systems this monitoring will involve patient reporting. Self-reporting of adherence has been an area of significant study. In 2008 Donald Morisky proposed a simple eightpoint questionnaire which could assess not only the level of non-compliance, but also the causes (such as forgetfulness). The key breakthrough in this work is the realisation of the importance of objective compliance measurement. All patient conversations are not equal. One doctor described the sensitive nature of adherence conversations thus: If the clinician asks a leading question “Did you take all your tablets this month?” a significant proportion of patients will incorrectly answer yes. Then, having lied once, they can never back down and the relationship proceeds that way thereafter. But if the clinician opens the conversation with “How many doses would you estimate you missed this month?”, the conversation can then address the reality openly. This illustrates to some extent the difference between treating the patient as a passive follower of instructions, and allowing them to take more ownership of their treatment. If, for example, dose-counting technology is there to monitor a patient who would otherwise misrepresent their compliance, it needs to be harder to circumvent than a dose-counter that is simply there to help a willing patient who struggles to comply. The relationship with the healthcare provider and the motivation of the patient can have as much impact as a technological solution. The Role of Technology Few doubt that if every patient had their personal physician by their side 24/7, compliance would be near 100%. The same principle applies for a personal dietician or a personal trainer. But for all but the super-rich, this is unaffordable. A technological solution may be imagined as either taking the place of such a personal assistant, to remind, motivate, inform, cajole, assist and record the patient’s daily treatment, or else as empowering the patient to do it for themselves. Different patients will respond to different approaches. In the simplest case, assistive technology uses a reminder system. A

smart pill bottle, a phone app, or an automated SMS or phone call may address the situation where the patient is either unsure or forgetful about the correct time and amount of treatment. Research shows that these interventions are highly effective at first, but the effectiveness declines with time. More sophisticated reminder systems may vary the message, but this approach only addresses a certain cause of non-adherence. If the system includes a feedback mechanism, some degree of near real-time monitoring is possible. There has been much work in telehealth systems, which can remind and report on compliance with treatment but also, via sensors or self-reporting, monitor symptoms of conditions such as chronic obstructive pulmonary disease (COPD). With some medical conditions there are significant cost and health benefits if early warning of exacerbations that would otherwise lead to emergency admissions can be acted upon. A sophisticated telehealth system has the potential to continually remind, motivate and educate the patient about their illness, using messages that are tailored to the particular patient and to their particular reasons for nonadherence. The challenge, as with any medical personalisation, is to create and maintain a patient-specific service while retaining the promised benefits of economy of scale. More sophisticated yet is a device which evaluates the quality of the treatment event. These range from the simple (an inhaler which whistles when the child achieves the correct inspiration flow) to the complex (one which measures, stores and wirelessly transmits the flow profile to the cloud, but also allows a patient to see it for themselves on a smartphone or tablet). The idea here is that your “personal physician” tells you how to use the device - a great improvement on an actual physician who, research shows, is 90% likely to not know themselves6. Linking Motivation and Behaviour There is a large overlap between the relatively new field of “wearable” technology and the use of smart, connected medical devices. Their designers often share a common goal of being able to effect and monitor long-lasting behavioural change. A key application for modern wearable technology, exercise tracking, already Spring 2015 Volume 7 Issue 1


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Manufacturing has a saleable value to both end users and public health bodies and although systems are available for relatively low cost, it remains to be seen as to whether they can sustain the desired behaviour.. If a foolproof system for making any given person exercise regularly could be found, the same principles would surely be at least partly applicable to therapeutic adherence. B J Fogg, at the Persuasive Technology Lab at Stanford University, has proposed a behaviour model7 in which desirable behaviour can occur as the result of suitable external triggers, provided that the products of motivation and ability are above a certain “activity threshold”. So an unmotivated person can be triggered to do something easy (high ability) but only a highly motivated person can be triggered to do something difficult (low ability). Trigger events need to get the user’s attention, be clearly associated with the target behaviour, and also be suitably timed so that they occur when ability and motivation combined put the user above the activity threshold. Applying this model to a smart medical device, the designer would ask “When is the optimum time to trigger this user to use the device to maximise the chance of success?” and also, “If the user is not above the activity threshold, is this because of motivation or ability?” Addressing ability does not just mean making the device physically easy to use for the target group. If it takes too long, costs the user money, can only be done in a particular place, or makes the user feel physically or socially uncomfortable, this contributes to the user having low ability. Even something which requires a bit too much thought may put the user below the activity threshold, depending on their mental state at the time. Just because the patient demonstrated that they could use the device after being instructed in the clinic environment does not guarantee high ability at home at all times of the day. Patients also find things easier if they can make the activity part of a routine - irregular treatment intervals reduce ability. Fogg identifies three fundamental categories of motivation. Pleasure/ pain, hope/fear and social acceptance/ rejection (and asserts that the positive side of each is the more ethical to target). 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Social acceptance has become more relevant with the rise of social media. It’s easier to stick to an exercise programme if there are other people doing it with you, and social apps aim to create that same effect even if the other people are remote (or strangers). Finally, the nature of the trigger itself is important. With systems based on modern smartphones or tablets, the trigger can involve text and other media tailored to the occasion. When a subject has both motivation and ability, the trigger need only be a reminder. If they lack motivation, the trigger should aim to remind them why they should want to take the action. (In November 2014, Medisafe announced that they were adding more informative content to their adherence smartphone app that would aim to further educate the patient about their condition, which they had clearly recognised as a key factor.) But if the patient at the time of the trigger lacks ability, the trigger should offer some assistance with actually taking the action. The wrong kind of trigger will have little or no effect. Habit The aim with long-term conditions is ideally to build habits rather than rely on finding ways to motivate the user forever. There has been much discussion (both academic research and in the popular literature) related to habit formation. Habit formation involves phases. In the first phase the new behaviour is hard and takes commitment to complete. In the second phase it has become relatively effortless but is still not embedded behaviour. If the subject were to not be reminded, they might stop doing the action and maybe not notice. But in the third phase the behaviour becomes normal, and to not perform the action might feel unusual. A daily habit is said to take approximately a month to build. One device company found from user feedback that contrary to expectations some patients preferred a daily selfinjection to a once-weekly injection. One theory was that an unpleasant injection once per week requires repeated application of motivation and willpower, but a daily injection is so regular it becomes a habit and as such is easier to face. (Of course, the daily injection may have been smaller and less painful.)

The upshot of this is that, for longterm treatment of a chronic condition, it makes sense to invest more in supporting compliance in the early stages (focusing on both motivation and ability) and then, once the habit is established, revert to less complex “reminder” systems. This approach is already used with “trainer” inhalers which are used for an initial period to establish behaviour. Technology Implementation There are several current trends which have no doubt accelerated the development of medical adherence devices. The increasing prevalence of smartphones, the internet of things, “wearables” and the ubiquitous internet all offer a landscape that supports more rapid development of working prototypes. Technologies such as Bluetooth Low Energy that make it viable for devices to monitor and report key parameters for months or years on a single battery are now widely supported by off-the-shelf control hardware. Whereas five years ago a developer might need to build an entire system end to end, there are now hardware development kits and reference designs for prototyping devices, and "out of the box" ready-made hubs and cloud systems that can be used to carry the data from the device all the way to the backend system. Furthermore, technology adoption is changing rapidly, with senior patients increasingly likely to be tablet- or smartphone-literate. Of course, while working prototypes can now be created more rapidly, the regulatory requirements for development of actual medical devices remain onerous. Any device or system which transmits identifiable patient data must also comply with various data security requirements (including high-strength encryption). Furthermore, recent FDA guidelines indicate that devices and systems will in future be expected to determine whether their data systems have been compromised. Addressing these requirements can be expensive, hence the attraction of using existing infrastructures where approvals are already in place. So Can Technological Solutions Work? Specific solutions that accurately target a known cause of non-compliance can be expected to provide improvements. Where improved compliance measurably reduces incidence of hospital admissions or irrevocable deteriorations, the Spring 2015 Volume 7 Issue 1


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Manufacturing expensive to meet the requirements for use in the UK. The metrics in other countries (and indeed other payer systems) may vary, and costs may fall in time. Conclusion Innovative technology can be used in many ways to improve adherence, for example: • • commercial case may be straightforward to make. Where compliance improvement results in marginal improvements in longterm therapeutic outcomes justification will depend on the cost model. When it comes to larger integrated telehealth systems, the intent is generally to address more than just adherence. Numerous studies have shown effectiveness for measures such as service utilisation, user experience and social care outcomes. However, the commercial assessments are less equivocal. An effective telehealth system requires significant investment. A March 2013 paper submitted to the British Medical Journal by researchers from the London School of Economics assessed the UK Government’s “Whole System Demonstrator”programme. It determined that the addition of telehealth cost £92,000 per quality adjusted life year (QUALY). The UK’s National Institute for Health and Clinical Excellence (NICE) has a threshold to approve a drug or technology of £30,000 per QUALY. Put another way, even if telehealth is technically effective, it is three times too

72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

• • •

t­o track prescription drug followthrough (i.e. filling of prescriptions) to assist with or simplify complex ­ treatments to make correct use as easy as possible ­to remind users which treatment they should take and when ­to educate and motivate users about their treatment to provide patients and healthcare ­ providers with use feedback and in some cases, early warning of serious events.

However: • ­ it is necessary to ensure the technology addresses the actual causes of non-compliance, which will vary between therapies, between patients and even at different times of day with the same patient • because non-compliance is largely a behavioural rather than a technical issue, care should be taken to objectively report the noncompliance on which technological developments are to be based • ­ because subtle factors can have significant effects on adherence, any evidence-gathering trials must be truly representative and meticulously observed. And finally ­The interaction between HCP and patient

is key, as it establishes understanding of (and belief in) the treatment. It’s unrealistic to expect a technological solution to completely replace a professional interaction, however tempting the financial case. References 1. Levine et al. 2013, Annals of Neurology 2. American Society of Consultant Pharmacists. Adult Meducation. “Improving medication adherence in older adults. http://www. adultmeducation.com/downloads/ Adult_Meducation.pdf.Accessed 1/12/2011. 3. Study published in the Journal of the American Medical Association in 2008 4. A study from the Annals of Internal Medicine regarding drug colour / shape changes 5. http://www.ncbi.nlm.nih.gov/ pubmed/24920889 “The effect of medical device dose-memory functions on patients' adherence to treatment, confidence, and disease self-management”. Hall RL, Willgoss T, Humphrey LJ, Kongsø JH. 6. Thorax 2010; 65:A117-A118 doi:10.1136/thx.2010.150979.45 P94,”Do healthcare professionals have sufficient knowledge of inhaler techniques in order to educate their patients effectively in their use?” 7. “A Behavior Model for Persuasive Design”, BJ Fogg, Persuasive Technology Lab, Stanford University

David Griffin is a Senior Consultant at 42 Technology, a product development consultancy based near Cambridge, UK. 42 Technology helps major healthcare brands to bring new products and therapies to market, as well as assisting earlier-stage companies with commercialisation of novel technologies. The team offer a multidisciplinary service spanning fluidics, electronics and mechanical design, as well as extensive experience in regulatory submissions for medical devices and telehealth systems. Recent work in the field of usability has included a major programme of work to reduce the cost and skills level required for diagnostics in emerging economies, plus multiple projects in consumer electronics and functional packaging. Email: david.griffin@42technology.com

Spring 2015 Volume 7 Issue 1


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Manufacturing

Elastomer Gaskets for Injection and Infusion Systems In medical engineering and in the pharmaceutical industry, elastomer gaskets are often used for injection and infusion systems in order to fulfil the primary requirement, the guarantee of integrity of the medication in the primary packaging. The Three Material Groups: Basically, elastomer gaskets can be divided into three categories: pharmaceutical rubber (the most widespread), silicone and TPE (thermoplastic elastomer). With regard to the extensive and complex requirement profile of an elastomer gasket for injection and infusion systems, all three groups have both their strengths and their weaknesses. Some of the commonly recurring aspects of the customer-specific and product-specific requirement profile will be highlighted in more detail below. Extractables and Leachables: The extractables profile represents an essential issue, since the gasket comes in direct contact with the medication. The profile provides a quantitative and qualitative disclosure of all substances that may potentially migrate from the gasket material used under "strict" conditions, i.e. a more highly soluble extraction medium than the later formulation of the medication in connection with an

increased temperature will be applied. Within the various extraction methods and extraction media, it is the silicone formulations which exhibit the best results in comparison to pharmaceutical rubber and TPE formulations. Small amounts of non-critical substances tend to migrate. Among the various silicone formulations there is a gradient from the potentially harmless platinum-cured material mixtures to the peroxide-cured material mixtures. This is due to the cross-linking reaction that occurs in a controlled manner when the platinum catalyst is added. In contrast, a higher proportion of volatile components are released by the peroxide cross-linking reaction, which occurs in a less controlled manner. The generally good results of silicone in comparison to pharmaceutical rubber and TPE are attributable on the one hand to the relatively low number of components in the formulation, most of which can also be classified as noncritical, and on the other hand to the manufacturing process, which ideally occurs under clean room conditions. Contrary to pharmaceutical rubber produced from natural rubber, silicone has the advantage that any given contamination of the medication will not trigger any latex allergy symptoms in the patient. After all, approximately 2% of the entire population and approximately

10–17% of people who have frequent contact with latex are affected by a latex allergy. The leachables study is performed after the extractables study. It covers the substances released in the extractables study that are classified as critical, and analyses their potential interaction with the subsequent final medication. The pharmacist generally performs and analyses the leachables study on its own. Thanks to the generally good results of silicone in the extractables study, there is a high probability of good results in the leachables study as well. Sterilisation: Since the elastomer gasket of an injection and infusion system comes in direct contact with the medication, the unfilled, pre-assembled system is sterilised. The sterilisation is mostly performed with gamma radiation, since sterilisation with a gas (ethylene oxide) is limited by the enclosed chamber system. Superheated steam sterilisation is often unsuitable, because, at a constant temperature of 121°C, many of the thermoplastic raw materials used in injection and infusion systems tend to shrink, deform or even suffer thermal degradation with a resulting loss of mechanical properties. Silicone is generally compatible with all three of the sterilisation processes mentioned. Neither does irradiation with gamma rays exhibit negative effects, nor do long-term thermal stresses in the range of 120°C represent a challenge. Microbiological Purity: Despite subsequent sterilisation, it is also important for the elastomer gasket and the entire system to be produced under microbiologically "clean" conditions, according to GMP (good manufacturing practice) guidelines. The associated test is the so-called "bioburden test". "Bioburden" means the determination of the population of viable microorganisms on a product and/or in its packaging. The purpose of this test is to find out how many viable microorganisms are found on the product after production and to determine whether subsequent sterilisation is necessary. To keep the

74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2015 Volume 7 Issue 1


Manufacturing

number of microorganisms as small as possible, the production of the individual components, the intermediate transport and storage of the injection and infusion systems and their final assembly ideally occur under controlled clean room conditions as per ISO 14644. The Various Production Processes: Significant differences in cleanliness can be seen, particularly in the production of the elastomer gasket. Pharmaceutical rubber is either obtained from natural rubber or, in many cases, produced from synthetic rubber and provided with fillers, plasticisers and various chemicals, for instance propellants, antioxidants and processing additives in order to adjust its properties. The production process occurs entirely outside the clean room, starting with the harvesting of rubber, preparing it, processing it into semi-finished products, and the shaping process by means of pressing or injection moulding and subsequent stamping and tempering. In particular, the subsequent stamping of the plungers from the injection-moulded semi-finished mat entails a risk of particle abrasion. The necessary clean room quality is only obtained during the following washing process. By contrast, the silicone injection moulding process and the thermoplastic injection moulding process occur under clean room conditions, already starting from the process of shaping the gasket element and its follow-up process steps. This significantly reduces the risk of contaminating the elastomer gaskets. In addition, these processes neither require subsequent stamping nor subsequent 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

washing of the parts, as long as the process is performed in a clean room. Breakaway Sliding Friction Forces: Next to the biochemical and technical manufacturing issues explained above, forces also play a significant role in injection systems. The first is the breakaway force of the gasket on the syringe plunger within the syringe body. A high breakaway force may make precise and fine dosing during injection difficult for doctors. Secondly, it is to the doctors' advantage when the sliding friction of the injection plunger against the siliconised syringe body remains constant throughout the injection and does not show a stick-slip effect. Again, silicone plungers achieve best test results in direct comparison to plungers made of pharmaceutical rubber or TPE. Sealing: The real challenge in sealing an injection system is the guarantee of seal-tightness throughout the entire production life cycle under extremely varied environmental conditions. This begins with the sterilisation of the injection system which has not been filled yet, continues to filling the medication into the injection system, to transportation and the entire storage period of the system until its final use by doctors in their surgeries and clinics. However, seal-tightness is a property that must be tested according to the requirements of the particular application under the given environmental conditions. "Absolute seal-tightness" is practically unobtainable. Therefore seal-tightness is often given in terms of specified leakage rates. For instance, "watertight" is

defined as having a leakage rate of 10-2 mbar/s, and "bacteria-proof" is defined as 10-4 mbar/s. However, in addition to the basic gasket material, its hardness, the particular compression set, the environmental temperature, the ambient media and the design play a decisive role. Conclusion: In summary, there is no generally applicable formula for elastomer gaskets in injection and infusion systems; in each case the sealing system has to be developed, qualified and validated in a product-specific and customer-specific manner, since the requirements are diverse and complex. RAUMEDIC supports their customers from the initial idea, through product and process development up to industrial implementation.

Markus RĂśĂ&#x;ler is Product Manager in the Business Team, Marketing and Sales, within the strategic Moulding / Pharma Solution business unit of RAUMEDIC AG. Within this role, he takes care of RAUMEDIC’s products, such as Silicone Injection Moulded parts that are used in medical as well as pharmaceutical production Email: markus.roessler@raumedic.com Spring 2015 Volume 7 Issue 1


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Packaging Predictive Shelf-life Moisture Control Computer Modelling for Ultra-reliable Pharmaceutical and Medical Device Packaging Solutions The new computer model developed by Baltimore Innovations’ R&D Director, Dr Mark Valentine, is a highly detailed evaluation of humidity and desiccant adsorption behaviour within a product’s protective packaging to avoid decomposition, degradation or other forms of moisture damage. The model uses 3D numerical techniques based on the interaction between fluids and desiccants to accurately understand the role of desiccants within pharmaceutical packaging and their effect on shelf-life. This new model can help companies supplying pharmaceuticals or medical devices to develop optimised, ultra-reliable packaging solutions, whatever the environmental and climatic conditions. Vital Role of Desiccants Scientific modelling of fluid mechanics systems or ‘computational fluid dynamics’ (CFD) is well established in many industries, from streamlining the flow of air over a car bonnet, to investigating the bubble behaviour in a membrane bioreactor. However, the application of these techniques to desiccant systems has been neglected. Desiccants play a vital role in the protection of moisturesensitive drugs and products. By removing water vapour from the air, the desiccant prevents undesirable reactions between the product and the water molecules. These include degradation known as ‘hydrolysis’, the cleavage of chemical bonds by water. The desiccant and product are placed inside a protective barrier which will repel most of the external vapour from the interior. [See Figure (1) - Effervescent tablet degradation at 20oC and 80% RH.]

remains active during the shelf-life. However, this approach does not account for kinetic factors at play within the packaging. For example, as the desiccant reaches saturation, the rate at which it will pick up moisture will decrease. Therefore, even though the desiccant is still ‘active’, the humidity inside the package will increase. This increase in humidity places the product at greater risk of hydrolysis. A more advanced method will account for changes to both the rate of ingress of moisture, which will decrease as the internal humidity increases, and the rate of moisture adsorption of the desiccant. The balance between these factors gives the key picture.

Limitations of Established Methods The established practice in desiccant selection has been to determine the total moisture load for the required shelf-life of the product before being exposed for use by the consumer. This is a combination of the initial water vapour, and the vapour ingress through the boundary of the packaging. This mass of moisture is then fed into the desiccant’s capacity to determine the total mass of desiccant required. This ensures the desiccant

New Predictive Modelling Approach The analysis carried out to develop this new predictive modelling system for desiccants is based on sophisticated mathematical models. “Having previously worked on modelling gas-liquid-solid fluid systems at the University of Oxford Chemical Engineering group, it was clear there was substantial scope to develop new mathematical models specifically for the desiccant industry.” commented Dr Mark Valentine.

78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure (1) - Degradation of an effervescent tablet at 20oC and 80% RH. Failure occurs despite the absence of any liquid water. Extensive research and experimental tests were undertaken to develop a comprehensive understanding of desiccant adsorption behaviour in a variety of storage environments and packaging. The storage environment is defined by the temperature and relative humidity (RH) of the air, which will give the absolute humidity. The packaging includes aluminium foils of different thickness, and vials that might be employed for pharmaceutical applications. The model can be applied to any desiccant-based packaging system used for applications such as the protection of pharmaceuticals, vitamins, diagnostics kits, medical devices and healthcare products, as well as largescale ’work in progress’ containers. Desiccant-CFD Modelling The data sets from experimentation are used to develop a sophisticated desiccant ‘behaviour’ model. This is in the form of a set of differential equations that are flexible to accept all relevant variables, size and type of package, storage conditions, and type of desiccant. These are solved using normal Spring 2015 Volume 7 Issue 1


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Packaging numerical techniques. Once the desiccant behaviour is known, this can be coupled with existing fluid mechanics knowledge, creating a desiccant-CFD model for the water molecules inside the package. The relevant fluid mechanisms to consider are ‘advection’ and ‘diffusion’ of water molecules. Advection refers to motion resulting from a flow of air, as driven by pressure differences. However, for most packaging and storage environments the product is sealed and stationary in a uniform temperature field. As such, convection can typically be ignored. Diffusion is the motion of molecules from high concentration to low concentration. This is an important mechanism when considering the interplay between desiccants and their environments. As the desiccant adsorbs moisture it creates a low water vapour concentration around it. This draws in molecules throughout the package by diffusion. The convection and diffusion of water molecules is well understood; the original work in the model lies in the characterisation of the desiccant adsorption properties. Desiccants have a very large surface area to mass ratio. This surface area possesses many adsorption sites to which water molecules can stick. They adhere to the surface, hence adsorption. Further adsorption also occurs in layers away from the desiccant by H2O – H2O bonding. As the desiccant adsorbs moisture, the number of adsorption sites will decrease, hence the probability of a water molecule being adsorbed at any given time will decrease at a given relative humidity. This is an important consideration as it determines the rate at which the desiccant picks up moisture. As the desiccant approaches saturation the rate of moisture adsorption will become much slower. Eventually a tipping point will be reached where the partially-saturated desiccant will not be able to keep up with the moisture entering the package. At this stage the humidity will start to rise, even though the desiccant is still ‘active’. [See Figure (2) - Average humidity inside a foil pouch for the active lifetime of the desiccant.] Mapping the Humidity The interior of the package in the desiccant-CFD model is represented as a Cartesian or cylindrical grid depending 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure (2) - Modelling of average humidity inside a foil pouch for the active lifetime of the desiccant (logarithmic scales used for better illustration). Design lines of three-year shelf-life and below 20% RH are supplied by the customer. There is a brief initial moisture pick-up region, followed by a long, slow increase in RH as the desiccant adsorption rate falls below the moisture ingress rate. on its geometry. The ingress-diffusionadsorption equations are solved over the grid points, giving a 2D or 3D view of the humidity inside the package. These are progressed over each time step for the required shelf-life of the product. Thus the humidity for any given point inside the package can be determined for any time throughout its shelf-life. This knowledge is especially powerful to minimise the work and costs associated with getting a product to market. [See Figure (3) - Humidity map inside a foil pouch with desiccant.]

Accelerated Stability Trials In order to establish that the desiccant does its job in protecting the product, stability trials are undertaken. To help speed up new product launches, accelerated tests can be carried out. This is where the packaging containing product and desiccant is subject to a very high humidity, using the principle that if the test is done at five times the actual storage humidity then one month under test conditions equates to five months in storage. This is an effective and

Figure (3) - Shows the humidity map inside a foil pouch with desiccant during the initial moisture pickup stage. Cooler colours indicate lower relative humidity, hotter colours show higher humidity. The presence of the desiccant is clearly seen. Spring 2015 Volume 7 Issue 1


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Packaging established test method of more rapidly determining product efficacy. However, it is not without its limitations. The timescales make it important to minimise the number of trials undertaken. Even at an accelerated rate, a two-year shelf-life evaluation can still take six months to complete. Also, there is the risk of over-desiccation, as during an accelerated trial the ingress through the packaging will place a greater burden on the desiccant adsorption rate, resulting in a higher internal humidity than would be present under non-accelerated conditions. Desiccant Selection Quality The quality of the desiccant selection in a packaging specification is vital. An inaccurate initial desiccant quantity can also lead to stability failures and insufficient shelf-life performance, adding months to a product’s development time and delays in getting new products in the market. Additionally, any extra unnecessary desiccant used builds in additional cost for the entire line. Performance in Practice A snapshot of the result of modelling the humidity inside a typical effervescent tablet vial can be obtained. [See Figure (4) - humidity gradient from top to bottom of tablet tube.] Here the desiccant is in the lid at the top of the vial. As such, the desiccant will remove moisture from the top first as illustrated in the graphic. In practice, vials can be repeatedly opened and closed over a significant amount of time as the consumer removes each tablet one at a time. This raises the question: What effect will repeated opening and closing have on the actual product shelf-life? A product may be designed to perform satisfactorily whilst closed in terms of shelf-life, but may fail if repeatedly opened in a humid bathroom; when opened, the desiccant in the lid will be exposed and the vial headspace filled with humid air. The flexibility of the 3D model allows the effects of regular opening and closing of the package to be considered. This will ensure the quality of the product remains until the last tablet is removed. Ultra-reliable Optimised Packaging By including all critical variables, the desiccant-CFD model can help companies supplying pharmaceuticals and medical devices to optimise existing desiccant 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure (4) - Graphic showing a snapshot of the humidity inside a desiccated effervescent tablet tube. The desiccant is in the lid at the top as shown by the humidity gradient from top to bottom. packaging specifications, or to develop ultra-reliable packaging solutions with predicable humidity ranges; the mathematical model significantly improves accuracy in desiccant specification, to a high confidence level in the shelf-life and storage performance of a packaging system, whatever the environment and climatic conditions. By obtaining a full understanding of a product’s thermo-fluidic environment, companies can achieve both the optimal quantity and ideal placement of desiccant within packaging. This helps to maintain the ideal humidity, and ensures stated shelf-life and storage requirements. Dr Valentine explains: “The major advantage of the 3D modelling system is that one is able to get an in-depth mathematical analysis of moisture loading and desiccant requirements, tailored for specific atmospheric conditions from tropical to temperate. This ensures that the correct packaging and amount of desiccant materials are used to safeguard product stability.” Additional Cost Benefits Using the 3D modelling techniques developed by Baltimore Innovations offers significant benefits to companies, especially smaller companies (SMEs) who often don’t have in-house packaging expertise. These benefits include: lowering desiccant costs by eliminating excess usage; improving shelf-life and

performance by better desiccant selection and placement; and reducing packaging bulk volume and weight for lower packing and transport costs.

Dr Mark Valentine joined Baltimore Innovations Ltd. after completing his PhD at Oxford University, where he worked in the Chemical Engineering Group in the field of ‘Fluid Mechanics and Multiphase Flow’. In his current role as R&D Director, he works closely with the in-house business development team, strategic manufacturers and key supply partners to develop new moisture control related packaging products, as well as providing desiccant consultancy advice and technical support to customers within the pharmaceutical, medical device and food packaging industries. Email:mark.valentine@ baltimoreinnovations.co.uk

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Packaging Passive Temperature-controlled Packaging Reuse: Overcoming the Challenges of Quality and Asset Management Temperature-controlled distribution is an expanding market, with an average growth rate of approximately six per cent per year. But as the importance and value of temperature-sensitive pharmaceutical products increases, so does the legislation around how to safely store and distribute them. Therefore, the requirement for a compliant temperaturecontrolled distribution supply chain is on the increase, suggesting that the current status quo is perhaps no longer fit for purpose and needs to change to meet future demands. As a result, reuse of high-performance temperaturecontrolled packaging is becoming more widely accepted: however, there is still some resistance to multi-use based on issues of returnability and refurbishment. In recent years, the pharmaceutical industry has undergone significant changes, including stricter regulations controlling the conditions in which pharmaceutical products are distributed. Presently, seven of the top 10 largestselling pharmaceutical products require storage and distribution at 2-8°C, and by 2018 it will be 24 of the top 50. As products become more complex and costly, the need for stronger controls within the distribution network has grown to ensure patient safety is maintained. Subsequently, more and more biopharma companies are looking to multi-use temperature-controlled packaging solutions, as these often provide a higher performance, but come at a higher price point. To date, the main preventatives that stop companies from reusing multiuse temperature-controlled packaging are asset management – “it’s too hard and too costly to get back” – and quality – “how do we know the system is safe to reuse?” So how do we overcome these challenges?

The cGDP guidelines, while they don’t specifically focus on reusability, do introduce new requirements for the distribution of temperature-sensitive products in an attempt to improve the supply chain. Although these guidelines are created in Europe, this, in turn, has resulted in more emphasis on reusable temperature-controlled packaging solutions globally. This is largely because the guidelines have been adopted by many countries outside of the EU due to their respectability – such as Canada and South Africa – or they need to be adhered to if products are being shipped into the EU. Reviewing the Need for Change After North America and Europe, East Asia and Canada are the most active areas for clinical trials. However the emerging markets are the growth drivers of the future. Emerging markets such as Latin America, South East Asia, the Commonwealth of Independent States and Russia provide access to new patient subjects, but also provide additional logistical challenges. Indeed, the emerging markets can present significant challenges for clinical logistics: weather, customs delays, lack of flight availability and mechanical failures can all have an impact. Inexperience in handling highvalue temperature-sensitive materials, as well as challenging infrastructure within the destination country can also provide further problems.

In fact, a recent study conducted by the UK-based Medicines and Healthcare Products Regulatory Agency (MHRA) revealed that 43 per cent of critical and major product deficiencies are related to ineffective temperature control and monitoring during storage and transportation. Similarly, the World Health Organization (WHO) stated that 25% of all vaccine products arrive at their final destination in a degraded state. In response to the expanding demands of the healthcare industry, temperaturecontrolled packaging has evolved to reflect its needs. Solutions can now deliver high performance, while reducing size and weight, over longer periods of time. Furthermore, rather than being a singleuse consumable product, some highperformance temperature-controlled packaging solutions are developed for multi-use, to become an ‘asset’. However, the reality is that they are not always used to their full potential and are sometimes only used once, therefore not achieving their maximum proficiency in terms of cost saving and sustainability. Single-use Versus Multi-use Passive t e m p e r a t u r e - c o n t r o l l e d packaging that is single-use is probably the most commonly-used solution provided in the maintenance of refrigerated products between +2°C and +8°C. These systems can travel to destinations with little or no specialised infrastructure where there is no obligation

The Bigger Picture Given the high cost of conducting global clinical trials in particular and the even higher cost of failure, regulatory agencies and pharmaceutical companies alike now demand that every party involved in the clinical supply chain – transportation and logistics providers included − conform to the relevant guidelines, such as good distribution practice (GDP) and good clinical practice (GCP). 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Chapter Title

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Packaging affordable, the challenge of managing increased costs associated with economic growth and technological advancements, as well as regulatory compliance, is a constant battle to ensure the product’s integrity is not compromised. Realistically, it stands to reason that if the value of the payload goes up and becomes more unstable, it would be understandable that the packaging used to protect it would also increase. But obviously there are also the constant pressures of the costs associated with research and development (R&D), as well as logistics, including packaging, storage and transportation of investigative products, which alone can account for 30 per cent or more of a clinical study budget. The logistical needs of companies conducting clinical trials provide some of the most demanding parameters in terms of compliance, product integrity and cost pressures; however, patient safety is always the first priority. Those involved are thus considering alternative ways of meeting the needs of companies, whilst also balancing the requirements of their own business and shareholders.

to return either the cooling elements or the insulation materials. Historically, these would include water-based refrigerants, which, whilst they work, also have their limitations. This solution is qualified to a set of defined parameters, which means that if the package deviates from its specific course, such as being held up in customs too long, or left outside on the tarmac in a high ambient temperature, it could potentially struggle by not working for as long, or not working to its full potential. The implementation of newer technologies has led the industry to provide more durable systems: for example, the use of vacuum insulation panels (VIPs), which provide a much higher rate of insulation than traditional materials (producing R-values between five and seven times that of EPS) and create more robust thermal protection. Furthermore, the introduction of advanced phase change materials 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

(PCMs) introduces efficiency by only absorbing and releasing energy as required and at the temperatures needed. This capability enables higher precision and temperature control when maintaining product stability over long distances (often in excess of 96 or 120 hours), multiple time zones and through extreme climates. Because of the added cost of these technologies, high-performance temperature-controlled packaging solutions generally have a higher cost per unit than traditional packaging, initially. So if there is no way of getting the reusable components back, the investment ends there and the system becomes a consumable product rather than an asset. However, with the right recovery logistics in place, the return on that investment can be regained quickly. Achieving the Balance In order to make the clinical supply chain

This balance is achievable through using high-performance, reusable temperature-controlled packaging, which can actually reduce the risks of product excursions and improve the likelihood that the product will arrive in specification, integrity intact. As a result, reuse of robust high-performance temperature-controlled packaging is becoming more widely accepted. So improved quality, and reduction in risk and distribution costs, are achievable to organisations that are prepared to look at different ways of working. Embracing the Change In essence, by reusing a passive highperformance temperature-controlled packaging solution, it becomes a sustainable logistics asset rather than a consumable item and ultimately, to ensure the success of its reusability, the returned packaging has to be of an acceptable quality standard and be able to perform to its original qualified specification every time it is used. So there are essentially two ways to approach this. Firstly, a pharmaceutical company can manage the reusable packaging (or asset) themselves by factoring in the return logistics costs, as well as the frequency of use. Or, if they are shipping frequently to multiple Spring 2015 Volume 7 Issue 1


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Packaging Conclusion Whether a temperature-controlled packaging solution is single or multi-use, it is the thermal performance to recognised industry standards that is essential, as well as implementing a system that will complement the operation to a level that will meet quality standards. This has, in some cases, proved to be a barrier to effective operationalisation or rollout, which provides confidence that levels of compliance are actually being enhanced.

destinations, the reverse logistics are too complex to be managed internally, or it’s something that they ideally don’t want to have control of, they can work closely with a transportation provider that is willing to own and operate that asset on their behalf. By managing the process themselves, the pharmaceutical company is in complete control of the quality. It can set its own reuse standards and manage them accordingly within their overall quality management system, seeking the input of various functions such as quality assurance (QA), logistics, operations etc. Alternatively, transportation providers can also manage the asset themselves by working to an agreed standard for cleaning and refurbishment that the pharmaceutical companies accept. However, destination plays a vital role in a system’s returnability. For example, if a reusable solution is used to ship products to remote global regions, due to the country’s poor infrastructure a company may not be able get the packaging’s materials back and therefore, by default, a multi-use system would become singleuse. But during a time when everyone is being pressured to manage costs as well as maintain quality, if you can get it back, why wouldn’t you? Breaking the Taboo Whilst some companies may have apprehensions against reusing a passive temperature-controlled packaging solution that has been used to transport a different payload, in reality this is not a new concept and multi-use programmes have been commonplace 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

in the pharmaceutical supply chain for many years by using or renting active containers, which are sometimes deployed where bulk supply is required. Active containers offer a high level of protection and reduction in risk when shipping large quantities of investigational material within the clinical supply chain. Where active containers are utilised for temperature-sensitive distribution, they are based on rental or leasing methods. This approach means that the company is utilising an asset, which is not within its own quality management system. Using this approach means that potentially a different consigner is using the asset each and every time it is used. The cargo contained previously may or may not have been a healthcare-related product and the consignor would have limited or no ability to select an active container that had moved certain types of products. It is also pertinent to remember that temperature-controlled packaging is often tertiary or quaternary packaging. When clinical trial material is shipped, this will consist of the primary packaging, secondary packaging and then very likely a carton or kit. It is extremely unlikely that the pharmaceutical company’s product would come into direct contact with the temperature-controlled payload area at any point unless there has been a catastrophic failure during the shipment, which in many cases would render both the investigational product and the temperature-controlled packaging asset as useless.

Ultimately, with the increased pressures to manage costs, something has to give and it would be naive to believe that the current single-use practice can be a longterm solution in all cases to meet all needs. In an economy where patient safety, increased legislation and the pressure to use reusable and recyclable materials are rising, turning a consumable ‘singleuse’ item into a ‘multi-use’ logistics asset would reduce spend, as well as creating a more sustainable solution. And, if the current economy continues its growth rate, it is conceivable that in the future, reusable packaging will become the norm rather than the exception. It will be the forward-thinking biopharma companies who adopt the change now that get ahead of the game.

Stephen Healy joined Intelsius as Global Director of Sales in May 2013. Steve is focused on all customer and salesrelated activities to drive the company’s expansion within the pharmaceutical clinical trials and drug distribution arenas. Steve has over 10 years extensive experience in the pharmaceutical sector and is considered an industry speaker and thought leader in temperaturecontrolled, regulatory compliant packaging industry and the pharmaceutical supply chain. Prior to joining Intelsius, he held high-level sales and marketing management positions within the temperature controlled packaging industry. http://www.intelsius.com Spring 2015 Volume 7 Issue 1


Manufacturing


Packaging

Improving Adherence: Packaging’s Synergistic Role in Delivery, Communication and Education Across the pharmaceutical and healthcare spectrum, industry professionals are working diligently to solve the enduring challenge of patient compliance and adherence. Staggering statistics are often quoted with regard to patient compliance to medication regiments, as low as 30% for some grave disease states, and societal costs in excess of $290billion dollars in the US alone. With recent governmental reforms in healthcare across the US, Europe, and extending into other developed countries, there is more accountability for stakeholders to demonstrate the effectiveness of treatments in driving improved health outcomes. This is driving reimbursement within the healthcare provider community as well as a key determination for pharmaceutical and biotech manufacturers in market positioning of their therapies, namely being included on insurance formulary. At all points along the continuum, parties are investing significant resources to positively affect patient behaviours and attempt to drive better health outcomes. In the various clinical trial phases, patient compliance and adherence has significant impact on the results and conclusions of even the most carefully

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designed study. Study techniques to monitor patient adherence can provide widely differing results in patient behaviours and even more differences in realised patient health outcomes for the study medication. One example of a traditional and very basic method of analysing adherence is pill counts for packaging of returned study medications. Many published studies have demonstrated that patients will “pill dump” prior to returning packaging, rather than face the embarrassment of reporting their inconsistencies in dosing. This ultimately creates very unreliable data generation for monitoring true compliance and adherence. These behaviours may be represented over the course of several days, or in other instances masking much more lengthy drug holidays where the patient is off therapy. For many medications, this on-again / off-again cycle significantly hampers the medication’s therapeutic effect for the patient and ultimately hampers the sponsor’s expected outcomes for their study. Electronic compliance monitoring technologies are rapidly evolving to provide a more accurate view of patient behaviours. These innovations allow study administrators to delineate adherent versus non-adherent

study subjects, thereby focusing their analysis on the true health impact of their medication on patient health. Adherence is drawing significant attention in the clinical healthcare community because of its impact on the ultimate success of demonstrating investigational drug effectiveness in clinical studies. Sponsors simply cannot afford to waste the time, cost and associated resources when studies are undermined by nonadherence. Of course, clinical studies provide a closed environment relative to monitoring patient behaviours in the more general population. Clinical programmes utilise patients who have opted into study participation and are typically receiving therapy free of cost. For many studies this patient population is very motivated to try a new therapy that may provide hope in addressing their disease state. By contrast, analysing patient behaviour for commercially available medications ushers in many other considerations and environmental influences, most notably cost. What is recognised is that patient noncompliance in the general population is a multifaceted issue and rarely does a

Spring 2015 Volume 7 Issue 1


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Packaging for medication reimbursement, education tools about the drug or disease state, enrolment tools for integrated health programmes, lifestyle tips and guides, specific dosing guides for complicated drug regimens, patient diaries and goalsetting tools, and many others. These tools integrated directly in the packaging can yield tremendous results as a supplement to the activities of pharmacists, doctors, and other healthcare providers.

single remedy fully address the root cause or significantly affect the ultimate health outcome. Non-compliance is driven by both conscious and unconscious behaviours, and those conscious and unconscious behaviours and factors may vary significantly from one disease state to the next. Some behavioural factors for consideration would be reflected in the Chart below. Stakeholders within the broader healthcare community look to address patient behaviours and their causes at various patient touch-points. This may include doctor or nurse interventions, pharmacist counselling, external nursing or third-party clinical counseling and interventions, as well as gadgets such as electronic reminders, text messaging, phone or email prompts, and many others. Cost considerations can be addressed through discounting or co-pay mitigation strategies. Other innovative adherence strategies include predictive modelling to identify at-risk patients or goal-setting programmes and incentivising patients for positive health behaviours. Experts agree that the most effective strategies find synergies and address the root causes for the specific patient population and disease state. Published studies have demonstrated that one of the most effective singular strategies is providing medication in unit dose calendarised formats. This has proven to be effective both in increasing patient compliance and adherence, i.e. taking product as prescribed, as well as medication persistence, i.e. continuing to take medication and ensuring timely refill to avoid “drug holidays” or resulting in 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

conscious discontinuation or the regimen. A 2011 study of 3 million users of generic medicines, published in the journal Clinical Therapeutics, highlighted use of calendarised packaging demonstrating a 17-day increase in persistence as compared to patients using traditional pharmacy vials. With regard to patient adherence, patients receiving a calendarised blister design also realized up to a 37% increase in proportion of days covered (PDC). Released in 2011, a second study in the journal Dove Press analysed the effect of calendarised packaging’s impact for the drug Diovan HCT. This study affirmed the findings in the generic study, demonstrating up to a 44-day increase in length of therapy for users of calendarised unit dose formats. Other compliance and adherence studies measuring the effect of specialised packaging are outlined in a recent whitepaper published by the Healthcare Compliance Packaging Council (HCPC), available at the group’s website, http:// www.HCPConline.org/reportdownload. php It is then recognised that simple packaging interventions can realise modest gains in addressing patient health outcomes. What is more encouraging is the use of complianceprompting packaging in conjunction with other adherence interventions. Increasingly, physician samples as well as saleable trade packaging are utilising calendarised formats in concert with other adherence tools to address conscious and unconscious patient behaviours at the point of administration. These tools may include co-pay cards or instructions

Utilising packaging as part of a broader adherence strategy is best achieved with collaborative goal-setting and specific measures for return on investment. Effective package design is proven to deliver tangible results and adherence gains, translating into improved health outcomes for patients. The rise in prominence of complianceprompting packaging in the competitive landscape underscores its role in the new healthcare paradigm – proven effectiveness in better patient health as a competitive necessity.

Justin Schroeder is the Executive Director, Marketing, Business Development & Design at Packaging Coordinators Inc. (PCI). Mr Schroeder is responsible for new account development, global marketing, and creative package design with a focus on the development and commercialisation of unitdose and compliance-prompting packaging. He holds a Bachelor of Science from the School of Packaging at Michigan State University, and a Master of Business Administration in Marketing from Northern Illinois University. Mr Schroeder has been at PCI/Anderson since 2000, holding positions including Process Development / Packaging Engineer, Customer Project Manager, Director of Project Management and Planning, and most recently Senior Director, Marketing & Development Services. Previously, Mr Schroeder held package engineering positions with Hershey Foods Corp and at the J.M. Smucker Co. (Smucker’s). Mr Schroeder is a Certified Packaging Professional from the Institute of Packaging Professionals (IoPP) and is the Vice Chairman of the US Healthcare Compliance Packaging Council (HCPC). Email: info@pciservices.com Spring 2015 Volume 7 Issue 1


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Special Feature

Is There a Need for Virtual Pre-clinical CROs (vCRO) to Support the Life Science Industry? Pharma companies need in-vivo pharmacology and toxicology supplied by professionals. Virtual contract research organisations might be the future of drug development partnerships. But what does a vCRO CEO think about this? Is there a need for virtual pre-clinical CROs to support the life science industry? In the following interview, Urban Hoglund shares his views. Large pharma companies have been reorganised. What kind of changes have been made, and how did they manage to solve their funding? During the past decade large pharma companies have been struggling with discoveries of new drug entities. This has resulted in downsizing of discovery projects, and as a result of this a number of competent professionals have become unemployed. The reorganisation of large pharma companies has thus provided energy to

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individuals who have an urge to continue within their fields of expertise to establish new drug development companies. Fortunately, there are many national and international funds in addition to private investors, which provide support for interesting projects. The start-up companies soon realise that there is a huge difference between the work at big pharma, at which there was a large supply of drug candidates to evaluate and continuous financial support, and work in a small company where only a few possible candidates may be available to select among, with limited financial support. Many times small companies need to provide interesting results to keep investors happy, and it is not uncommon that projects are actually driven by this need rather than on scientific grounds. Another difference one may see between large and small pharma companies is that most studies need

to be outsourced. Often chemistry and in-vitro work is kept in-house, but pre-clinical in-vivo studies need to be performed by CROs. Large preclinical CROs traditionally have focused on GLP regulatory toxicological studies, but they have less ability to support the small pharma company with cost-effective ADME, explorative tox studies, and disease models. The virtuality means that organisations are project-driven. PK studies need only a few persons to perform but when it comes to cancer models to determine drug effectiveness or regulatory tox studies, the organisation needs to be larger. This flexibility makes possible high-quality production of data at a reasonable cost, which would mean that there is a need for small vCROs. However, when the virtual company is trying to market themselves it is hard to convince CEOs and CFOs of small pharma companies, who often have a background

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Special Feature from a large pharma company at which they were used to outsourcing to large CROs, that even a small company has capacity, competence and experience enough to also perform large studies. On the question “how many are you” the small company answers “it depends on the project” but the large company can provide explicit numbers of employees. What does virtual mean in the pharmaceutical industry, and being a CEO, what was your experience? From being CEO of small vCROs now for about eight years, my experience is that the vCRO is a sound idea which complements large CROs, but the vCRO is also dependent sometimes on the capacity large CROs have, especially when it comes to histopathological analyses of thousands of organs extracted at the end of a repeat-dose tox study. Thus, to provide the modern life science industry with the services needed for development of new effective drug entities to treat diseases more effectively, there is a need for a change in attitude among decision-makers in the small life science companies and large CROs. Actually, both parties would nurture vCROs since they will both benefit from the services these can provide in the long run. Although this is evident from my perspective, it is not likely to happen in the near future. One reason, as mentioned above, is that decision-makers believe that proper in-vivo drug development can only be performed by long-established large CROs. Another is that there are too many large CROs, with struggling economies, to take care of the all too few promising lead drug candidates. Thirdly, as a result of downsizing of large pharma companies, personnel that used to work with regulatory issues in an environment where the goal was to obtain sufficient pre-clinical data for all possible questions regulatory agencies may have, have established themselves in regulatory consultancy companies. Small pharma companies often approach these consultants, since they do not have internal knowledge about regulatory guidelines. Unfortunately, it is not uncommon that these regulatory consultants have kick-back agreements with large CROs. Together, this leads to a situation where small pharma companies often are guided towards too elaborate and costly pre-clinical studies, and that vCROs are not approached to provide 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

IPI_March2015_embedded.indd 96

services. Together, these circumstances lead to a counter-productive situation, which in the long run diminish the possibility for patients to get improved treatment. How can small pharma companies save time and money? The approach we have used successfully many times, and especially since we have often been involved in development processes for new therapies for which there are no standard guidelines to follow, is to propose a minimalistic set of studies to the Medical Products Agency (MPA) to be discussed at scientific advice meetings. This strategy is based on the knowledge that the MPA will not miss the opportunity to learn as much as possible about the effects of a new drug entity, but will definitely demand further studies to be performed should there be a need for more information. This approach has been extremely fruitful to evaluate new cancer therapies, where the approach has been to perform the first human study in drug-resistant cancer patients. Information about toxicity in rodents after repeat-dose administration mimicking the clinical dose strategy has been enough to approve applications for clinical trials of both protein and small organic molecules. The MPA seem to agree that the regulatory guidelines are posted to actually guide both pharma companies and regulatory agencies in the drug development process, and that each new drug entity should be evaluated case-bycase. An important issue we need to face is the ethical aspect of the use of animals in drug development. It is undoubtedly the case that we need to provide preclinical data obtained from animals since, until now, there are no other means to gather information about the possible toxicological effects a new drug entity may have in humans, which the MPA accepts, despite alternative methods having been under development for decades. The European legislation about the use of animals for scientific purposes defines the ethics procedure, which needs to be followed by the member states, with much emphasis on the three Rs (reduce, refine, and replace). It is possible that this legislation is among the most elaborate worldwide and thus provides the highest protection of animals used in drug studies. Now, in Sweden the regional animal ethics boards are

placed in cities where universities, which teach life science, are located. Thus, the board members are academics and lay people with little, or no, experience of the regulatory requirements regarding (GLP) documentation about toxicological effects of new drugs. Therefore, it is sometimes hard to convince members of the animal ethics board that it is necessary to dose animals to an extent that actually leads to toxic reactions to provide meaningful information in the guidance for doses and possible toxic reactions in humans. This situation, although necessary to a point to minimise animal suffering, is costly, both economically and in time, hampers the drug development process in Europe, and leads to a flux of pre-clinical studies being performed outside Europe, where costs for animals, housing, and staff are less expensive. In my view, European vCROs have few possibilities to have an influence on the legislative process regarding the use of animals for scientific research, and thus they need to take on a relatively larger burden than the large CROs to have animal ethics applications granted. The answer to the title question of this editorial is definitely yes, but! To increase the possibilities of having new drugs on the market for the benefit of diseased animals and humans, there is a need for changes in attitudes from decisionmakers within large CRO companies and small drug developing companies regarding the benefit of using vCROs. vCROs have the possibility to personalise the drug development process and may find more cost-effective ways to get lead candidates into clinical practice.

Urban Höglund has a PhD in Pharmacology and is Assistant Professor in Laboratory Animal Medicine. He has been working as CEO in virtual CROs since 2006 and currently in Adlego Biomedical AB. The company is GLP compliant and under inspection of the Swedish Medical Products Agency. Email:urban.hoglund@adlego.se Spring 2015 Volume 7 Issue 1

10/04/2015 13:50:03


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News or rake leaves, because this stirs up pollens and molds. Wash your hair after you've been outdoors, and don't hang sheets or clothes outside to dry. "There's no reason for people with allergies to suffer. As long as you take the proper precautions, you should be able to enjoy the outdoors and make the most of the warm weather," Rosenstreich said. Fecal Transplant Treats Serious, Recurrent Intestinal Infection MONDAY March 30, 2015, 2015 -- Fecal transplants, using stool from a donor, have been successful at treating a serious gut infection, researchers report. The infection is called Clostridium difficile. It causes diarrhea and severe abdominal pain and kills thousands of people worldwide each year, the authors of the small study explained. It's believed that the infection overwhelms the good bacteria required to maintain a healthy intestine. The fecal transplant method was developed to treat people with C. difficile infections, particularly those who have repeat infections. Fecal matter is collected from a donor, purified, mixed with a saline solution and transferred to the patient, usually by colonoscopy.

Spring Allergies Have Arrived SUNDAY March 29, 2015, 2015 -- It may not feel like it in some parts of the United States, but spring has arrived and that means it's allergy season. About 50 million Americans have seasonal allergies -- also called hay fever -- and suffer symptoms such as sneezing, stuffy or runny noses, and itchy eyes, nose and throat, according to the American College of Allergy, Asthma and Immunology. "Even with snow still on the ground, trees have started budding and are the first to produce pollen, creating major problems for people with allergies," Dr. David Rosenstreich, chief of the division of allergy and immunology at Montefiore Medical Center in New York City, said in a hospital news release. "The symptoms people experience often resemble a common cold, but, if it happens every year at this time, it's most likely to be allergies," he explained. Over-the-counter and prescription medications can help reduce allergy symptoms. "By taking medicine early, you can prevent the symptoms before they begin," Rosenstreich said. "If you start after the symptoms are in full swing, it's much harder to stop the allergic reaction than to prevent it from the beginning." There are a number of other things you can do to control allergy symptoms, such as limiting your time outdoors on days with high pollen counts, and keeping your house and car windows closed to keep pollen out. It's also a good idea to use an air conditioner, which filters the outside air before it enters your home. Don't mow your lawn 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

However, not much is known about the long-term stability of fecal transplants, the University of Minnesota researchers pointed out. The study, published in the current issue of the journal Microbiome, included 14 people who had recurring C. difficile infections. Four received fecal transplants. The healthy changes in the patients intestinal bacterial populations ("microbiome") were sustained for up to 21 weeks after transplant, according to the report. "Our study shows that there are both short- and long-term changes in the fecal microbiome following transplantation," study author Michael Sadowsky, director of the university's BioTechnology Institute, said in the news release. "The diversity and types of microbes present fall into a cloud of possibilities represented by those of 'normal fecal microbiota.' While we have many similarities in fecal microbiota amongst humans in general, there are individual differences that make us all unique, but do not affect apparent gut functioning," he explained. The study could have implications for the regulation of fecal transplants in the United States, the authors suggested. The U.S. Food and Drug Administration considers fecal transplants to be a drug and has said standardization will be important. However, the diversity of normal fecal bacteria in both donors and recipients suggests that this approach to regulation will not work for fecal transplants, the investigators said in the news release. Five new drugs put forward for approval in Europe Five new medicines have been recommended for approval in Europe by the Committee for Medicinal Products for Human Use, including an Orphan drug for thyroid cancer.

Spring 2015 Volume 7 Issue 1


News Eisai’s tyrosine kinase inhibitor Lenvima (lenvatinib) was backed for the treatment of adults with progressive, locally advanced or metastatic differentiated thyroid carcinoma, whose disease has progressed despite receiving radioactive iodine.

Meningitis Now also points out that the announcement “fails to provide parents with the essential information as to when the immunisation programme will begin,” and that, “until this is announced, babies will remain at risk”.

The drug was reviewed under Europe’s accelerated assessment program, and also picked up Orphan designation in 2013. Clinical data show patients treated with Lenvima lived on average 14.7 months longer without their disease progressing than those given a placebo.

SMARTTECH: Drones in healthcare The possibilities for drones are endless. From aerial surveillance in warzones, to the delivery of pizzas, emergency medical supplies for car accidents, or medicines and aid to disaster areas where roads are blocked, these miniature, unmanned helicopters have the potential to supply high-speed delivery anywhere in the world. Amazon is already looking at the possibility of using drones to deliver packages, while Google is currently testing its drones in the Australian outback. Perhaps not surprisingly, the industry is forecast to be worth $5.4 billion within the next decade.

While the CHMP concluded that the drug has a safety profile consistent with other similar therapies with “predictable and manageable” side effects, it has requested a further study to investigate the most appropriate starting dose to optimise the benefits and reduce risks. The Committee also put forward Sanofi Pasteur MSD’s human papillomavirus vaccine Gardasil 9, for the prevention of certain diseases caused by nine types of HPV (6, 11, 16, 18, 31, 33, 45, 52, 58), covering five more strains than its predecessor Gardasil. Positive options were also handed down for: Helsinn’s Akynzeo (netupitant/palonosetron) for the prevention of chemotherapyinduced nausea and vomiting; Boehringer Ingelheim’s Synjardy (empagliflozin/metformin) for the treatment of type II diabetes; and Hospira’s generic Voriconazole Hospira(voriconazole) for the treatment of fungal infections. The Committee also recommended extending the use of Roche’s Tamiflu (oseltamivir) to include the treatment of influenza in infants below one year of age. UK gov't reaches deal with GSK for MenB jab UK babies will be the first worldwide to be routinely vaccinated against Meningitis B, after the UK government finally reached a deal with drug giant GlaxoSmithkline over the jab’s price. As a result Bexsero, the only licensed MenB vaccine, will now be added to the national childhood immunisation programme, with children to receive their first shot at two months of age, followed by two further doses. The Joint Vaccine Committee on Vaccine and Immunisation (JCVI) recommended Bexsero for the national immunisation programme more than a year ago, but negotiations on price only started in August. Campaigners have long slammed this lengthy process which, they claim, has cost lives and also put children at risk from suffering other devastating consequences of the disease, such as limb loss. Professor Andrew Pollard, Chair of the JCVI, said the Committee anticipates that introduction of the new meningitis B vaccine for babies “will reduce the number of cases in early childhood, ease the burden of the disease for the NHS and defend the health of the nation’s children.” GSK said it is delighted to have reached an agreement with the government that it believes “offers fair value for the NHS and allows a reasonable return for [the company]". But while applauding the “historic” move, UK charity www.ipimedia.com

Healthcare test pilots are already underway. In 2014, the World Health Organization and the Bhutan Government collaborated with drone developer Matternet to test how successful drones were in connecting the country’s main hospitals with rural communities. There is now a roll-out planned for 2015. DHL has also been involved with testing the use of drones in delivering drugs to the Island of Juist in the North Sea. Meanwhile, in Papua New Guinea, Médecins Sans Frontières and Matternet have joined forces to deliver saliva samples to laboratories for tuberculosis testing and diagnosis, overcoming the issue of patient access to labs in the country. And in the Netherlands, a prototype ambulance drone equipped with a defibrillator for heart attack incidents suggests this could dramatically increase survival rates. The advantages are clear. Drones are potentially cheaper than traditional forms of transport, can offer faster delivery, and would require less support, particularly if delivery points and schedules could be pre-programmed, and if the drone was connected to a smartphone app. Besides saving lives by supplying access to medicines in hard-to-reach places, drones could be used closer to home, for example in home delivery of medicines and ferrying lab samples. In short, drones could form part of the humanitarian response or even be an extension of telemedicine. There are of course obstacles. “Reliability is by far the biggest issue,” says Alec Momont, project lead for ‘the ambulance drone’, which is particularly pertinent if a drone is carrying a contagious biologic sample. “But once the technology is proven to be reliable, the regulations will follow.” Scalability is also a problem, adds Dr Arthur Richards, deputy director at the Bristol Robotics Lab. “It’s easy enough to have one or two drones operating in very sparse areas, but the technology to have large fleets interacting in cities is much further off. You’d need to develop a whole new infrastructure for flying.” The weight the drones could carry, how they might operate in adverse weather conditions and the current price tag (which can be several thousand pounds per vehicle) are three other concerns. When can we expect the first healthcare drones? Initially, the likely focus will be on developing countries and humanitarian aid first, though Momont expects a timeline of at least a decade before drone technology will be fully applied to healthcare in Western countries.

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