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Autumn 2010

International Pharmaceutical Industry

Supporting the industry through communication

Peer reviewed

Social Media and Patient Recruitment The Continuing Conversation Clinical Trial Insurance a Pathway through a Complicated Minefield Temperature Indicators for Cold Chain Distribution Enabling Technologies for Attractive Paediatric Oral Dosage Forms

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Contents

International Pharmaceutical Industry

Supporting the industry through communication

EDITOR: Dr. Patricia Lobo patricia@ipimedia.com DIRECTORS: Martin Wright Mark A. Barker

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Regulatory & Marketplace 8

Social Media and Patient Recruitment: The Continuing Conversation Social media has provided a powerful new channel of communication for sponsors in search of study participants. Social media gives sponsors unprecedented ability to: Listen, Inform and Engage. So how exactly do social media serve in a patient recruitment capacity? Bonnie A. Brescia guides us in this informative article towards an understanding of social media in relation to enhancing the application of social media to clinical research studies.

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The Netherlands: Cooperation is in our Genes Through the ages, the Dutch have always been masters of innovation, not just in the arts but also in science and business. Creativity, entrepreneurship and a strong inclination to reach across boundaries enabled a small low-lying country to become a world player. The Dutch are also world champions in seeking consensus and collaboration. Ingeborg van der Heijden of the Life Sciences Health Innovation Program identifies many good reasons why any search for European life sciences and health partners should begin in The Netherlands.

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Clinical Trial Insurance: a Pathway through a Complicated Minefield. The clinical trials insurance arena is characterised as having rare but potentially catastrophic levels of risk. It is coupled with a minefield of national legislation and regulatory requirements. Claims are infrequent, with payments over the last decade in the EU estimated at only 2% of gross premiums, but when they are made, the sums involved are often very large and can have very serious ramifications for all parties involved in the conduct of the clinical study. Andrew Catton of Miller Insurance talks about how not to fall foul of the myriad regulations when working in the clinical trials arena.

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Botanicals Legislation between Drugs and Food Ida Caramazza of Temas srl reviews the botanicals legislation between drugs and food, where classification is not so easy today, with botanical extract-based products being used for both food and medicinal purposes. The same botanical is often differently classified in the overall world market. Manufacturers must make sure that product label information is truthful and not misleading. Both in the US and the EU, there is an urgent need for dialogue between the pharmaceutical and the food sector, in order to come to a constructive approach to medicinal plants for the benefit of patients/ consumers, and for the harmonisation of the market.

PUBLISHER: Clive Baigent clive@ipimedia.com EDITORIAL ASSISTANT: Linda Stewart info@ipimedia.com BOOK MANAGER: Anthony Stewart anthony@ipimedia.com BUSINESS DEVELOPMENT: George Brookman-Mensah info@ipimedia.com DESIGN DIRECTOR: Ricky Elizabeth CIRCULATION MANAGER: Dorothy Brooks dorothy@ipimedia.com FINANCE DEPARTMENT: Martin Wright martin@ipimedia.com RESEARCH & CIRCULATION: Gramatikov Vilian gramatikov-vilian@ipimedia.com COVER IMAGE: iStockphoto Š PRINTED BY: SW TWO UK www.swtwo.com PUBLISHED BY: Pharma Publications Building K, Unit 104 Tower Bridge Business Complex, 100 Clements Road, London, SE16 4DG, UK Tel: +44 0207 2375685 Fax: +44 0207 3947415 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 Feburary 2011. 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.

Editor’s letter

2010 PHARMA PUBLICATIONS

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Open Innovation according to Donny Strosberg Mark Barker of IPI speaks with Donny Strosberg of Scripps Florida about Open Innovation - in particular the ‘marriage’ of R&D centres and SMEs.

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Combination Products – an IP Perspective There are an increasing number of combination products entering the marketplace. The majority of these products are directed towards drug delivery technologies that combine a medical device and a drug. These drug delivery technologies focus on new ways of introducing drugs to the body, to achieve controlled release of the drug, and/or targeted delivery of the drug to a specific part of the body. The trend for combination products seems to be continuing, as more and more companies seek to make the most of limited resources and extend the life of existing drugs that may be coming to the end of their patent protection. Jenny Donald of Forresters discusses why it is important that the appropriate patent protection is obtained for new and advantageous combination products. Drug Discovery, Development & Delivery

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The Role of In Vitro Studies in Assessing Drug-drug Interactions Drug-drug interactions are a common issue during drug treatment and give rise to a large number of hospital admissions within the EU. Guy Webber of Quotient Bioresearch examines the roles of The Regulatory Landscape, Cytochrome P450 Inhibition, Timedependent CYP Inhibition, Cytochrome P450 Induction, Enzymology and Drug Transporter Interactions. In vitro science assisted by an increasingly sophisticated array of models and instrumentation in conjunction with powerful in silico modelling, now allow scientists to make accurate predictions about certain kinds of DDIs in vivo. Near-Infrared Fluorescent Probes for Optical Imaging of Disease Optical imaging is a rapidly developing biomedical technology that enables the examination of cellular processes in the context of a living animal. Fluorescent proteins and bioluminescent reporters are useful for optical imaging of laboratory animals, but targeted agents labelled with near-infrared fluorescent dyes have the additional potential to translate to human clinical use. Mike Olive at LI-COR Biosciences reviews several optical imaging technologies currently in use, with a particular focus on targeted near-infrared (NIR) fluorescent optical probes. The Role of Outsourcing Cryostorage in the Future of Regenerative Medicine Regenerative medicine using human stem cells to repair or replace tissue or organ functions lost through age, disease, damage or birth defects is a fascinating subject for the man in the street, as is the possibility of finding cures for Alzheimer’s disease, autism, diabetes, Parkinson’s disease, schizophrenia, and

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other devastating disorders. Patrick Jackson of Vindon Scientific Ltd discusses the advantages of cryostorage, and how your chosen partner should remove any tension, as their cryobank will facilitate the safe and specialised storage of human tissue and other biological materials. Clinical Research 50 Harmonisation: Finding the Balance Companies are faced with many challenges when expanding their business through mergers or acquisitions. This is especially true for the small- to midsized companies whose employees are likely to view the business as an extension of their own families. Roles must be redefined for personnel in both the existing structure and the new addition, as both find their place in the new organisation. A larger challenge, however, can loom for management as the work begins to absorb or replace the practices and processes that “have always been done this way.” Kathleen Hodges of BASI explains that, in addition to benchmarking best practices across the new organisation, management must also cope with the inevitable silo protection and developing rivalries, as well as the culture shift that must happen to make a successful new organisation operational. 54 Basic Biostats for Clinical Research - Multiple Comparisons in Drug Development, Part I. In this Part I article, Dr Rick Turner of Quintiles ECG Services examines the various issues in basic biostats for clinical research and statistical challenges in multiple comparisons in drug development. Multiplicity can have a significant impact on clinical trials, in the design, in the analysis of the data, and in the interpretation of the results. It can show up in several ways: multiple comparisons among the treatment groups; comparisons of different endpoints; comparisons of endpoints at different timepoints; interim analyses; and at the programme level. 62 ePRO Solutions – How do you Choose? Regulators around the world are increasingly asking to hear the perspective of the patient in clinical trials, and as a result, the adoption of electronic methods for collecting patient-reported outcomes is increasing. Consequently, patient self-reported data are increasingly playing a key part in areas such as understanding efficacy and quality of life, patient recruitment, symptom and safety information and medical compliance monitoring. Mike Federico of ERT Inc discusses how the last decade has seen the industry begin to embrace electronic initiatives such as electronic patient reported outcomes (ePRO) to help streamline the clinical trials process, maintain regulatory compliance and monitor patient safety.

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Contents Labs & Logistics 66

Temperature Indicators for Cold Chain Distribution Temperature indicators based on the thermal properties of chemical compounds (chemical indicators) have been commercially available for many years, providing accept/ reject information for perishable goods within the food supply chain. While many believe chemical indicators may fall short of compliance with global regulations and industry best practices, these devices have, over time, migrated to last-mile cold chain applications in the life science market. Jeff Hawkins of Sensitech Inc. explains the considerations for temperature indicator usage.

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Can Coding Technology Revitalise the NHS? Roger Lamb, Healthcare Sector Manager at GS1 UK, examines the issue in this in-depth article. With a reassessment of public spending and a government focus on exploring new methods, now is the right time to think about how the NHS can be revitalised. The results of GS1 UK’s 2010 surveys show that doctors and nurses are clear about what the fundamental issues within the NHS are, and how they can be resolved. The simple solutions they suggest, and the previous success stories of these technologies being implemented, show that other healthcare institutions should be following suit to increase efficiency, reduce costs and, most importantly, improve patient safety.

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The Urgent Need for Qualified Transportation Providers in Global Clinical Research Although the transport and storage of investigational drugs and supplies represents only a small part of the overall quality equation, pharmaceutical sponsors who take proactive steps to secure their supply chains now may well eliminate unnecessary risk and regulatory exposure later on. Dr Rüdiger Lomb of World Courier explains that “There is no ‘cookie-cutter’ approach to clinical research” and recommends that pharmaceutical practitioners select their service providers with care. Manufacturing

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Active Pharmaceutical Ingredient (API) Outsourcing – a Perspective from an Integrated Drug Development Solutions Provider The pharmaceutical industry is facing challenging times. Downsizing and rationalisation are daily news stories, and the turmoil of global recession is placing additional stresses on the biotechnology sector. The traditional drug development challenges of time, cost and attrition remain, and the necessity to add value for investors and shareholders alike adds further pressures. The contract research and manufacturing sector is changing to meet the new demands and opportunities that the marketplace presents. Quality, customer care and delivery are baseline expectations, and new demonstration of additional delivered value at the right price is taking centre stage. In this article, Dr Austin McMordie of Almac presents the argument for effective integration as a new way to deliver outsourced services.

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86 Enabling Technologies for Attractive Paediatric Oral Dosage Forms Formulating oral dosage forms for paediatrics is very challenging due to the specificities of this patient population. Depending on the age group, different oral dosage forms are administered. Formulators face challenges like ensuring active stability, either in readyto-use dosage forms or reconstituted dosage forms; improving palatability with a pleasant taste and a smooth texture, often preferred by children; and easing swallowing with specific dosage forms. These issues can be solved with appropriate formulation of attractive dosage forms. Cécile Dusautois of Roquette gives some indications in this article. Packaging 94 Dr. Patricia Lobo, Editor of IPI, speaks with Fran L. DeGrazio of West Pharmaceutical Services, Inc. about reducing the risk of needlestick injuries. New technologies include passive systems that allow for safer injection without altering the caregiver’s administration technique in the hospital and clinical setting. 98 How can Intelligent Packaging best Aid Patient Compliance? Patient non-compliance (not taking the right medication at the correct time) causes thousands of deaths, and costs the healthcare industry billions of pounds per year. Innovative medical packaging can combat noncompliance, and so is an area which is likely to see considerable emphasis in the next few years. New areas of development like smart materials and nanotechnology will add to the possibilities of smart packaging, but it has to be recognised that in many areas of the world, the absence of the otherwise ubiquitous internet and mobile phone technologies will mean that the most sophisticated packaging advances will not be applicable. Chris Penfold of Design Cognition Ltd, suggests that those involved in the pharma industry will need to be up to date, not only with the latest developments in drugs, but also with the latest developments in drug packaging. Exhibition Reviews & Previews 104 CPHI/ICSE CPhl Worldwide / ICSE review 106 ScanBalt BioRegion 1st Baltic Forum

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Editor’s Letter Vaccines on the rise - even Bill Gates, the world’s richest man, has promised 10 billion dollars to develop vaccines for the world’s poorest nations So now we know - the National Institute for Health and Clinical Excellence (NICE), the UK’s drug-rationing body - may lose its powers to decide the fate of patients’ healthcare by forcing pharma companies to jump a fourth hurdle of cost-effectiveness, effectively preventing clinically useful new medicines to be prescribed in the NHS. The pharmaceutical and biotech sectors of industry have vigorously lobbied governments for a long time, arguing that NICE is an obstacle to innovation, delaying the introduction of their new drugs into the NHS, and sometimes turning them down or restricting the numbers of patients for whom they can be used. Presumably the cost of continuing to be nice to NICE outweighs the savings to the public purse. While this quango-burning exercise could bring an end to longrunning emotive battles involving patient groups - to say nothing about delivering a much-needed boost to the fortunes of the industry - there’s the looming spectre of a chaotic free-for-all with a postcode lottery for healthcare. The Health Secretary, Andrew Lansley, wants the decision on whether a patient should receive a medicine or treatment to be taken by the patient’s doctor. A local commissioning body will be asked to agree to pay for it. The cost of the treatment will be decided through a new “value-based pricing” system. The NHS will negotiate with the manufacturer on a price for each new drug, taking into account not only how clinically effective it is and how it reduces the burden on the patient’s care provider, but also what other treatments are available and how “innovative” the company has been in producing the drug. As Lansley points out, “We need a system that encourages the development of breakthrough drugs addressing areas of significant, unmet need”. Under the new system, pharma companies will be able to pitch a premium price for a drug in a new class, for example, or for a new product that required a substantially greater outlay 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

for its discovery and development. Value-based pricing may replace the current, somewhat complicated, system known as the PPRS (pharmaceutical price regulation scheme), which reimburses companies for the drugs they supply to the NHS. At the moment, there are some regional bodies assessing the usefulness of medicines while primary care trusts (PCTs) have pharmacy advisers and formularies – lists of drugs they are willing to buy – which the industry hopes will all go. An important aspect of healthcare provision that is of growing importance is in prevention – a keynote theme that was picked up at the World Vaccine Congress in Lyon, October 2010. Globally, there is better awareness of what preventive vaccines can do for the public, and the use of therapeutic vaccines in treatment. Investment in vaccines, driven by new technologies, is helped by the emergence of Intellectual Property (IP) protection, as vaccines that were virtually unknown about 20 years ago enter the market. Vaccines are now seen as “strategic” for many major pharma companies. In 2009, five companies dominated the sales revenues in vaccines – GlaxoSmithKline, Sanofi Pasteur, Merck, Pfizer and Novartis, whereas in 2005, only three of the top ten pharma companies had a presence in vaccines. We now have vaccines against 20 diseases – viral vaccines (e.g., influenza, mumps, Japanese encephalitis, chickenpox) and bacterial vaccines (e.g., diphtheria, cholera, tuberculosis, pneumococcal infections). There are about 70 infectious diseases as “vaccine targets”, of which 25 have already been developed, with more than 40 remaining to be developed. Among those where market potential exists, there are technical challenges: antigenic diversity (e.g., HIV, HCV, rhinoviruses), pathogen biology (e.g., chlamydia, HSV), limited natural immunity (e.g., HIV, chlamydia), immunopathology (e.g., SARS, RSV, Dengue).

Dr Jeffrey Almond, Vice President, Discovery and External Research and Development, Sanofi Pasteur, gave an overview from his personal global experience of what he thinks pharma R&D chiefs really want. He said that they want growth in two directions – in sales and in profitability. “We are seeing not only pressures to expand to new markets and develop new products, but also downward pressures in costs, particularly in manufacturing costs. There’s an impressive growth expectation since the 1990s, fuelled by better products and vaccines, so that the expectation would be well above 23 billlion euros by 2017. Innovation is likely to play a significant role in this growth coming from existing vaccines and combinations, and also new vaccines in development (e.g. against, Dengue, C.difficile and Staph A). The pressure is now on R&D for new vaccines, and this leads to more work in discovery, proof of concept and development.” In 2010, we are seeing a significant movement in the vaccine field, with three new companies entering the market by acquisition or joint ventures – Johnson & Johnson, AstraZeneca and Abbott Laboratories. This issue of IPI has a wide range of articles, including open innovation between R&D centres and SMEs collaborations, appropriate patent protection for combination products, active pharmaceutical ingredient (API) outsourcing, harmonisation through mergers and acquisitions, cold chain logistics, paediatric oral dose formulations, clinical trials insurance, botanicals legislation and packaging of pharmaceuticals. A big vote of thanks to all our authors for their superb articles – please keep them rolling n Dr Patricia Lobo, Senior Consultant, Life Science Business Solutions. Email: patricia@ipimedia.com Autumn 2010


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Social Media and Patient Recruitment: The Continuing Conversation BBK Worldwide Instinctively, this article may seem antithetical. Like any discussion of social media, it is a snapshot of constant motion; it captures a momentary configuration of an entity that is continually reconfiguring itself. The paradox, however, is more superficial than it seems. For while social media is in constant motion relative to every industry seeking to leverage it, the relationship between social media and patient recruitment is uniquely anchored by a shared concept that is both constant and timeless: the instinct of every human to connect with other humans. For social media, it is expressed by individuals eagerly looking to contact and form relationships with one another through online portals. In clinical research, the same instinct shapes the relationships formed when patients and researchers collaborate with one another to grow their knowledge of diseases, treatments, and one another. So even though social media’s constant evolution may seem to defy examination of the channel’s momentary manifestations, social media is nonetheless adjunct to patient recruitment in a special and essential way – especially for the millions of patients who not only inform their healthcare decisions online, but also eagerly expect to build a range of crucial relationships there. Hence this discussion of the current state of play between social media and patient recruitment – the point of first contact between these patients and clinical research. Social Media and Patient Recruitment The term “social media” is generally understood to include portals as diverse as social networks (e.g., Facebook), video and photo sharing sites (e.g., YouTube, FlickrTM), and interactive encyclopedias (e.g., WikipediaTM). However, all such 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

sites are variations of a model: an online location where individuals gather, share files and information, converse, connect, educate themselves, and for all intents and purposes “live” an online extension of their personal lives among other social media users. The channels through which this occurs are also the site of the latest evolution in patient recruitment methodologies. This evolution is different from all preceding changes in patient recruitment practices. Unlike the introduction of radio, TV, or internet advertising, social media has not simply provided a new way to deliver a message (“New clinical trial now seeking patients”) in expectation of a direct response (patient referrals). It has introduced a whole new advertising paradigm – one in which messages are introduced, discussed, transferred, and debated among millions of interconnected recipients. In doing so, social media has provided a powerful new channel of communication for sponsors in search of study participants. Social media gives sponsors unprecedented ability to: • Listen: Social media provides more information than any other media about where potential study participants meet, talk, and, interact; how they do so; what they talk about; and the language they use to converse with one another. • Inform: Because of intense personalisation of most users’ social media experience and activity, social media can be used to deliver extraordinarily targeted messages to individual patients. • Engage: Social media gives sponsors the ability to join and involve their studies in the online interactions taking place among patients – and to make a study opportunity part of active conversations and discussions. The

channel makes it possible for a clinical trial to literally be “what everyone’s talking about.” The Role of Social Media in Clinical Trial Enrolment So how exactly does social media serve in a patient recruitment capacity? It does so in three primary ways that correspond to the channel’s “Listen, Inform, Engage” functions. In each of these ways it serves as a method of accomplishing the key goals of online patient recruitment: identifying potential participants, directing them to a source of more information, and prequalifying them via an online prescreener. User Expectations vs. Sponsor Priorities You can easily infer from the “Listen, Inform, Engage” functions that they represent a sliding scale of user-sponsor interaction. On the one end, Listening to social media is for all intents and purposes a sophisticated form of market research – one that takes advantage of the vast amounts of information that users share and distribute online. In the Worldwide Social Media Portals The sites patients use to live their social media lives are as diverse as the patients themselves. While sites like Facebook® and YouTubeTM do have global reach, social media users in other major markets are often far more familiar with myriad other locally prominent portals. FACEBOOK N. America / W. Europe ORKUT Brazil & India QZONE China FRIENDSTER Asia Pacific STUDIVZ Germany

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REGULATORY & MARKETPLACE middle, Informing allows sponsors to use social media’s personalisation and targeting power to vastly increase the impact of traditional online advertising. Finally, “Engaging” with patients is the most truly “social” and interactive way to raise awareness of a trial through social media (and the only function with the potential to deliver the “Holy Grail” of viral impact). All three functions have the potential to serve patient recruitment strategies. The catch, however, is that Engage is essentially the only one of the three functions for which patients actually use social media. Engagement is why social media users became users in the first place: it serves the defining purpose of social media for those seeking to “live” an online extension of their actual lives. Users Listen, of course – but only as an instinctive part of their regular interaction with other social media users. And as for Inform – in the sense that we mean Targeting One significant advantage to deploying traditional clinical trial ads via social media is that this channel gives sponsors an unprecedented amount of control over how, when, and where those ads appear. Through a number of different methods, social media makes it easier than ever to ensure the right patients hear about your study: Behavioural Targeting • Serves ads to users based on content they search for, the amount of time they spend on a topic, and the actions they take within a site. • Applicable to patients actively searching for certain content or whose behaviour matches those of the eligible study participant (e.g., targeting diabetes patients seeking insulin supplies for an insulin-dependent clinical trial). Contextual Targeting • Serves ads based on user searches within a specific site. • Matches users and ads based on relevance to users’ search terms, whether keywords or subject categories (e.g., targeting parents searching for ADHD information on a general health website). Demographic Targeting • Used for sites on which patients create a personal profile (e.g., Facebook). • Serves ads based on gender, age, income, or employment status. Geographic Targeting • Serves ads based on the location of a patient’s computer (identified by its IP address) or information provided in the user’s profile. • Can be used to deliver ads based on state, city, postal code, or radius in miles from a study site.

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it here – it is the exclusive province of advertisers (including sponsors in need of trial participants). Social media certainly may be used to deliver ads to potentially interested users – but those

users are by no means on social media for the purpose of receiving that content. (Consider the decline of MySpaceTM a cautionary tale for organisations that think otherwise.)

Table 1 Listen •T  oday’s market research apparatus lets us target, observe, and record much of the incredible activity taking place on social media portals. • Information gleaned by “listening” to these portals indicates where patients meet online, what they talk about, and the language they use. • These findings can be used to direct, refine, and target the content and call to action of traditional advertising and outreach.

Inform •W  ith basic knowledge of patients’ social media use, ads and outreach can be served directly to those patients via specific portals – with unprecedented precision.

Engage •T  he most dynamic use of social media is to deliver your study’s message in a space where target patients can discuss and interact with that message – and involve you and each other in the activity. •T  his space might take the shape of an online patient community, a blog, a message board, an e-mail list, or social media pages dedicated to a study.

Related Tactics: • Web listening projects • Blogs and message boards •T  raditional outreach: radio, TV, print, internet ads, direct e-mail, etc. • Study website and prescreener

Related Tactics: • Targeted social media ads: display, text, rich media, or other internet ads delivered through a social media portal • Study website • “Flat” study social media pages (posting / messaging functions disabled)

Related Tactics: • Online patient community • Blogs and message boards • Dynamic study social media pages with posting / messaging functions either monitored or fully enabled • YouTube

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REGULATORY & MARKETPLACE and the people and information they encounter on it – and they expect that engagement will be free-flowing and organic. Contrast these expectations with the regulatory environment surrounding clinical trials. In clinical research, all messages and topics are thoroughly reviewed and tightly controlled at all times. They are reviewed by the sponsor’s internal regulatory department, perhaps a compliance group, one or more ethics committees or institutional review boards, and often by a country’s ministry of health equivalent. Throughout this review process, common sponsor concerns include: • Human subject protections and patient privacy • Sponsor intellectual property and proprietary data • Scientific validity of study results • Critiquing of study sites • Introduction of therapeutic bias

What does this mean for patient recruitment? Not that Listen and Inform are half-measures in the effort to leverage social media to enroll a clinical trial. In fact, both functions provide exactly that kind of leverage. They both put social media to work recruiting patients – but only as a way to extend, enlarge, or recapitulate the function of traditional advertising like TV or internet ads. They do not actually use social media for the purposes that millions of people use it every day: connection, communication, and interaction. Instead, they still either observe or direct a message at an audience in hopes of eventually evoking a response – and only incidentally do so using social media portals, in the same way that radio happens to be delivered via airwaves. It is at the point of Engagement, then, that user and sponsor priorities for social media diverge. The Conversation Today All sponsor needs and goals notwithstanding, of course, patients expect to Engage with social media www.ipimedia.com

Implications of Engagement In social media, “engagement” means users freely interacting, communicating, and sharing with each other online, and with the content they encounter on the internet. For patient recruitment, this ability defines the separation between the Inform and Engage functions of social media – between unilaterally directing advertising content at patients via social media, and allowing that content to be integrated into the dynamic exchanges of information taking place among patients online. It also represents a daunting new level of regulatory complexity: it’s difficult to achieve the natural spontaneity of social media interactions when all communication from one side of a conversation has to be approved by an IRB or EC. Because of this critical restraint, it’s all the more important for sponsors to inform themselves when evaluating patient response to the Listen and Inform functions of social media. While regulatory constraints may not allow sponsors to communicate “naturally” with patients via social media, the feedback received by listening to and informing those patients still provides invaluable, actionable information: about topics that will come up in future social media conversations, and about the results patients expect those conversations to have. This information can be used to develop long-term, proactive plans for responding to patient activity relative to a social media patient recruitment campaign.

Follow the Conversation on Twitter® At BBK, we’re always watching the developing engagement between social media and patient recruitment. Whenever we get a step closer to answering it, we’ll Tweet on our progress. To get the latest, follow us at www.Twitter.com/ BBKworldwide.

(sharing feedback on symptoms/lack thereof) • Possibility that patients can un-blind themselves In many ways, then, trying to communicate with patients using content under this level of scrutiny may seem antithetical to the free-flowing nature of social media. How does a sponsor truly “Engage” with potential study participants when their communication is under that level of oversight? This is no longer a theoretical question for sponsors. Patients already have myriad attitudes, habits, behaviour, and expectations fully formed and defined by social media; connecting these patients with new study opportunities will mean developing advertising and outreach methods that play by – or around – the social rules collectively established by these hundreds of millions of internet users. For the time being, bending social media around traditional tactics and channels will continue to be an effective method of recruiting patients, as efficient methods of accomplishing this are already in place. But the line between these two objectives will continue to blur. Soon, it will reach the point when it won’t suffice for sponsors to ask themselves: “How do I make social media a part of the current approach to patient recruitment?” The time is quickly approaching when they will have to ask: “How do I make patient recruitment a part of social media?” The answer is simple: Determine how to “engage.” n

Bonnie A. Brescia A founding principal of BBK Worldwide, Bonnie guides the continual evolution of the company as a leader in marketing consultation for the patient recruitment industry. She leads the field in understanding and enhancing the application of social media to clinical research studies – a topic on which she writes and speaks frequently. Email: bbrescia@bbkworldwide.com

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The Netherlands: Cooperation is in our Genes Through the ages, the Dutch have always been masters of innovation, not just in the arts but also in science and business. Creativity, entrepreneurship and a strong inclination to reach across boundaries enabled a small lowlying country to become a world player. The Dutch are also world champions in seeking consensus and collaboration. There are many good reasons why any search for European life sciences and health partners should begin in The Netherlands. Exploiting Public-Private Innovation to the Fullest From the golden century until now, the Dutch have cooperated in ventures and have been fighting the water. The Dutch life sciences and health sector is now leading a trend towards public-private research and development collaborations, open to partners worldwide.

With successful public-private R&D projects up and running in The Netherlands, the other layer of its life science infrastructure, the Life Sciences and Health Innovation Program, ensures that many of the seeds derived from public-private partnerships will come to full fruition. In addition, it will help promote the country as a prime candidate for international collaboration. In recent years, the global life sciences and health sectors have undergone significant changes. 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Centralised, large-scale knowledge development has given way to dynamic, open and flexible innovation networking between multidisciplinary research organisations. Product development, once the exclusive domain of just a few corporate players, has become a game in which thousands of actors from academia, big industry and small and medium-sized enterprises have to work and play together. Knowledge sharing, partnering and the creation of global networks have become crucial elements of the innovation game. Public and Private, Hand in Hand The Dutch life sciences and health sector has been no different in this respect. In one way, however, The Netherlands has been leading the way. As it did before in the social and economic sectors, this little country’s knack for cooperation, coalition and consensus-building has produced a new brand of public-private research and development collaboration that has attracted attention from far abroad. Like most of the world’s life sciences hot spots, the Dutch life sciences and health sector offers a mix of dozens of firstclass academic research organisations, hundreds of small biotech companies and an array of local centres and branch offices of multinational industry corporations. In itself, such a diverse scenery within a 120-mile radius already offers great opportunities for knowledge creation and innovative product development. In recent years, however, Dutch academia, industry and the national government have added intensive cooperation to that fertile mix. Together, they have invested more than one billion euros in programmes and partnerships in which public and private partners work closely together. Their scopes range from basic genomics research to developing medical, agricultural and industrial applications.

An Array of Partnerships The result has been an array of very successful public-private partnerships (PPPs) such as the Netherlands Genomics Initiative (NGI, www. genomics.nl), Top Institute Pharma (TI Pharma, www.tipharma.com), the Center for Translational Molecular Medicine (CTMM, www.ctmm.nl) and the BioMedical Materials Program (BMM, www.bmm-program.nl). Other, smaller but similar public-private initiatives include the Translational Regenerative Medicine Program (TeRM, www.term.nu), Cyttron (www. cyttron.org), focusing on imaging technology at the molecular and cellular level, and the ‘String of Pearls’ initiative (www.parelsnoer. org), which links the biobanks of eight Dutch university medical centres. CTMM is just one example of a multipartner, multi-disciplinary network that promises to yield exciting and tangible results. Combining 22 major industry players, such as Philips, DSM, MSD and FEI, as well as 62 small & mediumsized enterprises, with 22 academic partners including eight university medical centres, Eindhoven University of Technology, Delft University, and the Dutch Cancer Institute (NKI), CTMM will invest €275 million into 21 collaboration projects, in the areas of cancer, and cardiovascular, neurodegenerative and infectious/ auto-immune diseases. All of these public-private partnerships are working to take bright ideas conjured up in academia and quickly translate them into potential products for patients – whether drugs, vaccines, diagnostics via imaging, biomarkers, new devices or targeted therapy or innovations in cell and tissue engineering. Among major research-oriented EU countries, The Netherlands ranks number one in the number of Autumn 2010


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international collaborations per scientist. In Europe’s collaborative Research Programs, Dutch leadership often proves beneficial for success. In other words, The Netherlands is built upon people working together, so anyone in search of collaborators should really start with the Dutch. Science Shapes our Minds The Netherlands is one of five European countries characterised by the EU as ‘having a high number of high-impact universities’. Indeed, 11 out of the country’s 14 universities ranked within the first 200 of the 2009 Times Higher Education Supplement World University Ranking, which rewards reputations for academic excellence and high research citation scores, among other things. In fact, the average citation impact of the high volume of research papers originating in The Netherlands is thirty percent above the global average (only Switzerland and the US manage to top that score). In biomedicine, the Dutch excel in areas such as cancer research, infectious diseases and molecular imaging. The Netherlands is a world leader in plant and animal breeding technologies. In addition to reputable universities are over one thousand life sciencerelated companies, and eight top-quality university medical centres, which have all partnered up in recent years to create a vast infrastructure rich in patient cohorts and biomedical databases. Dutch science is really world-class — one more reason to put The Netherlands at the top of your list when shopping for partners. 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

All of Europe close at hand The Netherlands is a perfect hub from which to explore the European continent. Tucked in between the UK, France and Germany, and a stone’s throw away from Brussels, the European capital, the Netherlands occupies a unique spot. The country has superior logistics and an outstanding technology infrastructure. It is well known for operating within an international business environment. More than 100,000 people have jobs related to research and development. Basically all staff master the English language. Financial Benefits Apart from the Dutch strengths and advantages mentioned, there are also some distinguishing financial facts worth mentioning. The health-related life sciences industry in The Netherlands already represents about 3% of GDP, and it is set for growth. The Dutch government, companies and academia have invested billions of Euros in the Dutch life sciences industry, which will also secure your investment or business operations in The Netherlands. And last but not least, The Netherlands has a distinctive favourable tax climate for international investors. If you would like to take advantage of the Dutch life sciences and health business, and would like to explore the possibilities of investing in Dutch life sciences companies, or seek a business partnership in The Netherlands, please do visit www.lifesciences.nl n

program aims to improve the investment climate of the health related life science sector in the Netherlands. We facilitate both small and medium sized enterprises (SME) to thrive in the Netherlands, as well as foreign companies that want to invest in the Netherlands. For more information look at: www.lifescienses.nl<http:// www.lifescienses.nl>, or send an e-mail to info@lifesciences.nl<mailto:info@ lifesciences.nl

Ingeborg van der Heijden – As Communications Manager of the Life Sciences Health Innovation Program, Ingeborg van der Heijden is among others responsible for the (inter)national positioning of the Dutch health related life sciences sector and has developed the Dutch Masters campaign. She studied communications sciences at the University of Amsterdam and graduated in 1994. After that she held various positions in the field of communication. Email: ingeborg.vdheijden@ lifescienceshealth.com

Life Sciences & Health Program The Life Sciences & Health innovation Autumn 2010


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Clinical Trial Insurance: a Pathway through a Complicated Minefield Andrew Catton, head of the Life Sciences team at Miller (an independent specialist insurance and reinsurance broker) talks about how not to fall foul of the myriad regulations when working in the clinical trials arena. The clinical trials insurance arena is characterised as having rare but potentially catastrophic levels of risk. It is coupled with a minefield of national legislation and regulatory requirements. Claims are infrequent, with payments over the last decade in the EU estimated at only 2% of gross premiums, but when they are made, the sums involved are often very large and can have very serious ramifications for all parties involved in the conduct of the clinical study. As may be expected, the volume of liability claims and the sums awarded in damages are far higher in North America. Legal Origins Specific clinical trial insurance initially came into being as a result of legislation enacted in France and Germany in the 1970s. Since then various EU directives and guidelines, most recently directive 2001/20/EC and ICH GCP, have highlighted the moral principle of providing adequate and timely compensation to both healthy volunteers and patients injured through participation in a clinical trial. How this might be achieved in individual EU member states was left open for each territory to decide. Trial patient and volunteer protection insurance is now mandatory in 22 out of 27 EU member states. However, the details of terms, conditions, exclusions and limits of indemnity required per patient or for the protocol and duration of protection (after the conclusion of the study) vary substantially from country to country. 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Through a combination of different triggers to indemnify the injured research subject, i.e. non-negligent harm (no fault compensation), strict liability and legal liability, there exists a plethora of policy wordings designed to meet the requirements of the directives and guidelines and the nationally enacted legislation. To further complicate matters there are many territories where protective laws on the placement of insurance mean that only admitted insurance (effected with a locally licensed insurer) is permissible. An insurance broker with the experience of handling and placing such business is essential in helping the trial project manager through this complicated minefield. The Need to Engage with a Specialist Globally there are very few specialist underwriters with the real capabilities, infrastructure and understanding to provide truly worldwide insurance programmes. There are, however, a growing number of insurers in individual countries that have an increasing knowledge base in the life sciences sector, albeit their policy wordings need to be carefully scrutinised. The insurer’s ability to provide sufficient limits of indemnity beyond what can be a very low mandatory requirement can be problematic. Common to all underwriters is the need to gather all relevant trial information for the purposes of both risk assessment and to enable them to issue correct evidence of cover certificates. For single trials and multi-centre multinational studies this information will include: • Sight of full protocol • Sight of patient or volunteer information sheet and informed consent form • List of countries where the trial is to be conducted together with the estimated number of research subjects (to be screened and to be enrolled)

• List of principal investigators and trial sites • Anticipated start and end date • For certain countries a specific application/proposal form may be required In countries where insurance is mandatory the ethics committee and/ or regulatory approval authority (or combination of both) will require evidence of cover – they will generally need sight of a compliant certificate, usually in local language, at the time of submission for approval. Irrespective of directives and legislation, insurance cover can be effected for Phase I (healthy volunteer studies), Phase II and Phase III patient trials, and for Phase IV (marketing studies) in respect of all clinical research in areas such as innovative new drugs, novel chemical entities, biologicals, generics, drug comparison, treatment regimes, medical devices, surgical procedures and non-invasive studies. With 25% of industry-sponsored trials now being conducted in study sites in emerging territories it is very important to understand the requirements and potential pitfalls in both managing contractual liabilities with local investigators, hospitals and clinics and research contractors, and the arrangement of insurance coverage. Managing expectations, especially with regard to timeframe, can be critical. Employing experienced service providers to procure insurance protection with secure local insurers, backed by specialist reinsurers where necessary, is essential for avoiding the possibility of costly delays in the submission process and commencement of the trial. Quality and accuracy of documentation from insurers and brokers with the global reach to provide a fully worldwide service is hugely important. Autumn 2010


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REGULATORY & MARKETPLACE TGN1412 Incident In the UK, the Association of the British Pharmaceutical Industry (ABPI) guidelines have been in place since the late 1980s, but are not required to be implemented by law. Following the serious adverse reactions in the Tegenero trial, the ABPI, the Bio Industry Association (BIA) and the Clinical Contract Research Association (CCRA), along with ethics committee representatives and specialist insurance advisers, were mandated by the Department of Health to completely review the insurance recommendations for Phase I trials in the UK and revise the guidelines accordingly. The TGN1412 cytokine storm incident was treated as an isolated and rare event attributed to a combination of cumulative factors, and the actions of the UK government in commissioning the Expert Scientific Group (the “Duff Report”) and establishing the Phase I trials insurance working party were immediate. Similarly, insurance underwriters reviewed the circumstances and implemented more stringent protocol and risk assessments. Certain factors, perhaps more obvious in hindsight, are now critical matters for insurers to have full knowledge of and are therefore also very relevant risk management issues for Phase I sponsors and clinical research organisations. Such factors include: • Confirmation that no regulatory body in another country has declined to approve the trial. • Signed contracts between all relevant parties are in place before the trial commences. • State of the art scientific knowledge on first-in-man compounds has been properly assessed by the sponsor, contract research organisation (CRO) and the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK, or equivalent regulatory body in other countries. • Dosing regime time span between first volunteers, particularly on day one, is sufficient. • On-site emergency medical facilities, such as an intensive care unit, are continuously available with staff fully informed about the nature of the trial. • Financial security of the sponsor. • If providing insurance for the CRO, that the sponsor has proper and adequate no-fault compensation and legal liability insurance in place with a 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

UK-regulated insurer. • Accreditation status of the CRO. Post TGN1412, it was also evident that for clear delegation of responsibility and liability, it is important to have the appropriate contracts in place and signed between all relevant parties. A key difference, for instance, between the US and the UK and the majority of the EU states is that most policies cover separate entities for their responsibilities towards subjects in trials, whereas for the majority of states in the EU where compulsory insurance is demanded, the coverage enables a volunteer or patient to make a single claim without the need to determine which party was to blame for their injury. For CROs with the option of purchasing parallel no-fault trial insurance, biomedical errors & omissions policies are also available to cover claims against the CRO by the sponsor or the volunteer. Such policies are specifically designed to meet the liabilities of CROs, whether it is for their financial loss, exposure to a claim for negligent error or omission from the client sponsor, or a bodily injury claim from a patient or healthy volunteer. However, CROs should seriously consider their exposures to research subject claims arising as a result of failure of the sponsor to indemnify them or under their contractual commitment to provide compensation in the volunteer consent form. In addition, sponsors and CROs should be aware that when the sponsora is not domiciled and does not have a registered or legal entity in the EU (and in other countries such as Australia and Switzerland), there is a requirement for a local entity or person to act as

the legal representative sponsor. These responsibilities can be onerous, and such legal liability accepted contractually in agreeing to act as the legal representative sponsor should be addressed by confirming inclusion on the sponsor’s insurance contract or by making suitable contingent insurance arrangements. In order to reduce timelines, minimise administration, obtain best value for money and optimise the decisionmaking process it is recommended you enlist the help of a specialist broker who works with capable and competent insurers. That way you can be sure that you’ll be led through the complicated minefield and be fully compliant with the necessary regulations n

Andrew Catton - Andrew has worked in the insurance industry since 1971, and joined Miller, a specialist insurance and reinsurance broker, in 1996. He specialises in pharmaceutical, medical, life science product liability, clinical trials medical malpractice, professional indemnity, biomedical errors and omissions products recall and intellectual property insurance. Andrew has spoken at numerous biotechnology and clinical trials conferences and has contributed to a large number of articles and book contributions Email: Andrew.Catton@ miller-insurance.com Autumn 2010


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Botanicals Legislation between Drugs and Food Ida Caramazza Temas srl In the 1st century Pedanius Dioscorides, a Greek medical botanist, grouped the plants under three headings: as aromatic, culinary, and medicinal. Such a classification is not so easy today, when botanical extract-based products are used for both food and medicinal purposes. The same botanical is often differently classified in the overall world market. In the US, the category of dietary supplements holds the largest share of the whole botanical market, while in the European Union (EU), the dietary supplement segment accounts for a minority of the European herbal market, with huge differences between each single European country: in Germany or the UK, most herbal products are on the market as medicinal, often prescribed and reimbursed, while in Italy 80% of marketed herbal products are classified as food supplements. Considering the EU countries, there is a continuum from considering nearly every herbal preparation as a medicine, to strongly denying all herbal preparations as medicinal products. In most cases, the choice of legal framework to apply lies with the manufacturer, and is determined by the indication/claim of the product. Compositional criteria in relation to botanicals have not yet been harmonised, and national rules are still in force. The European Medicines Agency (EMA) has been drafting a series of monographs on medicinal plants that have built the basis for the harmonisation of herbal medicinal products in the EU. On the “food side”, the European Food Safety Agency (EFSA) is in charge of the evaluation of food health claims according to the new EU Nutrition and Health Claims Regulation (Regulation EC No, 1924/2006), ensuring that each claim is scientifically substantiated and authorised by the EFSA. 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Moreover, the validity of history of use data in demonstrating the effect of a product is accepted in the regulation of medicines under the EU Traditional Herbal Medicinal Products Directive (2004/24/EC) (THMPD), which allows that a medical indication can be accepted even without scientific data, just with the demonstration of 30 years’ history of use of the product to treat a particular condition (limited to minor illnesses, usually for self-medication). So, while historical data is taken into account when considering the safety and efficacy of botanicals medicinal products, the Nutrition and Health Claims Regulation does not formally take account of historical data in assessing the evidence for a claim for the effect of a food product, always asking for scientific substantation. Considering tha complexity of the issue, the European Commission has recently decided to temporarily remove botanicals from the nutrition and health claim process, for further review. Similarly, in the US the law regulating dietary supplements is different from that regulating pharmaceuticals, and dietary supplements cannot bring claims that they treat or prevent disease, but only that they affect structure and function. While medicinal products are subjected to FDA approval, the Dietary Supplement Health and Education Act (DSHEA) of 1994 requires the manufacturer to ensure that a dietary supplement is safe prior to bringing it to market. Manufacturers do not need to register their products with FDA nor get FDA approval before producing or selling dietary supplement . * Manufacturers must make sure that product label information is truthful and not misleading. FDA’s post-marketing responsibilities include monitoring, safety, and product information, such as labelling, claims, package inserts, and accompanying

literature. Both in the US and the EU, there is an urgent need for dialogue between the pharmaceutical and the food sector, in order to come to a constructive approach of medicinal plants for the benefit of patients/consumers, and for the harmonisation of the market n References: 1. Facilities that manufacture/process, pack, or hold food in the United States are required to be registered with the FDA

Ida Caramazza Ida Caramazza is a Pharmacologist with experience in preclinical research and regulatory affairs, involved in regulatory strategy projects in medicinal and health care sector. She is the R&D and Operations Director of Temas, an Italian Consultancy Company focused in International Regulatory Affairs and educational activities. Ida has also in charge the scientific revision of training programs organised by Temas. Email: ida.caramazza@temasis.it

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Open Innovation according to Donny Strosberg (Scripps Florida)

Donny Strosberg will be participating in BioWin Day 2010 “Science for Business”, which will be devoted to Open Innovation, on 8 December next in Louvain-La-Neuve/Belgium (www.biowinday2010.org). He has shared with us, on the basis of his experience and professional career in the United States and internationally, his thoughts on the development of pharmaceutical groups: R&D activities and venture capital investors, the differences between European and American stakeholders, Open Innovation (in particular the ‘marriage’ of R&D centres and SMEs) and technology transfers. Changing Attitudes of Pharmaceutical Groups to R&D Activities Donny Strosberg has noted a change of attitude among pharmaceutical companies as regards their suppliers, namely biotechnology companies. Over the last ten years, the number of new chemical entities for therapeutic purposes has been very modest, whereas the number of new molecules from biotechnology has continuously increased. Based on this observation, major pharmaceutical groups have decided to acquire biotechnology companies (for example, the purchase of Genentech by Roche and the acquisition of Wyeth by Pfizer) to enrich their product development and marketing programmes, shedding or integrating in the process the teams in place. Here and there, teams that have been integrated have formed new departments within pharmaceutical groups, for example at Foveia, which is today the spearhead of the new ophthalmological division of Sanofi-Aventis. This trend can even lead some pharmaceutical groups to transform themselves into genuine biotechnology companies split into autonomous units, using as their slogan 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

“small is beautiful”. At the same time, Donny Strosberg has also noted that pharmaceutical groups are increasingly cooperating with the best biotechnology R&D centres of universities, especially American ones (for example, Novartis has transferred an important part of its research from Switzerland to Cambridge in the USA). Some pharmaceutical groups are also working in partnership with each other. This is known as Open Innovation. A striking example of this is the international laboratory ViiV Healthcare, which is entirely dedicated to HIV research and treatment. Set up in November 2009, it is based on an innovative development model between GlaxoSmithKline (GSK) and Pfizer. ViiV Healthcare has signed a research agreement with its shareholders to continue their individual HIV research work to identify new molecules on behalf of ViiV Healthcare. As soon as a candidate drug developed by the two laboratories has successfully completed the first development stages (Proof of Concept), ViiV has a first option to buy it. At this stage, ViiV becomes responsible for the product development strategy, while GSK or Pfizer will handle the operational organisation of the clinical development of the molecules resulting from their respective research and the registration of the molecules. Once the marketing authorisation has been obtained, ViiV Healthcare has sole responsibility for marketing the product (source: press kit from GlaxoSmithKline, March 2010). A New Venture Capital Investment Model Investors have drastically changed their model. Instead of creating numerous small companies by injecting seed financing, followed by three or four more substantial financial contributions before seeking a stock market listing,

they now prefer to invest more sparingly but in larger amounts (from 30 to 50 million dollars) to finance fairly advanced projects, often with molecules already in the clinical phase. To identify such projects, investors do not hesitate to form partnerships with research institutes or pharmaceutical companies to create spin-offs. Thus, investors finance industrial spin-offs focusing on high-potential projects owning the related intellectual property rights. For example, researchers left Roche, taking with them a cardio-vascular programme developed within the pharmaceutical group, to form Actelion with the support of financial backers. It is now one of the top ten biotechnology companies in Europe. According to Donny Strosberg, the rare new start-ups based on the old model very often go hand in hand with an incubation financed by one or more investors within a research institute, rather than in an external incubator. The companies maintained in this way in their original cocoon are often practically virtual companies. The idea is to form companies that can be sold rapidly to large pharmaceutical, biotechnology and life science groups, as soon as the validity of the concept has been demonstrated. This trend was illustrated by the formation in December 2009 of the venture capital fund Kurma Biofund, dedicated to a new generation of biotechnology financing, in which Natixis Private Equity and CDC Entreprises have already invested 50 million euros. It now benefits from the strategic support of the Institut Pasteur and the Institut Curie. Several other European research institutes will very rapidly join the Kurma Biofund network in order to share their technology transfer competencies and their scientific investment opportunities. Donny Strosberg also sees a major difference in the behaviour of Autumn 2010


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stakeholders in Europe and the United States. Whereas American investors and companies (whether they are active in the pharmaceutical or biotechnology fields) are very mobile, between the East Coast and the West Coast, in Europe the approach tends to be more local, with the emphasis on local competencies, and very little effort being made to develop cross-border initiatives. This explains to some extent the difficulty of financing Phase III of R&D projects, and the failure to develop large biotechnology companies, since the funds invested are raised locally and are more modest. Nevertheless, there are interesting national initiatives in Europe, such as seed financing for projects in the start-up phase. Donny Strosberg also sees opportunities for European biotechnology companies, and believes that they should follow the lead of their Indian, Chinese and Singaporean colleagues in recruiting researchers who have recently been made redundant by pharmaceutical groups in the United States. These researchers represent a pool of talent to be tapped. Donny Strosberg is an advocate of Open Innovation, provided that it is well thought out. He considers that companies should only finance research 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

projects which have a clear timetable, with fixed deadlines and a commercial aim, as is the case with the projects supported by BioWin. It is not their role to support research for its own sake. He is also a fervent supporter of the pooling of R&D centres in order to develop synergies, as is the case with clusters in Europe. He also agrees with the idea that the wellbeing of innovative SMEs depends on either developing the necessary specialisation to enable them to target accurately a given market, or a good marriage with other companies or R&D centres where they retain control over the intellectual property rights. “The Scripps Institute, Florida was set up with a contribution of 650 million dollars from the State of Florida, using the same model as that for the Californiabased institute. But these funds have a limited life. In addition, as the institute owns the intellectual property rights of the innovations of researchers, it has to file the patents and defend them. We therefore need to find industrial partners rapidly in order to optimise the potential of our intellectual property rights, as we have done with Pfizer. In this regard, Open Innovation is crucial in our eyes since it guarantees the institute’s continuity,” concludes Donny Strosberg n

Prof. Arthur Donny Strosberg A. Donny Strosberg is Professor of Infectology at The Scripps Research Institute in Florida where he manages a program on Hepatitis C. His current work focuses on developing novel small molecule therapeutics based on inhibition of proteinprotein interactions.Prof. Strosberg was trained as a Dr. Sci at the Free University of Brussels and did a postdoctoral fellowship at Massachusetts General Hospital in Boston. After serving at the Harvard Medical School as an Instructor and later as a Visiting Professor, he became Professor of Biochemistry and Immunology first in Brussels, then in Paris. With his teams he published over 360 peer-reviewed original scientific articles, several books and dozens of book chapters. He authored over twenty issued patents of which several were licensed to pharmaceutical companies. Prof. Strosberg is a co-founder of several biotechnology companies including Chemunex, co-founded with the University of Paris; Incyte, Praecis, co-founded with M.I.T.;and BioRelix co-founded with Yale University. From 1998 to 2004 Prof. Strosberg was the Chairman and CEO of Hybrigenics, a company, which he co-founded with the Pasteur Institute from 1998 to 2004

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Company profile

We care, we cure

Cardiovascular disease is the leading cause of mortality worldwide. The mission of Cardio3 BioSciences is to discover and develop regenerative and protective therapies for cardiovascular diseases caused by illnesses where cardiac tissue is lost due to chronic or acute injury. By seeking to repair heart lesions, Cardio3 BioSciences intends to go beyond current paradigms of clinical practice in this field by seeking to heal the failing organ, as opposed to palliating the hemodynamic consequences of disease. Cardio3 BioSciences – a Belgian company founded in 2007 – aims to become a leader in regenerative biotechnology, with a pipeline portfolio of innovative product candidates including cell therapies, protein therapies and devices, based on landmark scientific work. Cardio3 BioSciences in Action – Seeking to Tackle Heart Failure with C-Cure® Heart failure is a serious and increasingly common condition, in which the heart cannot pump enough blood through the body, leaving the patient debilitated and increasingly unable to conduct normal life. Heart failure can result from heart attacks or a number of other causes. Patients suffering from heart failure can experience shortness of breath and exhaustion. Cardio3 BioSciences estimates that 84 million people suffer from heart failure, and that this number will double by 2020.* Current therapies available for chronic heart failure are palliative therapies aiming at relieving patient symptoms, rather than curative (with the exception of heart transplant). A transformative solution for patients is on the horizon – regenerative therapy candidates. Cardio3 BioSciences’ lead product candidate, C-Cure®, is designed to offer a highly innovative approach for the treatment of heart failure, a pressing unmet medical need. Leveraging technology licensed from Mayo Clinic (Rochester, Minnesota, USA), Cardio3 BioSciences has developed a regenerative product candidate, C-Cure, consisting of a patient’s own stem cells guided to achieve cardiac lineage specification, and aimed at rebuilding the failing heart. C-Cure is produced by taking the patient’s own stem cells and, through a proprietary process, differentiating them into lineagespecified stem cells (“cardiopoietic cells”) that are designed to regenerate damaged heart muscle. Cardiopoietic cells are then injected into the heart of a patient with heart failure, without carrying the risk of rejection, and are designed to achieve 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

tissue regeneration not achievable with existing therapies for this indication. C-Cure is the outcome of multiple years of research conducted at Mayo Clinic, and clinical expertise gained at the Cardiovascular Center Aalst (Aalst, Belgium). Cardio3 BioSciences has announced positive results from its C-Cure® clinical trial. Six months after receiving C-Cure, patients with heart failure of ischemic origin showed significant improvements in left ventricular ejection fraction (indicative for heart function) compared to the control group. In addition, patients in the C-Cure group had a much better exercise capacity as measured by a standard test called the “6 minutes walking distance” test. “The highly promising data we have reported build on the favourable safety profile we have observed through the Phase II trial and documents in patients our belief that we have with C-Cure a product candidate with the potential to make a real difference in the treatment of heart failure. Through the Phase II trial, we gained significant experience in working with a highly innovative stem cell therapy in a clinical setting, and we are using this acquired knowledge in the design of our planned Phase III programme. Cardio3 BioSciences is committed in taking the steps needed to bring to patients a new treatment for a condition where current therapies do not address the underlying cause of the disease.” – Dr Christian Homsy, CEO of Cardio3 BioSciences. Beyond C-Cure – Building on our Understanding of Cardiopoiesis The scientific understanding underlying C-Cure, designed to convert stem cells into new heart cells and repairing heart tissue, also underlies additional Cardio3 BioSciences research and development programmes in heart failure and heart attack (acute myocardial infarction). C3BS-CQR-2 Autologous therapy using Mesenchymal Stem Cells (MSCs) originating from adipose tissue and guided to cardiopoietic lineage. C3BS-CQR-2 could offer a second iteration for C-Cure, and could allow Cardio3 BioSciences to facilitate the manufacturing process due to increased cell yield and a faster population doubling time. C3BS-AQR-1 A research programme for allogeneic MSC-derived cardiopoietic cells which would be injected primarily in the setting of acute or sub-acute myocardial infarction, intended to serve as a reservoir of growth factors to activate and differentiate endogenous cardiac stem cells in order to regenerate the injured myocardium and prevent heart failure deterioration. Autumn 2010


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C3BS-AQR-2 A research programme for cardiopoietic cells derived from cardiac stem cells. Envisaged to be used in acute or sub-acute settings. The concept of C3BS-AQR-2 is based on the same concept as C3BS-AQR-1. C3BS-GQR-1 An a-cellular development programme consisting of a combination of growth factors intended to be injected in the acute phase of an infarct to reduce apoptosis and necrosis, and stimulate endogenous cardiac stem cells to limit infarct size. C3BS-GQR-2 An a-cellular research programme designed to replicate the secretome of cardiopoietic stem cells. C-Cath Cardio3 BioSciences is also developing a proprietary intramyocardial injection catheter designed to ensure accurate and safe delivery of bio-therapeutic agents with superior retention capacity. Promising results from a preclinical study carried out at a renowned preclinical research organisation in Canada were announced in 2010. A Growing Presence Based in the area of Louvain-La-Neuve, in the Walloon Region of Belgium, Cardio3 BioSciences has grown rapidly, and currently employs more than 50 people. It has developed its own research laboratories and clinical grade manufacturing facility in compliance with Good Manufacturing Practices and quality assurance standards. Cardio3 BioSciences has established strong ongoing collaborative programmes with Cardiovascular Center Aalst (Belgium) and Mayo Clinic (USA). An Experienced Management Team The Cardio3 BioSciences team, led by Dr Christian Homsy, in previous roles has gathered significant experience and expertise in developing and commercialising new pharmaceutical products and medical technologies. To complement strong in-house clinical, regulatory and business experience, Cardio3 BioSciences consults with international experts throughout the development process of products from bench to, ultimately, bedside. Cardio3 BioSciences has also developed interactive collaborations with major academic institutions, governmental organisations, and industry partners, positioning the company at the forefront of the cardiovascular regenerative biotechnology space. www.ipimedia.com

Christian Homsy, MD, MBA has served as Chief Executive Officer and member of the Board of Directors since Cardio3 BioSciencesâ&#x20AC;&#x2122; inception. Christian gained his business experience in senior research & development, marketing, business development and sales positions at Guidant Corporation, a leading medical device company active in the treatment of cardiovascular disease. He also founded the Guidant Institute for Therapy Development, a landmark facility for physician and healthcare professionalsâ&#x20AC;&#x2122; education that gained international recognition. Christian excelled in building businesses with well-respected teams, setting standards inside and outside the organisation. Christian is a physician by training, and received an MBA from the IMD in Lausanne, Switzerland. For more information contact: Cardio3 BioSciences SA Dr Christian Homsy, CEO Tel: +3210394100 Anne Portzenheim, Communication Manager Tel: +3210394100 aportzenheim@c3bs.com www.c3bs.com Citigate Dewe Rogerson Chris Gardner/Nina Enegren Tel: +44(0)2076389571 Chris.gardner@citygatedr.co.uk Hill & Knowlton Katia Delvaille Tel: +3227379500 kdelvail@hillandknowlton.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 27


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Combination Products – an IP Perspective

Background There are an increasing number of combination products entering the marketplace. The majority of these products are directed towards drug delivery technologies that combine a medical device and a drug. These drug delivery technologies focus on new ways of introducing drugs to the body to achieve controlled release of the drug and/or targeted delivery of the drug to a specific part of the body. These products can enable time release or specific dosage release of drugs into specific parts of the body, thus maximising the effect of the drug and helping to minimise any sideeffects. The emergence of combination products has led to more and more medical applications and technological advances. Combination products now treat a broad range of conditions and provide improved therapeutic results compared to the use of the medical devices or drugs alone. It has even been found that some of the new drug delivery technologies have helped increased patient compliance, which can otherwise be a big hurdle for effectively treating a condition. One example of a combination product is the paclitaxel eluting stent, known commercially as the ‘Taxus’ stent, the patent for which has been successfully defended before at least the European Patent Office, UK House of Lords (now the Supreme Court) and Dutch courts (with Forresters acting as the European and UK patent attorneys). The trend for combination products seems to be continuing, as more and more companies seek to make the most of limited resources and extend the life of existing drugs that may be coming to the end of their patent protection. It is important that the appropriate patent protection is obtained for new and advantageous combination products. 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Obtaining Maximum Protection for Combination Products A patent portfolio is one of a company’s most important assets. Patents not only provide protection for the company’s products and can be used to prevent a competitor from entering the marketplace; they can also be used as a great business tool. To gain the most from their combination products, companies need to develop a valuable patent portfolio to place them in a strong position for future ventures; be that to demonstrate the wealth of technology that has been created by the company to potential investors and clients to move the company forward, or to enter into beneficial partnerships in order to commercialise the product. This is of particular relevance for combination products that may require expertise and practical assistance from both the medical device and pharmaceutical industries. Accordingly, it is important to ensure that your patent portfolio is as strong as possible. The emergence of combination products has raised the question of how best to obtain patent protection for such products. The answer is slightly muddied by the fact that European patent law specifically excludes patent protection for methods of treatment. Therefore, the protection available is not always as straightforward as one would like! Possible Protection Theoretically, protection can be provided for the following, provided that each category of protection meets the requirements of patentability (the main requirements being that they are new and non-obvious over what is already known): • the device alone • the drug alone • the device and drug in combination • a method of making the device

• a method of making the drug • a method of integrating the drug and the device • the medical use of the drug • the medical use of the drug, in combination with the device In Europe, protection can be obtained for drugs (substances and compositions) that are limited to the intended medical use. The intended medical use can provide the new and non-obvious feature to meet the requirements of patentability. In one aspect, the medical use claims can provide protection for the drug when packaged for the medical use. It is not possible to obtain protection for the use of a device in a method of treatment, regardless as to whether or not the use of the method is new and non-obvious over previous uses of the device. Accordingly, the protection available for a combination product consisting of a device and drug must be considered carefully when preparing a patent specification. Ideally, protection should be sought for all of the categories outlined above. However, for the majority of combination products, one or both of the medical device and drug are already known and may well be the subject of patent protection independently. Therefore it is necessary to think carefully about what is new and non-obvious about the combination product. New Modes of Administration The highest appeal board of the European Patent Office, the Enlarged Board of Appeal, recently indicated that a European patent can be granted for a drug for use in a method of treatment of a disease, even where the same substance is already known for the treatment of the same disease. In other words, the new and non-obvious feature of the patent claim does not need to be Autumn 2010


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the treatment of a new disease. There must simply be a distinction between the known treatment and the new treatment that would not be obvious. For example, it may be known that disease X can be treated by administering a drug. In this known treatment, the drug is administered in the form of a conjugate; the conjugate being required because the drug itself is toxic whereas the conjugate is non-toxic and enables the drug to cross the cell membrane without causing any damage to the surrounding area. Once the conjugate is taken across the membrane of the cell, the drug is cleaved from the conjugate and treats disease X. A new treatment would be the delivery of the drug itself by way of a drug eluting stent that is placed in close proximity to the target cell. The same drug is treating disease X. However, this distinct way of delivering the drug to the target area is advantageous, because it does not necessitate the preparation of a complicated conjugate. Moreover, there may be reasons why one would not believe that the toxic drug could be delivered by way of a drug delivering stent without causing unwanted damage to the delivery site. Accordingly the new delivery method is considered to be non-obvious over the known delivery 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

method. The distinction between the known treatment and the new treatment is the mode of delivery, rather than the treatment of a new disease or the use of a new drug to treat the same disease. In light of the above, the treatment may differ by the provision of a new mode of administration of the substance, including the platform from which it is administered or by way of a new a dosage regime. It is important to note that a new mode of administration is only patentable if it is new and not obvious over the prior modes of administration. It may be that the clever part of the combination product is that a new mode of delivery is provided by the device, or the drug has a different function within the body when delivered by the device. Even if the combination of the device and drug may be known, it may be possible to protect the low dosage and/or a new unknown function achieved by the known combination at certain dosages or uses. It is also worth considering whether the device has been adapted in order to achieve the new function, which could provide the new and non-obvious feature. All of these angles need to be considered when determining how best to protect the combination product. In light of the fact that the decision is fairly recent, the exact modes of

administration that will be considered to be patentable have not yet been tested. Moreover, it will very much depend on the specifics of the case and the technologies already available in the relevant field. Therefore, it is important to ensure that all eventualities are considered when preparing a patent specification n

Jenny Donald Senior Associate â&#x20AC;&#x201C; Biotechnology. Jenny specialises in patent prosecution in the UK, Europe and elsewhere in the world. She mainly works in the fields of biotechnology, pharmaceuticals and medical devices. Jenny has particular experience of patent prosecution at the European Patent Office, including experience with opposition and appeal procedures. She also has comprehensive experience in obtaining Supplementary Protection Certificates. Jenny is a UK and European patent attorney and is a member of epi and CIPA. Email: jdonald@forresters.co.uk

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Drug Discovery, Development & Delivery

The Role of In Vitro Studies in Assessing Drug-drug Interactions

Drug-drug interactions are a common issue during drug treatment and give rise to a large number of hospital admissions within the EU. During the past 20 years, scientific progress has made it possible to predict clinically relevant pharmacokinetic drug interactions based on a limited number of in vitro and in vivo studies. In response, the European Medicines Agency (EMA) has recently released a draft guideline regarding the investigation of drug interactions (CPMP/EWP/560/95/Rev. 1, April 2010). Previously, the FDA had issued draft guidance regarding the drug-drug interaction assessment of new drugs (September 2006) and how in vitro methods in particular may be used to assess the interaction potential of new drugs. This discussion will compare the main aspects of these guidance documents with particular emphasis on the increasing importance of using in vitro methods to assess and predict drug-drug interactions in vivo. The Regulatory Landscape Since 1997, both the FDA (Food and Drug Administration, USA) and EMA (European Medicines Agency) have endorsed the use of in vitro studies to assess the drug-drug interaction (DDI) potential of new chemical entities (NCE). Over the past 10 years however, scientific progress has been rapid, fuelled by sophisticated in vitro models and in silico predictive programmes, and today, the use of modern in vitro techniques now allows accurate prediction of the DDI potential of NCEs. With a greater understanding of the enzymes and transporter proteins that determine the disposition of drugs in the body, scientists can now make more accurate extrapolations from in vitro data to the in vivo situation. In vitro data can assist in predicting the dose, pharmacokinetics, efficacy, DDIs 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and toxicity of new drugs before they enter Phase I clinical development. In addition, the data can be used to help predict inter-individual variations in drug response, giving rise to the concept of personalised medicine. To reflect this scientific progress, both the FDA and EMA have issued recent draft guidance/ guidelines1, 2 outlining what in vitro data should be obtained and how this should be presented in Investigational New Drug (IND) brochures or New Drug Applications (NDA). The overall economic evaluation of a pharmaceutical requires that adverse as well as beneficial aspects of therapy are considered. When the incidence and/ or severity of adverse drug reactions (ADRs) result in an unfavourable risk/ benefit profile, regulatory authorities contain risks by imposing restrictions. These may include restrictions regarding dose, specific patient sub-groups or the use of concomitant medications. Ultimately, of course, if the scales of risk-benefit are tipped too far, the drug may be withdrawn from the market. Consequently, the assessment of DDI and hence ADR potential is an integral and increasingly important component to drug development - and not only to the sponsor company. ADRs can cause significant morbidity and mortality amongst patient populations, thereby substantially increasing the burden on health authorities. Between 1999 and 2009 it has been estimated that over 500,000 hospital admissions in the UK alone were due to ADRs3. One major source of ADRs arises from DDIs caused by an alteration of drug metabolising enzyme activity in the body. Drugs may be viewed as either a victim drug (where the metabolism of the drug itself is affected by other drugs) or a perpetrator drug (where the drug itself causes changes to the metabolism of other drugs) The majority

of marketed drugs are metabolised in the liver by cytochrome P450 (CYP450) enzymes, and as a result the majority of DDIs result from interactions with this enzyme superfamily. Hence the majority of regulatory guidance available to assess new drugs for DDIs focuses on the CYP450 superfamily. Cytochrome P450 Inhibition Inhibition of CYP450 is the major cause of DDIs. Drugs that are inhibitors of CYP450 enzymes (perpetrator drugs) will reduce the metabolism of other drugs that are metabolised by CYP450 enzymes (victim drugs). In some cases the inhibition is so potent that the perpetrator drug is withdrawn from the market. An example of this was the withdrawal of Mibefradil (posicor) in 1998 after just a year of market release. The withdrawal came after reports of fatal interactions with at least 25 other commonly prescribed drugs. It was found that Mibefradil inhibits cytochrome P450 2D6 and 3A4 and interacted by increasing the plasma concentrations of concomitantly administered drugs (sometimes to fatal levels). Both the FDA and EMA recommend that the inhibition of CYP450 enzymes be assessed using in vitro methods, and the agencies suggest a similar study design: • a panel of [agency] recommended CYP450-selective chemical substrates and inhibitors to assess individual CYP450 enzymes • to investigate CYP450 enzymes where clinical relevance has been shown or is understood (currently these include CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) • recommendation to determine the inhibition constant, known as Ki, to help assess the potency of inhibition and in vitro – in vivo extrapolation (IVIVE). Autumn 2010


Drug Discovery, Development & Delivery FDA The FDA proposes that the likelihood of an in vivo interaction is projected based on the [I]/ Ki ratio (where [I] = mean steady-state Cmax (maximum concentration in plasma) value for total drug (bound + unbound)) following administration of the highest proposed clinical dose. If [I]/Ki >0.1 = an in vivo evaluation is recommended (clinical interaction study). EMA In the draft guideline, the EMA proposes that the risk of inhibition in vivo is evaluated by comparing observed Ki values with a worst case estimation of the unbound concentration near the enzyme during clinical use. An in vivo interaction study is recommended with a sensitive probe substrate if the conditions below are fulfilled: For an orally administered drug if the enzyme (for example, CYP3A4) has marked abundance in the intestinal absorptive cell (enterocyte): Ki < 10-fold the maximum dose taken on one occasion/250ml, or 50-fold the maximum concentration predicted in the enterocyte. For drugs inhibiting enzymes present in the liver, kidney or other organs: Ki < 50-fold the unbound Cmax obtained during treatment with the highest dose or, 250-fold the unbound Cmax for drugs with a plasma protein binding >99.0 %

For reversible inhibition, the major experimental difference between the approaches is that the FDA suggests use of total drug concentrations for Ki estimation while the EMA guideline recommends that the free fraction present in incubation mixtures be determined (particularly for basic drugs – where non-specific binding may be high) and unbound concentrations be used to estimate Ki. Time-dependent CYP Inhibition Time-dependent inhibition (TDI) of CYP450 enzymes is assessed in vitro as a potential marker for mechanismbased inhibition (MBI), which in turn can be indicative of irreversible binding of the inhibitor (drug) to the enzyme. This type of binding can lead to a prolonged period of enzyme inactivation and is also associated with idiosyncratic adverse drug reactions (IADRs). Therefore, TDI is coming under increased scrutiny by regulatory authorities. At the time of its publication in 2006, the toxicological and clinical implications of TDI were not as well understood and this is perhaps reflected by the rather 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

limited guidance regarding TDI offered by the FDA DDI guidance document1 at the time. However, the assessment of TDI has been an area of intense research by DMPK groups over the past five years, and the publication of a pharma perspective in 20094 has summarised current knowledge and provided key opinion in the area. As a result, the EMA draft guideline2, which is a more recent publication, is more explicit in its recommendations surrounding the issue of TDI, and recommends that if TDI is detected then further in vitro experiments should be conducted to determine Kinact (maximum inactivation rate constant) and Ki. Furthermore, if the TDI is due to the formation of a metabolite that reversibly inhibits the affected enzyme (rather than irreversibly inhibits the enzyme), then this also has consequences for the further assessment of the interaction in vivo. Cytochrome P450 Induction Some drugs can induce (increase) levels of drug-metabolising enzymes following repeat exposure. Although generally DDIs arising from enzyme induction tend to be of a lesser magnitude than observed with CYP inhibition (that is, a lower AUC (Area Under the Curve) shift of victim drugs is generally observed), enzyme induction can lead to decreased efficacy and/or increased formation of toxic metabolites. The FDA recommended the determination of induction potential in their 2006 guidance. In their previous adopted guideline (1997) the EMA guidance was to consider enzyme induction in a qualitative fashion which was not required for all drugs. However, similar to the arena of CYP450 inhibition, a publication of a pharma perspective in 20095 provided current knowledge and presented key industry opinion about enzyme induction, and the recent draft EMA guideline now requires the assessment of CYP induction for all investigational drugs with the following outline: • CYP1A2, 2B6 and 3A4 induction to be assessed • human hepatocytes recommended as the most relevant model • measurement of the free concentration of drug on the last day of exposure. Apart from this final aspect (measurement

of free drug concentrations) specified in the EMA guideline, the study design to fulfil both FDA and EMA guidance is similar, and involves: •c  ultured human hepatocytes from multiple donors (n = 3 recommended), exposed to multiple doses of test compound(s) at various concentrations •a  fter exposure, samples are analysed for CYP450 activity using UPLC-MS/ MS (catalytic activity) and/or real timePCR (mRNA analysis) •p  rototypical (human) cytochrome P450-inducing agents, such as omeprazole (induces CYP1A) and rifampicin (induces CYP2C and CYP3A) are included as controls to help rationalise the potency of any inductive effect(s) observed with the test compound(s). FDA The FDA proposes that a drug that produces a change that is equal to or greater than 40% of the positive control in vitro can be considered as an enzyme inducer, and in vitro and in vivo evaluation is warranted. In addition, the EC50 (effective concentration at which 50% maximal induction occurs) should be considered as a potency index for comparative studies. EMA The EMA recommends that the in vitro study is considered negative for enzyme induction if incubations with the investigational drug (at the relevant concentrations) give rise to a less than 50% increase in enzyme activity. In addition, to certify adequate assay sensitivity, any increase in activity also has to be less than 20% of the response to the prototypical inducers (rifampicin at 20 µM and omeprazole at 25 – 50 µM).

Both agencies stress the importance of other methods to identify induction, in particular the use of real time-PCR (RTPCR) to assess levels of mRNA of the relevant CYP protein. This is particularly important if the test compound has been shown to inhibit CYP450 enzyme(s), as this may mask the induction assessment if a catalytic endpoint is used as the sole index of inductive response. Enzymology Understanding which enzymes are responsible for metabolising a drug in the body is pivotal to the understanding of drug exposure and pharmacodynamics. This in turn, of course, impacts on potential DDIs, efficacy, individual response and safety. Both agencies recommend the use of in Autumn 2010


Drug Discovery, Development & Delivery vitro studies using human hepatocytes, microsomes and expressed enzymes (as appropriate) to characterise the enzymology of a new drug. These in vitro studies are termed reaction phenotyping studies, and are best conducted using radiolabelled compounds, so that the full metabolic profile of the drug can be determined. In general, it is the view of both agencies that a drug that is metabolised by multiple enzymes has a lower DDI potential than a drug that is metabolised by a single enzyme. Multiple metabolic pathways reduce the likelihood of DDIs, as the closure of one metabolic pathway (by concomitant medicines, for example) is unlikely to result in complete loss of the elimination pathway. In addition, understanding the enzymology of the drug allows a greater assessment of potential DDIs and interindividual variations in drug efficacy if, for example, polymorphic or inducible enzymes are involved. FDA The FDA recommends that companies should establish the extent to which CYP450 enzymes (currently 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) contribute to the clearance of a drug. In addition, the sponsor company should identify any other enzyme(s) (for example, FMO, MAO, UGT) that contribute 25% or more to a drugâ&#x20AC;&#x2122;s clearance (loss of such a pathway would result in a 33% increase in AUC, which is greater than what can be considered equivalent for generic equivalency). Above this threshold, the fold increase in exposure rises dramatically in response to the loss of a metabolic route that otherwise contributes more than 50% to a drugâ&#x20AC;&#x2122;s clearance. EMA The EMA recommends in particular that in vitro enzymology data is confirmed in vivo using potent CYP (or other enzymes) inhibitors. In general, enzymes involved in metabolic pathways contributing to >25% of the oral clearance should if possible be verified in vivo. This also includes any metabolites that are estimated to contribute to >50% of the in vivo pharmacological activity, and the enzymes contributing to >25% of the elimination of these metabolites should be quantified (if possible).

Drug Transporter Interactions Over the past five years, DDIs involving transporter proteins (rather than enzymes) have been increasingly identified and the development of in vitro transporter assays is an area of very active research for DMPK groups. Drug transporters can be considered to be protein pumps, embedded in the membranes of cells found primarily in the intestine, kidney and liver. Their www.ipimedia.com

function is to either pump drugs out of cells (efflux) or to transport drugs into the cell (uptake). It is interesting to note that the approach taken to study drug transporters is similar to the development of CYP technology during the 1980s90s, namely division into families, sub-families and individual proteins, identification of selective substrates and inhibitors and development of suitable in vitro models. When the FDA guidance was published in 2006, the major efflux transporter, MDR-1 (or P-gp) was the major focus of transporter interactions. However, in 2007 the International Transporter Consortium (ITC) was formed with the aim of clarifying and collating current knowledge and key opinion in the role of drug transporters in therapeutic and adverse drug response. The ITC consists of scientists from all sectors of drug discovery, development and regulatory approval, academia, industry and the FDA. The ITC met periodically from 2007 - 2009 and held an open Critical Path Transporter Workshop in October 2008, which resulted in a white paper publication6. This white paper proposed that interactions be assessed using in vitro methods for seven specific transporters, and this recommendation was subsequently endorsed by the FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee. The transporters it recommended to be assessed include those for which a clinical relevance to drug disposition has been identified, namely, the efflux transporters P-gp and BCRP and the uptake transporters OCT2, OAT1, OAT3, OATP1B1 and OATP1B3. In particular, it is recommended that in vitro testing is conducted to assess whether the new drug is either a substrate or inhibitor of these transporter proteins. Within the white paper decision trees for each of the transporters are provided outlining how in vitro data should be viewed, and the possible consequences for clinical assessment in vivo. The EMA recommends that if renal and biliary secretion account for >25% of systemic clearance, attempts should be made to identify the transporter(s) involved in the active secretion. In vitro studies investigating drug transport with and without inhibitor, or with and without expression of the

transporter, are usually the first steps of the identification process. It is also recommended to use a eukaryote system where the physiological functions are preserved and the concentrations of investigational drug should be relevant to the site of transport. Where possible, the study should involve controls verifying the presence of transporter activity. The choice of controls and inhibitors should be justified by the sponsor company and, as with CYP450 enzymes, preclinical transporter work should be completed in time to design clinical DDI studies to guide clinical trial design for exclusion/inclusion criteria and safety monitoring. This information will also be used for dosage and labelling information for approved drugs. Conclusion In vitro science has advanced greatly over the past 10 years, assisted by an increasingly sophisticated array of models and instrumentation. We now have at our disposal immortalised cell lines which are transfected with enzymes or transporter proteins (including double transfections), biogeneration of an increasing range of enzymes using mammalian cell or bacterial vectors (amongst others), cryopreserved hepatocytes that will attach for culture and human liver microsomes pooled from over 200 donor livers. We also have highpressure liquid chromatography and fast-scanning MS/MS instrumentation ever pushing the limits of detection to far lower levels. All of these factors, in conjunction with powerful in silico modelling, now allow scientists to make accurate predictions about certain kinds of DDIs in vivo. As a result, the interactions which caused high-profile drug withdrawals during the late 1990s (Terfenadine as a victim drug and Mibefradil as a perpetrator drug, for example) can now be largely predicted in the laboratory from in vitro data, and it is unlikely that this type of drug withdrawal (based upon inhibition of CYP450 enzymes) will happen again. The regulatory guidance now available for sponsors in this area provides a solid framework when considering the in vitro information required to assess the DDI potential of a new chemical entity n INTERNATIONAL PHARMACEUTICAL INDUSTRY 35


Drug Discovery, Development & Delivery

References 1. U  .S. Food and Drug Administration. Guidance for Industry, “Drug Interaction Studies–Study Design, Data Analysis, and Implications for Dosing and Labeling,” Clinical Pharmacology, September 2006. 2. E  uropean Medicines Agency, Guideline on the Investigation of Drug Interactions, Draft, CPMP/ EWP/560/95/Rev 1, 22 April 2010. 3. W  u, Tai-Yin et al, Ten-year trends in hospital admissions for adverse drug reactions in England 1999 – 2009, J R Soc Med 2010: 103: 239250. 4. T  he conduct of in vitro studies to address time-dependent inhibition 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of drug metabolising enzymes: A pharmaceutical research and manufacturers of America (PhRMA) perspective, Scott W. Grimm et al, Drug Metabolism and Disposition, July 2009 vol. 37 no. 7 1355-1370. 5. In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America Perspective: Valeria Chu, et al, Drug Metabolism and Disposition, 37:1339-1354, 2009 6. G  iacomini, K.M., et al. “Membrane transporters in drug development” Nature Reviews Drug Discovery, arch 2010; 9(3):215-36.

Guy Webber is Head of In Vitro Sciences at Quotient Bioresearch, a leading provider of early stage and specialist drug development services to pharmaceutical, biotechnology and medical device clients worldwide. His department conducts high-quality regulatory and GLP compliant in vitro studies to investigate the metabolism, DDI potential, transport and hepatotoxicity of new compounds in drug discovery and/or development. His previous companies include GlaxoSmithKline and another major CRO. E-mail: Guy. webber@quotientbioresearch.com

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Drug Discovery, Development & Delivery

Near-Infrared Fluorescent Probes for Optical Imaging of Disease

Optical imaging is a rapidly developing biomedical technology that enables the examination of cellular processes in the context of a living animal. Fluorescent proteins and bioluminescent reporters are useful for optical imaging of laboratory animals, but targeted agents labelled with nearinfrared fluorescent dyes have the additional potential to translate to human clinical use. Here we review several optical imaging technologies currently in use, with a particular focus on targeted near-infrared (NIR) fluorescent optical probes. Optical Imaging Modalities Optical imaging can be used to noninvasively interrogate an animal model for the progression of a disease, determine the effects of drug candidates on the target pathology, assess the pharmacokinetic behaviour of a drug candidate, compare candidate drugs for target binding affinity, and develop biomarkers indicative of disease and treatment outcomes. Three widely-used optical imaging modalities offer the potential for high sensitivity and good spatial resolution. Bioluminescent imaging is based on emission of visible light within the living animal. Firefly luciferase is expressed by genetically modified cells that have been transplanted into animals. The luciferase enzyme produces light through oxidation of a luciferin substrate, which is administered to the animal by injection or inhalation. Bioluminescence is widely used in laboratory animals, but this approach requires transgenic cell lines and is therefore not easily translated to clinical practice. In a second approach, modified cells that express fluorescent proteins are used to mark tumours. Transgenic cells can be implanted into animals and, 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

following excitation with an appropriate light source, the fluorescence from the expressed fluorescent proteins can be detected with a CCD camera. The excitation and emission wavelengths of commercially available fluorescent proteins generally fall in the visible region of the light spectrum. Performance in this region can be compromised by tissue autofluorescence and non-specific background (discussed below). Like bioluminescence imaging, fluorescent protein methods require genetically modified cell lines and cannot be translated to the clinic. A more flexible and direct approach employs targeted imaging agents (such as antibodies, receptor ligands, small molecules, or peptides) that are labelled with fluorescent dyes. The fluorescent labels can be visualised by excitation with an appropriate light source, and the emitted photons captured via a CCD camera or other optical detector. Fluorescent Optical Imaging Two important factors govern the performance and success of fluorescent in vivo imaging: absorption and scattering of excitation light, and detection of emitted fluorescence. Maximising the depth of tissue penetration is a fundamental consideration for optical imaging. Absorption and scattering of light are largely a function of the 1 wavelength of the excitation source , and in general, light absorption and scattering decrease with increasing 2 wavelength . At wavelengths <700 nm, tissue components such as oxy- and deoxyhemoglobin, melanin and lipids 2-4 display high absorption coefficients . This results in small penetration depths 1 of only a few millimetres , and allows only superficial assessment of tissue features. However, in the NIR region (700 nm-900 nm), the absorption coefficient of tissue is much lower, and light can

3,5

penetrate more deeply . Sensitive detection of emitted fluorescence from the targeting agent is also required. Tissue autofluorescence is a key determinant of detection sensitivity, because fluorescent signal from the probe must significantly exceed the background fluorescence. At visible light wavelengths (up to 700 nm), autofluorescence of tissue compounds 3,6,7 is significant and can interfere with 7 detection of the fluorescent probe . In contrast, tissue autofluorescence in the near-infrared wavelength range (700-900 1,5,7 nm) is much lower . The combined advantages of low absorbance and low autofluorescence at NIR wavelengths deliver high performance for in vivo optical imaging. Near-Infrared Optical Imaging Optical imaging requires NIR fluorescent dyes with high molar extinction coefficients, good quantum yields and low non-specific tissue binding. Several commercially-available fluorophores have been used for optical imaging, including IRDye® 800CW, IRDye® 680, IRDye® 700DX, Cy®5.5, and Alexa® Fluor 750. The excitation/emission ranges for these dyes are shown schematically in Figure 1. Quantum dots have also been used, but their size often precludes efficient clearance from the circulatory and renal systems, and there are questions about their long term 4 toxicity . A number of studies have been published using NIR dyes. Two of the dyes commonly used for optical imaging are Cy5.5 and IRDye 800CW. The excitation/emission maxima of Cy5.5 (675 nm/694 nm) do not fall in the most 1-3 favourable spectral region for imaging . In contrast, the more recently-developed IRDye 800CW fluorophore (ex/em 785 nm/810 nm) is precisely centred in the region that yields optimal signal-toAutumn 2010


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Drug Discovery, Development & Delivery

40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1. Molar extinction coefficient characteristics of water, hemoglobin (Hb), and oxygenated hemoglobin (HbO2). Emission wavelengths are shown for Cy®5.5 and IRDye® 800CW.

Cy 5.5

Extinction Coefflent (Hb/Hb02)

1,000,000

IRDye® IRDye® 680 &700DX 800CW

1.000

100,000 10,000

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1000 100

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Extinction Coefflent (Water)

background in optical imaging (Fig. 1; 1,5,7 ref . An intravenous toxicity study of 8 IRDye 800CW was recently published . A direct comparison of visible and near-infrared fluorophores for molecular 7 imaging was reported in 2007 . Epidermal growth factor (EGF) was conjugated with Cy5.5 or IRDye 800CW fluorophores, and used for targeted imaging of EGF receptor (EGFR) positive breast cancer xenografts. Although both agents targeted EGFR, use of the IRDye 800CW conjugate reduced background fluorescence and dramatically enhanced tumour-to-background ratios. This study indicates that NIR fluorescent labels may greatly improve molecular imaging performance. The performance of IRDye 800CW has also been compared to radiochemical detection in animal studies. Using gamma scintigraphy and NIR imaging, Houston et al. compared the ability of a cyclopentapeptide dual-labelled with 111indium and IRDye 800CW to image v3-integrin positive melanoma 9 xenografts . The tumour regions were clearly delineated by optical imaging of the IRDye 800CW fluorescent signal, but tumour boundaries could not be identified by scintigraphy due to high noise levels. Dual-labelled trastuzumab imaging agents have been evaluated for combined PET and NIR 10,11 fluorescence imaging for detection of HER-2 overexpression in breast cancer. Trastuzumab labelled with 64Cu and IRDye 800CW was able to identify distant metastases. In addition, NIR fluorescence imaging permitted visualisation of channels between the primary tumour and axillary lymph nodes. Dual-labelled trastuzumab may be useful as a diagnostic imaging agent for staging of HER-2-positive breast cancer patients and for intraoperative 11 resection . The epidermal growth factor receptor (EGFR) is overexpressed by many cancers. To exploit this characteristic, IRDye 800CW – EGF conjugates can be used as targeting agents to image progression and metastasis of 7,12-14 orthotopic prostate tumours . In vivo fluorescence of the EGF targeting agent was dramatically enhanced in tumours (Fig. 2a). Binding specificity of the fluorescent agent was demonstrated by pre-injection of animals with a blocking antibody against the EGF receptor,

0.001 400

500 Hb

600 700 800 Wavelength (nm) Hb02

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Figure 2. Tumour imaging with NIR fluorescent probes. Probe fluorescence is shown in pseudo-colour, overlaid on white light images. Images captured with LI-COR® Pearl® Imager. A) Subcutaneous prostate tumour detected with IRDye® 800CW – EGF. B) Subcutaneous prostate tumour detected with IRDye 800CW 2-deoxy-D-glucose.

7,12

which greatly reduced tumour signal . In this animal model, tumour size correlated well with intensity of probe 12 fluorescence . EGFR-specific Affibody molecules have also been used for NIR 15 fluorescent imaging of tumours . The increased glucose metabolism of cancer cells is an appealing,

broadly-applicable imaging target. PET imaging is widely used to detect uptake of 18FDG, a radiolabelled glucose mimetic. However, the specialised instrumentation and unstable isotope required for PET imaging can be impractical. IRDye 800CW conjugated to 2-deoxyglucose (2-DG) has been Autumn 2010


Drug Discovery, Development & Delivery evaluated as an optical targeting agent (Fig. 2b). Dose-dependent uptake of this probe was observed for several tumour types, and fluorescence microscopy confirmed localisation of the conjugate 16 to the cytoplasm . Specificity of uptake was confirmed in several ways: blocking by excess unlabelled 2-DG or D-glucose; stimulation of uptake by a phorbol ester activator of glucose transport, and blocking of uptake by an antibody against the GLUT1 glucose 16 transporter . For animal imaging, targeted NIRlabelled ligands can be used to visualise virtually any pathology, without the genetically modified cell lines required for imaging of bioluminescence or fluorescent proteins. Another key advantage of NIR optical imaging is its potential to translate into the clinic for image-guided surgical resection of tumours, real time assessment of surgical margins, and detection of lymph node metastases. The Zeiss Pentero and Leica FL800, currently used with indocyanine green for angiography and resection of aneurysms, can also be used for these purposes. In addition, 17 De Grand and Frangioni , Gurfinkel et 18 3 al. , Hawrysz and Sevick-Muraca , and 19 Chen et al. have described NIR-based imaging instruments that have yet to be commercialised or taken through clinical trials. Several new instruments from Fluoptics, Surgoptics, and O2View, designed specifically for image-guided surgery, are in clinical evaluation. NIR fluorescent labels, such as IRDye 800CW, offer the potential for good spatial resolution and sensitive detection of targets in both small animal and clinical imaging. In the future, NIR imaging technology is poised to augment surgical imaging technologies and may improve clinical outcomes and prognosis n References 1. L icha, K. Contrast agents for optical imaging. Topics Curr. Chem. 222, 1-29 (2002). 2. T  romberg, B. J., Shah, N., Lanning, R., Cerussi, A., Espinoza, J., Pham, J., Svaasand, L., and Butler, J. Noninvasive in vivo characterization of breast tumors using photon migration spectroscopy. Neoplasia 2, 26-40 (2000). 3. H  awryz, D. J. and Sevick-Muraca E. www.ipimedia.com

M. Developments toward diagnostic breast cancer imaging using nearinfrared optical measurements and fluorescent contrast agents. Neoplasia 2, 388-417 (2000). 4. F  rangioni, J. V. In vivo near-infrared fluorescence imaging. Curr. Opinion. Chem. Biol. 7, 626-634 (2003). 5. S  hah, K. and Weissleder, R. Molecular optical imaging: applications leading to the development of present day therapeutics. NeuroRx 2, 215-225 (2005). 6. W  agnières, G. A., Star, W. M., and Wilson, B. C. In vivo fluorescence spectroscopy and imaging for oncological applications. Photochem. Photobiol. 68, 603-632 (1998). 7. A  dams, K. E., et al. Comparison of visible and near-infrared wavelengthexcitable fluorescent dyes for molecular imaging of cancer. J. Biomed. Opt. 12, 024017 (2007). 8. M  arshall, M., Draney, D., SevickMuraca, E. M., and Olive, D. M. Single dose intravenous toxicity study of IRDyeŽ 800CW in Sprague-Dawley rats. Molecular Imaging and Biology. DOI: 10.1007/s11307-010-0317-x (2010). 9. H  ouston, J. P., Ke, S., Wang, W., Li, C., and Sevick-Muraca, E. M. Quality analysis of in vivo near-infrared fluorescence and conventional gamma images acquired using a dual-labeled tumor-targeting probe. J. Biomed. Optics. 10, 054010-1-11 (2005). 10. Sampath, L., Kwon, S., Ke, S., Wang, W., Schiff, R., and Sevick-Muraca, E. M. Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer. J Nucl Med. 48, 1501-10 (2007). 11. Sampath, L., Kwon, S., Hall, M. A., Price, R. E., and Sevick-Muraca, E. M. Detection of cancer metastases with a dual-labeled near-infrared/positron emission tomography imaging agent. Transl Oncol. 3, 307-217 (2010). 12. Kovar, J. L., Johnson, M. A., Volcheck, W. M., Chen, J., and Simpson, M. A. Hyaluronidase expression induces prostate tumor metastasis in an orthotopic mouse model . Am. J. Pathol. 169, 1415-1426 (2006). 13. Kovar, J. L., Volcheck, W. M., Chen, J., and Simpson, M. A. Purification method directly influences

effectiveness of an epidermal growth factor-coupled targeting agent for noninvasive tumor detection in mice. Anal. Biochem. 361, 47-54 (2007). 14. Kovar, J. L., Simpson, M. A., SchutzGeschwender, A., and Olive, D. M. A systematic approach to the development of fluorescent contrast agents for optical imaging of mouse cancer models. Anal. Biochem. 367, 1-12 (2007). 15. Gong, H., Kovar, J., Little, G., Chen, H., and Olive, D. M. In vivo imaging of xenograft tumors using an epidermal growth factor receptor-specific affibody molecule labeled with a near-infrared fluorophore. Neoplasia. 12, 139-49 (2010). 16. Kovar, J. L., Volcheck, W., SevickMuraca, E., Simpson, M. A., and Olive, D. M. Characterization and performance of a near-infrared 2-deoxyglucose optical imaging agent for mouse cancer models. Anal. Biochem. 384, 47-54 (2009). 17. De Grand A. M., Frangioni J. V. An operational near-infrared fluorescence imaging system prototype for large animal surgery. Technol. Cancer Res. Treat. 2, 553-62 (2003). 18. Gurfinkel, M., Ke, S., Wen, X., Li, C., Sevick- Muraca, E. M. Near-infrared fluorescence optical imaging and tomography. Disease Markers 19, 107-121 (2003). 19. Chen, Y., Intes, X., and Chance, B. Development of high-sensitivity near infrared fluorescence imaging device for early cancer detection. Biomed. Instru. Technol. 39, 75-85 (2005).

Mike Olive is Vice President of Translational Research at LI-COR Biosciences. He received his Ph.D. in medical microbiology from Loyola University, Stritch School of Medicine. He has held senior executive positions at Vysis, Third Wave Technologies and Applied Spectral Imaging before joining LI-COR. Email: mike.olive@licor.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 41


Drug Discovery, Development & Delivery

The Role of Outsourcing Cryostorage in the Future of Regenerative Medicine Regenerative medicine using human stem cells to repair or replace tissue or organ functions lost through age, disease, damage or birth defects is a fascinating subject for the man in the street, as is the possibility of finding cures for Alzheimer’s disease, autism, diabetes, Parkinson’s disease, schizophrenia, and other devastating disorders. Current scientific research on cells and tissues could play a vital role in the next stage of clinical medicine. The ability to obtain a plentiful supply of quality samples is therefore crucial to their studies. Stem cells can come from a variety of sources, such as embryo tissue and adult tissue, and each has different characteristics. The practice of collecting and storing specimens of cells, tissues, blood, and human flesh is clearly understood. Although innovation in the field of biobanking is progressing with the advent of automated systems, the current financial climate is restricting funding and the science of bio-preservation is still considered an esoteric speciality. Preventing Cell Damage Cryopreservation at very low temperatures, typically 77K or minus 196°C (the boiling point of liquid nitrogen), is a process where cell biology - whole biological tissues, including biochemical reactions, that would lead to cell death - is preserved. Cryogenic storage at these very low temperatures is acknowledged to offer an indefinite permanence to cells, although the actual longevity is somewhat more difficult to ascertain. However, when vitrification solutions are not used, the cell biology being preserved is often damaged due to freezing, during the approach to low temperatures or warming to room temperature. These multifarious factors led Vindon 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Scientific to believe the clear way forward for the biopharmaceutical and related industries is to implement an outsourcing affiliation with a respected organisation. This makes more sense than ever in today’s difficult economic climate, as the investment in expensive capital for in-house facilities can exert extreme pressure on a company’s cash flow. But you do need a company that is actively involved in the study of the behaviour of materials at these temperatures, with state-of-the-art facilities to match. Your chosen outsourcing partner should be able to provide a full range of services to store and manage biological materials at any given temperature. From barcoding frozen vials, to relocating an entire repository, the quality policy should be reinforced by a positive commitment to your needs. This starts with an assurance that samples will be stored in a high security facility with convenient access. All staff should be fully accountable and provide a service that complies with regulatory requirements. Cryogenic Storage Solution The storage of biological samples also necessitates an inventory management system that is precise and straightforward to access. Vindon’s Cryobank is a worldwide biorepository for the collection and storage of biological materials. These biospecimens can be tissue, stem cells, bacterial cultures, blood and even environmental samples. Therefore it is vitally important that the location of these samples is easily traceable should access be required. The automated system at Vindon creates a comprehensive cryogenic storage solution, which is accurate and fully traceable through an electronic audit trail. The sample control solution provides peace of mind for Vindon’s customers, who entrust these important samples for

potential, possibly life-saving, use in the future. It allows full details of the location and customer data for each sample at the touch of a button. The system has helped to facilitate the integration of a sample tracking process that has proven to be a precise and comprehensive tool for the management of all of our biological samples. Utilising the skills of a leading biobank as a partner will enable whoever uses the facility to exploit modern technology in their quest for increased efficiency and cost savings. Application Overview Vindon’s inventory management software (VIMS) provides a comprehensive management tool for your specimens. The VIMS system stores the precise location of each sample. It identifies the cryofreezer reference, rack reference, shelf or drawer reference and unique box and sample reference. All activities such as residency, removals, moves and relocations are recorded with the individual’s identification, plus the precise time, date and action. Vindon’s cryogenic storage solution uses barcodes and mobile terminals to enable the easy location of samples within the cryobank storage facility. It is extremely important to keep a record of the exact location of the individual sample for quick and easy extraction when required. Samples are received and their data is uploaded onto the stock control system, eliminating the need for tedious manual input. This data contains comprehensive information about the individual customer. It is therefore imperative that the information is logged into the system correctly. A secondary advantage of eliminating manual input is that the chance of human error in this important data entry process is removed. Once entered into the system, samples can then be put into storage. Autumn 2010


Drug Discovery, Development & Delivery

Foolproof Labelling The location of each sample is stored by scanning a series of barcode labels, using a Honeywell Dolphin 7600 scanner. Each cryofreezer is barcoded externally, using a 2D barcode label. Every rack within the freezer has a unique barcode label, as has every drawer within the rack, where samples are stored in barcode labelled cassettes. Up to ten cassettes can be accommodated per drawer. It would be impossible to remember the location of each individual sample. Having a paper audit trail is time consuming and data can easily be mislaid. So the automated audit trail provided by the inventory management system is a perfect solution because it is accurate and quick to use. The barcode labels used have been manufactured to survive in freezing temperatures down to -196째C, which ensures that the barcode data on each sample does not become damaged over time. The barcodes can be accurately scanned and read for future identification. Once the location of a sample is fixed, the data is stored within the Vindon inventory management system, whether that is for just one day, or over fifty years. Cryopreservation Limitations Cryopreservation is generally easier for small samples and individual cells. As they only need a low amount of toxic cryoprotectant, they can be cooled quickly. Therefore, the goal of cryopreserving human livers and hearts for storage and transplant is still some time away. Nevertheless, suitable combinations of cryoprotectant and regimes of cooling and rinsing during warming, often allow the successful cryopreservation of biological materials, particularly cell suspensions or thin tissue samples. Examples include: www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 47


Drug Discovery, Development & Delivery • Semen • Blood • Special cells for transfusion • Stem cells • Umbilical cord blood •Tissue samples like tumours and histological cross-sections • Oocytes • Ovarian tissue Cord Blood Storage The first cord blood transplant was performed in 1988 to treat a five-yearold patient with Fanconi’s Anaemia, a fatal blood disorder. Since that first successful transplant, more than 10,000 further cord blood transplants have been carried out to treat a wide variety of diseases including: * Leukaemia, lymphoma and other cancers * Bone marrow failure * Haemoglobinopathies * Histiocytic disorders * Myelodysplastic and myeloprolierative disorders * Inherited metabolic disorders * Inherited immune system disorders In the USA, cord blood has become the most frequent source of stem cells for transplantation in children. Along with ongoing research to improve the use of cord blood in stem cell transplants, a significant amount of research is being conducted to explore the application of cord blood in the field of regenerative medicine. Currently, there are ongoing clinical studies investigating the value of cord blood in the treatment of brain injury, cerebral palsy, type 1 diabetes, heart disease and critical limb ischemis. Congress is keen to move forward with stem cell research after some years of inactivity. President Obama has pledged to lift the ban on federal funding for embryonic stem cell research, and has stated that he will vigorously support scientists to this end. It is estimated that, by the year 2015, there will be up to 10,000 cord blood transplants worldwide per year, using banked cord blood. It is therefore vitally important to build repositories. A crucial aspect of this programme will be the storage of cells to guarantee continued successes in this exciting arena. Reprogramming Cells There is research being undertaken at 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Tel Aviv University to develop a method for tracking adult stem cells as they regress. This is a new technology that uses molecular therapy to coax adult cells to revert to an embryonic stem cell-like state, allowing scientists to later re-differentiate these cells into specific types with the potential to treat heart attacks or diseases such as Parkinson’s. But at this point in the technology’s development, only one per cent of cells are successfully being reprogrammed. While embryonic stem cells culled from live embryos can be manipulated to become new ‘replacement’ tissues such as nerve or heart cells, some scientists believe that these reprogrammed stem cells from adults represent a safer and ethically more responsible approach. These reprogrammed human blood cells show promise for future disease research. New Sources Cells from frozen human blood samples can be reprogrammed to an embryonic stem cell-like state, according to Whitehead Institute researchers at Cambridge, Massachusetts. These cells can be multiplied and used to study the genetic and molecular mechanisms of blood disorders and other diseases. The research is reported in the 2 July issue of Cell Stem Cell. To date, most cellular reprogramming has relied on skin biopsy or the use of stimulating factors to obtain the cells for induction of pluripotency. This work shows for the first time that cells from blood samples, commonly drawn in doctors’ surgeries and hospitals, can be used to create induced pluripotent stem (iPS) cells. Using blood as a cell source of iPS cells has two major advantages. “Blood is the easiest, most accessible source of cells, because you’d rather have 20 ml of blood drawn, than have a punch biopsy taken to get skin cells,” says Judith Staerk, first author of the Cell Stem Cell paper and a postdoctoral researcher in the lab of Whitehead Founding Member, Rudolf Jaenisch. Also, blood collection and storage is a well-established part of the medical system. Outsourcing Benefits Expensive equipment, automated filling systems, computerised data logging, sample tracking software, the need to

have a licensed establishment and the requirements to meet the high standards of The Human Tissue Authority, coupled with constant audits, put considerable strain on any organisation. Outsourcing can overcome this. Cryostorage Advantages Your chosen partner should remove any tension, as their cryobank will facilitate the safe and specialised storage of human tissue and other biological materials. These are the benefits: • Samples are only stored in the vapour phase above nitrogen (-178 to 150ºC). • Cryogenic expertise and capabilities reduces costs and improves the client’s profitability. • You work with trusted and experienced experts. • You save time and money. • It can help you to grow your business over forthcoming years. • You rely on the previous successes of your partner. • Your partner can develop strategies to optimise your storage requirements. • You’ll be using an HTA-licensed establishment. • Security is provided with a 24-hour monitored alarm, on-call team and back-up systems meeting all regulatory standards n

Patrick Jackson – Business Development Director – Patrick, a qualified engineer, was recruited in 2005. He has over thirty year’s experience in project management and business development. His responsibilities include development of new markets in the UK and overseas, ongoing sales, client liaison, marketing, negotiating and overseeing commercial and technical agreements, as well as general day-to-day management. Email: patrick@vindon.co.uk

Autumn 2010


Company profile

Astra Biotech GmbH Astra Biotech GmbH is an ambitious, young biotech start-up founded in 2009, and located due south of Berlin in Brandenburg, in the Biotechnological Park in Luckenwalde. The company specialises in CE-labelled in vitro diagnostics for use with human blood samples covering a wide range of medical indications. Materials available for sale are standard (96-well MTPs) lab test-kits in ELISA and in PCR formats, as well as semi-finished products such as antibodies, antigens, conjugates and calibrators, and varied production capacities for OEM manufacturing tailored to individual customer requirements. The indications covered are: • Hormonal diagnostics Adrenal functions Fertility (SHBG, testosterone, progesterone etc) Prenatal Neonatal Endocrine • Tumor markers CA125 • Anaemia • Allergy (IgE), both total and specific and • Osteoporosis • Thrombosis • Sensitivity towards anticoagulation medication • Cystic fibrosis* • Tendency to psychological diseases*(depression and others) • Infectious diseases* and • TORCH* * Planned NPLs Astra Biotech GmbH is a young company, whose team has skills and expertise extending to almost two decades of practical experience in various R & D fields and in the entire supply chain, thus allowing for a high degree of competency and professional handling. Astra Biotech’s primary guideline is that disease prevention or monitoring is better, easier and more cost-effective than curing the condition later. Accurate and prompt diagnostics constitute the first and indispensable element in the “therapy-to-health” link. We research, develop and create our products in order to make diagnostics available for everybody. 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2010


Advertisement

Our target is to offer high-quality affordable diagnostic reagents, comparable to, and even exceeding, the products of the world leaders, to laboratories, clinics, hospitals and diagnostic centres all over the world. This philosophy, coupled with state-of-art research in the various medical fields, leads Astra Biotech to work continuously on the design of test-kits which contribute significantly to achieving this goal. Thus, the available test-kits were designed with the health considerations in mind, which allow doctors to make diagnoses to help their patients reach informed decisions based on their current state of health. Goal achievement translates into a further guideline in Astra Biotech’s philosophy towards their customers: a total product concept which takes into consideration both the fulfilment of all technical specifications, and the elements to guarantee complete customer satisfaction: product, sales conditions, scientific and marketing support and logistics all come together. We offer our customers three distinct business lines: the ELISA test-kits are one, which mainly cover hormonal and immunological indications, as well as testing for ferritin, and for a tumour marker. High quality, very stable reagents are used to produce consistently reproducible results. A further business line is our group of PCR tests, which involves testing for genetic predispositions and which is being constantly expanded to include new areas. This area is a main pillar of Astra Biotech’s philosophy of determining pre-symptomatically the existence of diseases, and bringing these under control. Thirdly, Astra Biotech considers requests for OEM manufacturing and co-operation and strives to fulfil the customers’ requirements by affording products of high quality and the support necessary for them to keep and grow their own customer base. Astra Biotech GmbH is dedicated to broadening the parameters of the development of PCR-based diagnostic tests. Genetic tests are based on the principle that testing a sample of genetic material will allow pre-symptomatically determination of whether the patient has an innate predisposition to certain diseases. This determination can occur at any stage of the individual’s life, and allows those who test as carriers www.ipimedia.com

of certain previously identified polymorphisms to be identified and thus to (a) be aware of their predisposition towards the condition tested for, (b) initiate monitoring or preventive measures, or (c) start treatment. The conditions currently covered are some which affect large portions of the population, e.g. osteoporosis or thrombosis, or testing an individual for sensitivity to certain drugs. In the first case, there are over 75 million people affected by the disease in the European Community, the USA and Japan, 12% of whom suffered disease-typical fractures. This is a prime example of a condition, the predisposition to which can be determined quite early on, allowing preventive measures to be taken. Today’s reality shows that most often these helpful measures to reduce the effect of the disease are not started in time. As a result, bone fractures can cause a substantial reduction in quality of life, if not a terminal outcome. In the latter case, thrombosis affects increasing numbers of the population and has multifactorial causes. Any one of several gene polymorphisms affecting a stage in the coagulation cascade can cause predisposition to the condition. Patients at medium risk due to environmental factors may actually be at a higher risk due to – as yet – undetermined genetic factors. For them such testing is of great use as the risk of thrombosis can result in sudden death with very little or no warning. Likewise, testing a patient prior to deciding what drug or what dosage is much more effective in prescribing the appropriate treatment, rather than making use of a “trial-and-error” method which is neither cost-effective nor patient-friendly. This is what the Pharmaco Kit accomplishes, by identifying the degree to which an individual is susceptible to anticoagulants. Further kits are currently being designed and developed to continue contributing to the world of diagnostics. We strive to continue expanding our portfolio while achieving our targets of maintaining the high and stable quality of all our products. Contact: Alexandra Ghica Phone: +49 (0) 3371 / 681-450 Fax: +49 (0) 3371 / 681-451 E-Mail: info@astrabiotech.de Web: www.astrabiotech.de INTERNATIONAL PHARMACEUTICAL INDUSTRY 49


Clinical Research

Harmonisation: Finding the Balance

Companies are faced with many challenges when expanding their business through mergers or acquisitions. This is especially true for the small- to mid-sized companies whose employees are likely to view the business as an extension of their own families. Roles must be redefined for personnel in both the existing structure and the new addition, as both find their place in the new organisation. A larger challenge, however, can loom for management as the work begins to absorb or replace the practices and processes that “have always been done this way.” In addition to benchmarking best practices across the new organisation, management must also cope with the inevitable silo protection and developing rivalries, as well as the culture shift that must happen to make a successful new organisation operational. In order to initiate a change of mindset from that of an organisation of silos to one of harmony, a starting point is to show the flow of the work processes through the new organisation. This outlines how management views the departments or teams working together, where new internal customers will come from and how existing internal customers will continue to receive services and goods. Two elements will work together in all facets of the new organisation to maximise efficiency: communication and cooperation. These are tools to be used to create a smooth transition between the old and new. Communication It seems simple to state that communication is a key to a successful merger or major change of business, but what many employees miss is that communication is a two-way street of giving and receiving. Many see 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

communication as a straightforward exchange of information. Communication is a process in which the verbal elements are integrated with non-verbal elements. In today’s business environment, email is a standard communication tool. But how many messages are misinterpreted or lost because of the absence of cues such as tone of voice or eye contact? The management team bears a significant responsibility to make sure that its actions and decisions are both explained in sufficient detail to inform and reassure the employees, and that the message is interpreted correctly. A culture of open communication is crucial to making a new organisation successful. Rather than sending out a corporate newsletter or email, management needs to consider holding a live forum for the exchange of information and ideas, especially when introducing news such as a merger that will change the very nature of the organisation. While face to face meetings are probably best for disseminating important information or building cooperative teams, it is not always feasible. In many organisations, there are multiple independent sites spanning a variety of time zones and countries. Face to face meetings are next to impossible at times, and even organising a teleconference can be difficult. Finding a “golden hour” when all the offices are open to have live discussions can be a challenge. Otherwise, individuals end up communicating through a string of emails or playing phone-tag with their counterparts at the different sites. This is not the optimal method of communication. Managers at all levels should strive to promote an open door policy and show through serious discussions that different points of view are both accepted and valued. If an employee knows they can openly relay concerns,

they are more likely to be open to and supportive of change. On the flip side, however, employees also need to be aware that once decisions are made, full support is expected. Showing support to the face of management then speaking negatively about the change in the break room not only creates a divide between employees and management, it creates a false sense of solidarity. This top-to-bottom chain of communication is vital so that employees maintain a sense of belonging to the organisation even through its transformation. It can also provide motivation to become part of the decision-making process and give employees a greater interest in seeing the new organisation succeed. When employees feel a part of the process, they are likely to be less protective of silos and more willing to change. The communication chain must also originate in a bottom-to-top scenario if employees want management to know their needs, concerns or ideas. This is equally important when employees are faced with changes in the existing structure of independent departments. They must realise that aligning these needs, concerns and ideas with the overall goals of the corporation will provide a greater chance of accomplishment. Change is inevitable, and the earlier employees embrace the idea and become a part of the culture shift, the more smoothly things will run in the long term. There is truth to the adage, “don’t fix what isn’t broken,” but there is also truth to the Les Brown saying, “You can’t expect to achieve new goals or move beyond your present circumstances unless you change.” Cooperation Building excellence into a new organisation is not easy. Like building character, it takes time and patience. Autumn 2010


Clinical Research Of all the resources in short supply these days, however, these two seem to be particularly scarce. This is not a project that can be completed either. It is one that occurs on an ongoing basis and one that is built on a foundation of cooperation. Similar to the task of communication, cooperation is a dual role that is championed by leaders and followers alike. Expansion creates a competitive atmosphere. Existing employees may feel threatened in the new organisation. They may have been the sole subject matter expert in one area and now there are more joining the organisation. Additionally, an employee once considered an heir apparent to a higher position may now see others who could capably serve in the role, and worry the promotion is no longer imminent or guaranteed. On the other side, new employees will feel the need to justify their worth and laud their own accomplishments and strengths. It would be easy for both factions to simply dig in and wait out the inevitable changes, but the greatest benefit will be seen by both if they focus on building cooperative teams rather than independent silos. For management, the best way to promote cooperative team building is to reward team efforts as much as, perhaps even more than, individual contributions. There are undoubtedly some areas of the business where teams will not be viable. Sales is an area that comes to mind, especially given the fact that sales is often commissioned-based rather than a straight salary. Nothing will close up lines of communication more than the thought of losing income. But, even here, there can be a sharing of information and ideas, as long as the individuals contribute to the overall team with equal parts honesty and unselfishness. After all, they are working toward the same goal – a successful sales effort. Cooperation is born at all areas of an organisation, but employees will have to accept that some decisions are going to be made at a corporate level. What management can do to keep employees involved and positive about these changes is to welcome their input on how some changes will be rolled out to the entire organisation. This can mitigate a natural resistance to big changes, as well as empower employees to control how the change impacts them directly. 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

For example, a mid-sized accounting firm wanted to make significant changes to the health insurance selections in its benefits package. The cost of maintaining the existing plan had become problematic due to the costs of a handful of employees with catastrophic medical issues. The HR department had two choices: a 20% increase in the premium cost to its employees or offering an alternative high deductible option with lower premiums. A team was created with representatives from across the organisation. As expected, there were strong opinions in favor of or in opposition to each idea, so the team elected to roll both plans out and allow the employee to make a choice. Because the high deductible plan was new, the team didn’t expect a high rate of acceptance, aiming for ten percent of employees to join. Meetings were organised to explain the options. In the end, nearly 50% of the employees opted for the new high-deductible plan. The acceptance rate astounded the team. When employees were asked, they indicated that being given a choice was preferable to having the choice made for them. In the end, harmonising business practices and teams will come down a

joint effort between management and employees. Maintaining open lines of communication will create better avenues for a cooperative mentality. When given a choice, or at least given the opportunity to have serious input, team members are more likely to be accepting of additional responsibility and taking ownership of major changes n

Kathleen Hodges – Vice President of Quality. Reporting directly to the CEO, Kathleen Hodges has corporatewide responsibility for all matters relating to quality and regulatory issues. She joined BASi in May 2008, bringing a rich background in quality, documentation and compliance in the pharmaceutical industry. Kathleen holds a BS in Chemistry from Millsaps College and an MS in Technical Writing from Utah State University. She is a Certified Quality Auditor and a Certified Manager of Quality/Organization Excellence. Email: khodges@basinc.com

Autumn 2010


Clinical Research

Basic Biostats for Clinical Research Multiple Comparisons in Drug Development, Part I In clinical trials we often make comparisons. A common example is to compare the result for a test drug treatment group (perhaps how much an investigational antihypertensive drug lowered blood pressure) with that for a comparator treatment group (which could be a placebo or an active control). In everyday language, this comparison can be framed as a question: are the responses to the investigational drug and the comparator drug different from each other? In statistical language, we ask this question more precisely: are the responses statistically significantly different from each other? Statistical methodology then provides a quantitative determination of whether or not the responses are likely to be truly different from each other. This is the realm of hypothesis testing, inferential statistics, and statistical significance. In many cases we are interested in making just one comparison. However, in other cases we wish to make more than one comparison, which means that we have to face the statistical challenges that accompany multiple comparisons. Multiplicity can have a significant impact on clinical trials, in the design, in the analysis of the data, and in the interpretation of the results. It can show up in several ways: 1. M  ultiple comparisons among the treatment groups; 2. C  omparisons of different endpoints; 3. C  omparisons of endpoints at different timepoints; 4. Interim analyses; 5. A  t the programme level.

interpretation of the analyses conducted is to be legitimate. Accordingly, this article provides examples of how the challenges of multiplicity can arise, discusses possible misinterpretations that can occur if an appropriate

methodology is not employed, and introduces some statistical methods for appropriately accounting for multiplicity. This paper covers the first three of the five categories listed above. Part II of this series will address the others.

If appropriate statistical methodology is employed, the challenges of multiplicity can be dealt with perfectly satisfactorily. However, in order to employ one of several possible methodologies, one must recognise that such a methodology must be employed if the 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2010


Clinical Research The Essence of Hypothesis Testing Good clinical research requires a useful and well-constructed research question that can be answered by a diligently designed, executed, analysed, and interpreted clinical trial. Two key qualities of a useful research question are that it is specific (precise) and it is testable. The question “Do we think that this drug might be kind of good for people?” is not useful in this context. A better version was alluded to in the Introduction: does this investigational (test) drug alter systolic blood pressure (SBP) more than placebo?” Once this question is formulated, two hypotheses are created: the research hypothesis and the null hypothesis. (The research hypothesis is sometimes called the alternate hypothesis, nomenclature that emphasises the central role of the null hypothesis in inferential hypothesis testing.) These two hypotheses are written as follows: • Research hypothesis: the test drug alters SBP more than placebo. • Null hypothesis: the test drug does not alter SBP more than placebo. Another important term here is the treatment effect. This would typically be defined as follows: • Treatment effect: the mean response of the subjects in the test treatment group minus the mean response of the subjects in the placebo treatment group. Since all the columns in this “Basic Biostats for Clinical Research” series will take a conceptual rather than a computational approach, we will not discuss the computations necessary to answer this question. Rather, we will skip to the key part of the analysis and interpretation. The computations will produce a test statistic, and this test statistic will be associated with a probability value. All probability values are between zero and one (and sometimes expressed in percentage form as between 0% and 100%). The p-value that occurs at the end of this hypothesis testing strategy is the probability of finding an observed treatment effect in a new study that is at least as large as that observed in the study just completed, assuming the null hypothesis to be true. In other words, it represents the likelihood of 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

replicating the current results in another study, under the assumptions of the null hypothesis. The widely accepted cutoff for statistical significance is p<0.05. We say that a result is statistically significant if the p-value is less than the predefined cutoff, which in this case is 0.05. A p-value of less than 0.05 means that, if the null hypothesis were true, the chance of observing a treatment effect in a new study of at least the magnitude observed in the current study would be less than 5%. If the p-value < 0.05, this arose because of one of two mutually exclusive possibilities: (1) the null hypothesis is true, and we observed a rare event (unusual trial); or (2) the null hypothesis is not correct. Typically, we do not assume that the results are due to a statistical aberration, but are probably fairly typical given the underlying biology. Therefore, we conclude that the null hypothesis is incorrect, and the result obtained can be reasonably stated not to have occurred by chance alone. Other significance levels can certainly be used, as will be seen in this column. One is the p<0.01 level of significance. This is a more conservative level of significance, since it is harder to attain. A p-value of less than 0.01 means that, if the null hypothesis were true, the chance of observing a treatment effect in a new study of at least the magnitude observed in the current study would be less than 1%. In thinking about p-values, keep in mind that the emphasis is not on the results on the current study, but on trying

to predict what would happen in a series of new studies. Type I Errors A Type I error is said to occur when a statistically significant result is “found” when the null hypothesis is actually true. In the context of our examples here, a Type I error would occur if a statistically significant treatment effect was seen when in reality the investigational product was no more effective than the placebo. Even when making just one comparison it is possible that a Type I error can occur since, by definition, probabilities deal with probabilistic statements and not absolute statements. As noted in the previous section, a p-value that is less than 0.05 means that, if the null hypothesis were true, the chance of finding a treatment effect in a new trial of the magnitude seen, or greater, would be less than 5%. When we choose to use p=0.05 as our determination of the presence or absence of statistical significance, i.e., we set a=0.05, we are willing to accept a 1-in-20 chance that a Type I error will occur. If we wish the chances of a Type I error occurring to be less than this, we need to set a to a lower level, perhaps a=0.01. In this case, we are willing to accept a 1-in-100 chance that a Type I error will occur. Once we make more than one comparison, the chances of a Type I error increase, and do so quite dramatically as the number of comparisons made increases. Table 1 lists the maximum probability of committing a Type I

Table 1: Maximum probability of committing a Type I error when each hypothesis is tested at a=0.05

Number of hypotheses tested at a=0.05

Maximum probability of a Type I error

1

0.050

2

0.098

3

0.143

4

0.185

5

0.226

6

0.265

7

0.302

8

0.337

9

0.370

10

0.401

15

0.537

20

0.642

From Durham and Turner (2008)

Autumn 2010


Clinical Research error for an ascending number of comparisons being made when each comparison (i.e., hypothesis tested) is tested at the a=0.05 level. Examples where Multiple Comparisons are Needed Let’s consider a couple of examples where researchers would want to conduct multiple comparisons. First, consider a clinical trial in which four doses of an investigational drug and a placebo comprise the five treatment arms. Five treatment groups generate 10 pairs that can be tested, i.e., 10 pairwise comparisons can be made. Any two treatment arms (and hence every pair-wise comparison) could be made using a t-test at a=0.05—but this would be an inappropriate strategy. Even if the computations within each test are conducted correctly, this strategy does not limit the Type I error rate to 0.05. Inspection of the values listed in Table 1 shows that, when 10 such pair-wise comparisons are made, the probability of rejecting at least one null hypothesis (and therefore declaring that test to show a statistically significant difference) is limited to 0.401, not 0.05. In statistical terms, this incorrect analytical strategy has resulted in an inflated Type I error. If the researchers were to conduct the 10 pair-wise comparisons in this manner, there would be up to a 40% chance that they would “find” a statistically significant difference when in fact all of the treatments have the same effect. Naïve researchers might get very excited by this statistically significant finding and proclaim that they have found something very interesting. However, the issue of multiplicity, and the considerably increased chance of ‘finding’ a statistically significant result, would actually drastically decrease the faith that could be placed in any statistically significant result that was ‘found.’ Second, let’s consider a trial that offers the opportunity for even more comparisons to be made, even though the number of treatment arms is less than those in the previous example. Consider a (fairly typical) study design with four treatment arms (Placebo, and Dose 1, Dose 2, and Dose 3 of the test drug). Imagine that the researchers are interested in four efficacy endpoints, each of which is measured at three 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

timepoints post-dosing. In the standard analysis, each dose of the test drug is compared with placebo at each timepoint, for each endpoint. That gives us 3×4×4 = 48 comparisons, each at a particular a-level. If we pick the standard a=0.05, we have up to a 91% chance of finding at least one result statistically significant, under the assumption that there are no differences in activity between the active doses and placebo. That is, there is up to a 91% chance of committing a Type I error. Again, the degree of faith that could be placed in any statistically significant different ‘found’ would be drastically reduced.

A Simple Methodology to Address the Challenges of Multiplicity The Bonferroni test takes a straightforward approach to multiple comparisons. Imagine a trial in which three doses of a drug are being compared for efficacy (e.g., how much they lower blood pressure). The doses are 10 mg, 20 mg, and 30 mg. There are three comparisons that can be made: • 10 mg vs. 20 mg; • 10 mg vs. 30 mg; • 20 mg vs. 30 mg. The strategy employed here is to make it more difficult for any of the three comparisons to attain statistical

Autumn 2010


Clinical Research significance by dividing a (usually 0.05) by the number of tests, i.e. three in this example. Hence, a=0.017 is used in each case, and this more conservative value means that it is commensurately more difficult to ‘find’ a statistically significant result that does not really exist. In the literature, this is often referred to as the Bonferroni procedure. The probability of finding at least one statistically significant difference has been reduced to 0.143/3 ≈ 0.05 (see Table 1 for the value of 0.143). Other Statistical Methodologies to Address the Challenges of Multiplicity Having seen the challenges posed by multiplicity, what are some of the strategies that can be used to mitigate the inherent difficulties of multiple comparisons? That is, how can the likelihood of committing Type I errors be reduced? Statisticians reduce this probability by two methods: 1. Reduce the number of statistical comparisons on which most interest will focus; 2. Adjust the Type I error rate to control the overall error rate for the entire trial (called the family-wise error rate). Let’s consider strategies that could be implemented in the second example we just considered, i.e., the trial with four treatment arms, four endpoints, and three timepoints of interest. We can reduce the number of tests by declaring one endpoint to be the primary endpoint, and one timepoint to be the primary timepoint. All others become the secondary endpoints, and while we may produce statistical comparisons of the secondary endpoints and timepoints, we do not trust them as much. If the comparisons of the primary endpoint fail to achieve statistical significance, one would be hard pressed to believe that a statistically significant comparison on a secondary endpoint was anything more than statistical variability. All p-value adjustments to account for multiple comparisons reduce the power of the trial. The power is defined as the probability of rejecting the null hypothesis when the null hypothesis is false; in contrast, Type I error is the probability of rejecting the null hypothesis when the null hypothesis is true. In an ideal test, we want low Type I error, and high power. Several adjustment procedures have been crafted to increase power relative to 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Table 2: Common multiple comparison procedures, and when to use them

Multiple comparison procedure

Comments

Bonferroni procedure

General procedure, often preferred by FDA because it is the most conservative.

Dunnett’s test

When multiple comparisons with a single control (e.g., placebo) are planned, but not among the other groups.

Tukey’s Honestly Significantly Different test

For multiple pairwise comparisons, this has more power than the Bonferroni.

Sidak’s test

Similar to Bonferroni, but slightly more powerful.

Adapted from Kirk (1982). The reference provides details on how to construct these comparisons

that which would be obtained by using the Bonferroni procedure; these are designed for various situations. Table 2 lists some of the more common procedures used in clinical trial analyses. In some cases, using p-value adjustment may not be desirable. Brown and Muirhead (2004), for instance, report that insomnia is a condition with a number of symptoms, but not all patients have all of them. In a trial, we may look to improve the onset of sleep, and to improve the length and continuity of sleep. Effect on either condition would be an improvement. An approach is to construct a composite endpoint. Consider a rheumatoid arthritis composite endpoint, consisting of adding together the components: •2  0% weight for improvement in tender joint count; •2  0% weight for improvement in swollen joint count; •2  0% weight for best three of the five: o Patient pain assessment o Patient global assessment o Physician global assessment o Patient self-assessed disability o Acute phase reactant.

In summary, multiple comparisons arise from either multiple treatment groups, multiple endpoints, multiple timepoints, or some combination of these. Multiple comparisons inflate the Type I error rate, and this inflation must be controlled to yield valid statistical conclusions. There are multiple methods for controlling Type I error rate: (1) reduce the number of comparisons to a primary comparison, rendering the remaining comparisons secondary or supportive; (2) use a multiple comparison procedure; and (3) for multiple endpoints when several must be primary, use a composite endpoint.

In constructing a composite endpoint, the individual components will be analysed as well, but these should be regarded as secondary endpoints and used only to support the primary endpoint. If the composite endpoint is not statistically significant, then we cannot conclude statistical significance based on the secondary endpoints, as that would inflate the Type I error rate. If the secondary results are to be believed, one must treat these as hypothesis generating tests, to be confirmed in another trial.

Dr. Rick Turner is Senior Director, Cardiac Safety, Quintiles ECG Services. He specializes in the design, conduct, analysis, interpretation, and reporting of clinical trials, with a particular interest in the cardiac and cardiovascular safety of non-cardiac drugs. He has published over 50 peer-reviewed papers and 10 books. Email: rick.turner@quintiles.com

References 1. Brown MJ, Muirhead RJ (2004) Multiple primary endpoints in clinical trials. Talk presented at BASS XI, November 2, 2004, Savannah, GA. 2. rham TA, Turner JR (2008) Introduction to Statistics in Pharmaceutical Clinical Trials. London: Pharmaceutical Press. 3. Kirk, RE (1982) Experimental Design, 2nd Edition. Belmont, CA: Brooks/Cole Publishing Company.

Autumn 2010


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Clinical Research

ePRO Solutions – How do you Choose? Regulators around the world are increasingly asking to hear the perspective of the patient in clinical trials, and as a result, the adoption of electronic methods for collecting patient-reported outcomes is increasing. Consequently, patient selfreported data are increasingly playing a key part in areas such as understanding efficacy and quality of life, patient recruitment, symptom and safety information and medical compliance monitoring. Increasingly therefore, drug developers are facing a new challenge in choosing the ePRO modality which is most likely to help generate the highest quality, most cost-effective data for specific scientific requirements. At the beginning of 2010 it was predicted that 30% of new global clinical trials would employ subjective patient data as their main form of clinical trial assessment1. Traditionally paper diary collection has been the standard method for patient assessment. However, the last decade has seen the industry begin to embrace electronic initiatives such as electronic patient reported outcomes (ePRO) to help streamline the clinical trials process, maintain regulatory compliance and monitor patient safety. The most recent example of this is in the area of suicidality assessment. There is a wide variety of technologies available for sponsors who choose to capture patient reported outcomes data electronically, all of which offer significant benefit when compared with paper-based diary methods. Sponsors now have many options to select from in order to identify the ePRO method that best fits their trial needs. The four main methods accepted by Regulatory authorities are hand-held devices such as PDA, interactive voice response (IVR), web capture solutions and the digital pen solution. ePRO devices function primarily by presenting patients with questions 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

that will automatically vary depending on the responses received. The devices typically facilitate compliance with routine reminders, alerting patients when to take medication, complete diary entries and submit their data to the clinical trial site. Advances in both technology and the methodology of real-time data collection have enabled researchers to capture reliable and accurate data from patients. The solutions have increasingly become more sophisticated, with their development reflecting the diverse needs of sponsors. The implications of communication technologies on the accuracy and overall success of clinical trials are significant, with ePRO overcoming many problems associated with traditional paper methods. Problems that can be mitigated or removed by ePRO include patient failure to enter data at the correct time and the resulting tendency for patients to ‘invent’ data, high numbers of queries and a long time period to database lock. By eradicating third party involvement and possible clinician bias, ePRO also facilitates a higher level of data accuracy and reliability. Selecting an ePRO Tool There are four key areas of concern which must be considered before the selection of an ePRO tool. These are patient compliance, the presence of visual data, established protocols and site limitations. It is also essential to consider factors such as patient population, the indication and budget requirements before embarking on a project. The patient reporting process must be able to fit into the patient’s everyday life to ensure the success of the clinical trial and reduce falsified data resulting from non-compliance which threatens data validity. Therefore protocol and patient compliance must be part of the design, execution and write-up of a trial. To

facilitate patient compliance, it is vital for sponsors to select a single provider that can offer a comprehensive, unbiased choice of solutions. This diversity of choice ensures the ability to tailor devices to patients’ needs, thereby increasing patient compliance and overall clinical trial success. Access to a vendor offering a diverse range of solutions provides the ability to ensure an ideal match between available technology and the scientific and operational requirements of the specific study. For example the VIAPhone solution, offered by ERT, might be used for screening or safety assessments, while the VIAPad hand-held approach, may be used in the same study for diaries completed at home. Interactive voice response (IVR) technology has been successfully implemented to optimise the collection of clinically valid and sensitive data directly from participating patients. Due to its easy availability and capacity to integrate seamlessly with other applications on the market, IVR is a popular choice amongst ePRO solutions. ERT, the leading provider of centralised services to global pharmaceutical, biotechnology and medical device companies, offers VIAPhone, an IVR device which can be utilised either via a landline phone or a cell phone. For people reluctant to embrace more innovative technologies or with reduced physical function, this provides the perfect solution, as it is easy to use. Similarly, those with busy schedules and who travel frequently can use their cell phones to feed back information. IVR automates interactions with telephone callers through a set of pre-defined intelligently branching questions, and allows a computer to detect patient responses through voice and telephone keypad inputs. IVR assessments offer several advantages over traditional paper diaries. Questions are standardised, asked and scored Autumn 2010


Clinical Research

through automated methods, and patients can access IVR assessments via telephone at investigator sites or in their own home. Currently the most popular method of ePRO is the hand-held device, which can also improve patient compliance. ERTâ&#x20AC;&#x2122;s VIAPad is a pocket-sized mobile computer device used to collect data from patients while they are at work, at home or travelling. Electronic capture on a hand-held device efficiently supplies patients with relevant questions/ items at appropriate times, making 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

diary completion less complex for the patient, therefore enabling sponsors to receive accurate, clean data with logical response structures. The compact devices are programmed to collect data in logical and accessible formats. Questions which require a visual representation of scales can easily be placed on the hand-held device platform. Adaptable touchscreen technology for those with physical impairments such as arthritis or motor disorders greatly improves compliance and quality. If a client requires visual scales and

graphical elements to be utilised in collected data, a device such as IVR is often not the most suitable approach. Typically, the IVR and digital pen modalities are best suited for shorter and simpler data collection. In particular the digital pen approach is useful where a paper-based scale does not currently exist in electronic format, yet there is a need to capture high quality digital data. Internet web capture and the handheld device both have the capacity to execute complex, extensive diaries and questionnaires with images and visual scales. The visual analog scale (VAS) is a widely used assessment format that allows patients to rate a variety of subjective symptoms on a continuous scale. Recent studies show that VAS ratings obtained on an electronic diary are at least as reliable as paper-based ratings, if not more so. As the global population of frequent internet users steadily increases, the usage of the internet as an ePRO collection modality is also set to further increase. The internet can be accessed either at the clinician site or in a private setting such as home, office or school. Practically speaking, internet web capture has really only been utilised via laptop and desktop computers. Internet web data capture via hand-held devices is currently under development, but has yet to be widely accepted by users and regulatory authorities alike. Many sponsors who have employed an ePRO device before may have established protocols based on the requirement of a specific device, therefore they will need a provider that offers this specific tool. With multiple clinical trials being executed, all with their own established protocols and correlating devices it is essential to have a provider that can ensure they offer the full range of available tools. Each of the distinct ePRO collection methods as mentioned have all been used for successful data submission to regulatory agencies, and each has specific utility within protocol requirements. Another important area to consider in the selection of an ePRO provider is the possibility for limitations at the site. For example, if the sponsorâ&#x20AC;&#x2122;s clinical trial is being conducted in a rural location in Africa, the sponsor needs to consider whether the provider offers devices which are practical for use in such a Autumn 2010


Clinical Research location. For this reason, selecting a provider that offers a diverse range of modalities is crucial. Cost is also a factor to consider when determining which ePRO modality to use, and is an important issue to address in the context of a modality decision regarding the best ePRO solution. Furthermore, the location of patients in a study can also have implications on mode choice. For devices, the process for managing both the shipment of and payment for handheld devices can be significant. Device setup, deployment and support may become more complex for device-based ePRO if many countries are involved. Conclusion - A Choice of Solutions In addition to enhancing the quality and integrity of data collected, the use of technology including PDAs, IVR systems, internet web data capture solutions and digital pens provide additional features that enable sponsors to take new and enhanced measurements from patients. The selection of the ideal ePRO modality is reliant on multiple factors, which

include survey complexity, length, site location, patient population, budget and size of trial. Electronic patient diaries have revolutionised the way study teams manage the clinical trial process, reducing costs, time and effort and increasing patient compliance and data quality. Today, sponsors of clinical trials have turned to a variety of R&D productivity initiatives to achieve these goals. Central to all of those activities are rapid recruitment and retention of patients, proper site and drug management, and having data collected electronically to accelerate decisionmaking and drive trial success. One size does not fit all. In order to ensure an accurate and successful clinical trial, vendors must offer technologies that are as diverse and varied as the clinical trials themselves. Bearing this in mind it is crucial for sponsors to select a single provider that can provide a fully comprehensive, unbiased and complimentary collection of ePRO approved modalities n

Mike Federico, Vice President, ePRO Solutions, ERT Inc. Michael is responsible for managing all aspects of the ePRO Solutions suite at ERT, including product development, operations and sales. The ePRO group has organized ERTâ&#x20AC;&#x2122;s capabilities into products and services to provide the complete patient experience from recruiting right through to suicidality monitoring. Prior to his current position, Michael was VP for Business Development at ERT. Prior to joining ERT six years ago, Michael spent over 20 years in systems design, evaluation and equipment management in the healthcare field,. He holds Bachelors and Masters Degrees in Engineering from Rensselaer Polytechnic Institute in Troy, New York. Email: mfederico@ert.com


Labs & Logistics

Temperature Indicators for Cold Chain Distribution Temperature indicators based on the thermal properties of chemical compounds (chemical indicators) have been commercially available for many years, providing accept/reject information for perishable goods within the food supply chain. While many believe chemical indicators may fall short of compliance with global regulations and industry best practices, these devices have, over time, migrated to last-mile cold chain applications in the life science market. In response to the increased demands for last-mile monitoring, electronic temperature indicators have emerged over the past decade as viable alternatives to chemical indicators, providing superior performance and functionality. In addition, manufacturing costs of electronic devices have dropped substantially, enabling costeffective deployments in a wide variety of applications. Considerations for Temperature Indicator Usage Time and Temperature Accuracy: Typical temperature accuracies for chemical indicators are ± 1-2ºC, as opposed to electronic devices providing accuracies of ± 0.5-1ºC. Time accuracy specifications for chemical indicators vary widely with specifications such as threshold indication after “a minimum of 30 minutes” or “within 15 minutes” of exposure above/below set point temperature. For electronic indicators, typical time accuracies are in the order of ±0.01% of elapsed time (less than a five-minute error per month of operation). Some chemical timetemperature indicators (TTI) provide evidence of the accumulated effects of temperature exposure. The dynamic temperature response of TTI’s is governed by the Arrhenius equation, 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

more specifically the activation energy (EA) of the temperature sensitive material. TTI manufacturers strive to emulate the dynamic temperature effects of the monitored product via matching EA values within the indicator. In practice, this matching is often sub-optimal, leading to substantial inaccuracies. Device Validation: Electronic indicators can be validated prior to activation and deployment. The technology enables every indicator to be tested for accurate operation during the manufacturing process, thereby establishing the veracity of the measurement for 100% of device production. Chemical indicators cannot be validated in this fashion, as validation or testing at operational time/temperature thresholds would be destructive.2 In addition, electronic indicators can typically be post-use validated by the manufacturer. Chemical indicators cannot be reset and tested after initial activation and use. Custom Threshold Alarm Settings: Most electronic indicators can be customised to fit unique transport conditions dictated by product storage requirements, packaging/pack out parameters and transportation route variability. Chemical indicators are generally offered in a limited number of time-temperature threshold or activation energy variants. Furthermore, most electronic devices can be programmed with several independent time-temperature alarm conditions. As a result, a single device can be deployed to monitor both high and low temperature limits, eliminating the need to procure, stock, and deploy multiple indicator devices for each shipment. Interface Ambiguity: Chemical-based TTI’s incorporate user interfaces that are dependent on colour-matching of the reactive material, or the determination

of a “migration” distance of the reactive material relative to a graded timescale, necessitating subjective interpretations of the results. In contrast, electronic indicators integrate user interfaces and displays that offer clear, unequivocal results of time-temperature alarm conditions. Pre-deployment Storage and Shipment Environment: Many chemical indicators must be stored and shipped within controlled conditions prior to deployment. In comparison, electronic indicators offer broad storage and shipment temperature ranges prior to deployment, since they are commonly supplied inactivated and are therefore unaffected by temperature conditions prior to start. In addition to these onerous storage and shipping conditions, some chemical indicators require specific temperature pre-conditioning protocols to ensure proper operation. In summary, these attributes highlight many of the advantages of electronic temperature indicator technology for “last-mile” cold chain monitoring applications. Viewed holistically, electronic indicators offer effective, accurate, and cost-efficient temperature monitoring in support of global regulatory requirements n

Jeff Hawkins is a Strategic Marketing Manager at Sensitech Inc. and provides product management for the company’s temperature indicator product line. Jeff has an MBA from F.W. Olin Graduate School of Business at Babson College and a Mechanical Engineering degree from University of Massachusetts. Email: jhawkins@sensitech.com

Autumn 2010


Labs & Logistics

Can Coding Technology Revitalise the NHS? The NHS is an integral part of British society. Many of us work in, or directly with it, pay taxes to fund it, and at some point everyone in the UK will have experienced its services first hand. Therefore it is a subject that many people feel passionately about, particularly as most agree that the system is struggling. Considering it deals with a staggering one million patients every 36 hours, this is unsurprising. It is no secret that the NHS has had its fair share of challenges over the years; its resources are being significantly stretched, resulting in long waiting hours in A&E and records going missing. Despite doing an impressive job with these limited resources, the National Patient Safety Agency in the UK reported that in 2007 alone there were over 80,000 NHS medication blunders; which is a lot of people, when there are simple and cost-effective ways by which such errors can be avoided. For instance, the implementation of basic data standards and automated identification systems, such as barcoded patient wristbands and medical equipment, could have a great impact. This kind of basic technology can help trusts to improve efficiency and at the same time save costs, precious time and staffing resources, and most importantly, improve the quality of patient care. As the new government has pledged to ringfence resources to support the NHS, while all other public services are experiencing dramatic budget cuts, it is even more important for money to be spent wisely. But how should they do so, and what do frontline health staff think? What are the Symptoms? In light of this debate, GS1 UK conducted independent research with hospital doctors and nurses to gauge their opinion about improving ward services 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and quality of care, as well as the role of technology in enhancing patient safety and efficiency. In partnership with leading British medical publications, GS1 UK surveyed 861 hospital nurses and 409 hospital doctors across the UK. The results of this were rather serious. The survey respondents were asked to assess how often they were unable to locate vital patient data. The findings of this research highlighted that a large number of doctors and nurses struggle to locate patient data on a daily basis, with over 20,000 doctors spending over an hour a day waiting for vital patient data, while a quarter of nurses find that patient records and lab results go missing at least once a day. When asked about the time they have to check patient data, a large number of our doctor and nurse respondents felt that they had little time to check patient records thoroughly before treating them. To be precise: • 12% of hospital doctors feel they rarely have enough time to check patient records before treating them • Only 10% of nurses feel they have the time to check patient records thoroughly all of the time Another major issue highlighted by both doctors and nurses was miscommunication, whether it is through shift handovers or the misplacement of physical patient records: • 78% of hospital doctors explained that miscommunication in multiple shift handovers is responsible for causing problems with patient care • 38% of hospital nurses believe care is compromised because patient data is not shared between different doctors These findings highlight key areas for improvement in the NHS, and the need for processes and technology to be put in place to enable key hospital staff to work as efficiently as possible, freeing up time to help them administer the best patient care possible.

Using Technology to Improve Patient Care The doctors and nurses surveyed were also asked to highlight which processes could be put in place to improve these issues and standards, the result of which was an outcry for technology that makes information available electronically, to help frontline staff work more efficiently. 48% of hospital doctors feel that the use of physical records instead of electronic systems is the cause of problems in patient care, and over three-quarters of doctors specify they’d like to see realtime electronic records in place, while 69% of doctors feel that better structured handovers would improve overall patient safety, highlighting that electronic systems and tracking need to be in place to abate existing inefficiencies. 52% of doctors believe bar-coded patient wristbands would help doctors and nurses perform their roles more effectively, with 44% of nurses feeling that barcoded wristbands could reduce patient safety incidents by 50%. Nearly two-thirds of nurses said they require a real-time view of vital stock levels, which is not currently available in many trusts. It is clear from these responses that frontline health professionals have ideas about what needs to be done to improve the NHS, but can it be done successfully and within budget? Successful, Cost-effective Treatment Given the scale of the budget deficit, whilst everyone agrees that frontline services should be protected and the government has pledged to ringfence the NHS budget, it is obvious that the service will be affected in some way. Therefore, making the best use of doctors and nurses time on wards and enabling them to treat patients quickly and effectively is key. As the GS1 UK research suggests, simple changes to the way hospitals organise wards and Autumn 2010


Labs & Logistics promote staff communication can have a major impact on the quality of patient care given by doctors and nurses. At the root of this communication is the demand from medical professionals for more realtime accurate, electronic data. The use of GS1 standardised barcodes and Radio Frequency Identification (RFID) technology has been shown to reduce errors, track medication, improve the quality of patient care and prevent counterfeit medication from entering the NHS supply chain. In turn, from an operational perspective, there are real efficiency gains, including less paperwork, reduced manual processes, automatic stock replenishment, reduced time wasted by inaccurate data sharing, and access to centralised, accurate and standardised data. This means that doctors and nurses can spend less time on administration, and more time with their patients. Technology in Action There are several examples of hospitals who have successfully implemented simple technologies and GS1 UK standards to save money and improve their processes. Moorfields Pharmaceuticals – Barcoded Hospital Medicines In response to growing demand for barcoded medicines from its customers, which include hospitals and pharmacies, Moorfields Pharmaceuticals, part of Moorfields Eye Hospital, implemented GS1 barcodes on all its products. It has benefited from a more efficient pharmacy manufacturing process by reducing labelling time, and can now uniquely identify its products quickly and easily. Moorfield’s customers can also use the GS1 barcodes in their robotic dispensing units and for automated stock control systems. Leeds Teaching Hospitals – Automated Stock Control Leeds Teaching Hospitals implemented an automated stock control system which reduced stock levels by £570,000, while improving the service level to 98% over the last three years. This has released significant nursing time from routine stock matters to direct patient care, and has improved the hospital’s efficiency. Leeds identifies 3000 medical items, including consumables and implanted 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

products, using GS1 barcodes which are scanned at its 270 stocking points throughout the hospital. Wythenshawe Hospital – Electronic Asset Tracking The use of GS1 barcodes to track and trace surgical instrument trays at the hospital has improved traceability of the decontamination process and enabled staff to store historical information on individual instruments electronically. This information can be accessed easily in the unlikely event of a recall procedure. The tracking system also ensures that the right trays are returned to the right hospital or department from its outsourced decontamination facility. Airedale NHS Trust – Barcoded Patient Wristbands Following national guidelines for patient wristbands from the National Patient Safety Agency’s Safer Practice Notice (SPN 24) and the NHS Information Standards Board for Health and Social Care’s Advanced Notice, Airedale has implemented a system that prints labels and positively identifies patients at their bedside using GS1 barcoded (Datamatrix) wristbands in 27 of its wards. The hospital is currently working on using the unique patient ID to ensure accurate labelling of blood samples and also for medication prescribing. Mayday Healthcare NHS Trust – Electronic Blood Tracking and Patient Wristbands Mayday Healthcare NHS Trust have implemented barcoding and RFID technology for its electronic blood tracking pilot to track blood from ordering through to sampling and transfusion. This helps ensure the right blood is administered to the right patient. The trust has adopted GS1 standards for its passive RFID enabled patient wristbands using unique GS1 codes to help ensure positive patient identification. Now is the Time to Revitalise With a reassessment of public spending and a government focus on exploring new methods, now is the right time to think about how the NHS can be revitalised. The results of GS1 UK’s 2010 surveys show that doctors and nurses are clear about what the fundamental issues within the NHS are, and how they

can be resolved. The simple solutions they suggest, and the previous success stories of these technologies being implemented, show that other healthcare institutions should be following suit to increase efficiency, reduce costs and, most importantly, improve patient safety. What’s the First Step? The first step is to become a GS1 UK member, which is free for all NHS Trusts in England. GS1 data standards underpin all of the technologies that frontline health staff are asking for, enabling the systems to operate at their best. The Department of Health fully recommends the use of GS1 standards throughout the healthcare system in the UK. It’s an important part of their ‘Coding for Success’ policy. Members of GS1 UK are inducted into the use of global and interoperable standards within their hospital, and gain free access to implementation guidelines, education modules and dedicated experts in their field. They also have the chance to define GS1 UK healthcare standards through working groups. With all of these resources to hand, there is no reason why the NHS cannot be cost-effectively revitalised with improved patient care and greater efficiency n Roger Lamb, has been the Healthcare Sector Manager at GS1 UK since 2006. He is part of the GS1 Global Healthcare User Group (HUG) and leads the GS1 UK healthcare team. Roger has over 25 years of international supply chain experience advising many Fortune 500 companies as well as devising and implementing innovative, cost-effective solutions to meet business critical requirements with an emphasis on the adoption of IT. Roger has significant experience of working in the healthcare sector having worked in Supply Chain Management for NHS Supplies Wholesaling, UK and NHS Central Services in Northern Ireland. Roger also previously worked for General Electric, Fujitsu and IBM. Email: roger.lamb@gs1uk.org Autumn 2010


Labs & Logistics

The Urgent Need for Qualified Transportation Providers in Global Clinical Research According to a recent study conducted by the UK-based Medicines and Healthcare Products Regulatory Agency (MHRA), a staggering 43% of critical and major product deficiencies are related to ineffective temperature control and monitoring during storage and transportation*. Similarly the World Health Organization (WHO) has maintained that 25% of all vaccine products arrive at their final destination in a degraded state**. Given the high cost of conducting global clinical trials and the even higher cost of failure, regulatory agencies and pharmaceutical companies alike now demand that every party involved in the pharmaceutical supply chain − transportation and logistics providers included − conform to GxP guidelines. What is GxP? Pharmaceutical ‘Good Practice’ embraces a variety of different processes and oversight mechanisms that apply to each sequential stage within the supply chain. Good Manufacturing Practice (GMP), for instance, pertains specifically to the production and control of marketed and investigational products during the manufacturing process, while Good Storage Practice (GSP) and Good Distribution Practice (GDP) deal with the appropriate storage and distribution of pharmaceutical products. All are guided by Good Clinical Practice (GCP), or ethical clinical trial conduct. These conventions have been designed and are accepted by the industry as the international standards for ensuring public health and safety as it relates to product quality. In recent years international regulatory agencies have worked diligently to eliminate any inherent ‘weak links’ in the supply chain, and now routinely extend their guidance documents to cover all 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

individuals or companies involved in any aspect of pharmaceutical product handling, including transport, storage and distribution. Key international guidelines currently in effect as products move off the factory floor include: • WHO’s “Guide to good storage practices for pharmaceuticals”

practices, and applies to all persons and companies involved in the storage and transportation of drug products. • Ireland’s “Guide to control and monitoring of storage and transportation temperature conditions for medicinal products and active substances”

Intended for those involved in the storage, transportation and distribution of pharmaceuticals, this document is closely linked to other existing guides (e.g. GMP), and supplements them by describing the special measures considered appropriate for the storage and transportation of pharmaceuticals. • WHO’s “Good distribution practices for pharmaceutical products”

This document provides guidance for manufacturers, wholesalers, transporters of human medicinal products and API manufacturers in Ireland in relation to conditions for cold storage / cold chain and controlled temperature storage. • EU’s “Guidelines on Good Distribution Practice of Medicinal Products for Human Use” (94/C 63/03)

A comprehensive guidance document that applies to all persons and companies involved in any aspect of the distribution of pharmaceutical products. • FDA’s “cGMP / 21 CFR 211” This document outlines general GMP rules for storage. • US Pharmacopeia (USP) <1079> “Good Storage and Shipping Practices” This document provides general guidance concerning the storing, distributing and shipping of pharmacopoeial preparations, outlining (among other requirements) storage in warehouses, pharmacies, trucks, shipping docks and other locations, as well as the distribution and shipment of pharmacopoeial articles. • Canada’s “Guidelines for Temperature Control of Drug Products during Storage and Transportation” This guide states that every activity in the distribution of drugs should be carried out according to… the principles of GMP, good storage and good distribution

This document outlines storage conditions that must be observed during both storage and transportation, as well as requirements for personnel, documentation, premises and equipment, deliveries, returns and self-inspections. Several of these guidelines − including those issued by Health Canada, USP and the EU − are currently under review. Others, such as WHO’s Good Distribution guidelines, were recently updated, underscoring the dynamic nature of the regulatory process and the diversity and complexity of today’s pharmaceutical supply chain as compared to the past. Need for Professional Partners Even with these guidelines in place, pharmaceutical practitioners can still face enormous uncertainty once clinical trial materials leave their control, unless they are working with a proven GxPcompliant logistics provider. The application of regulations in the real world presents tremendous challenges, particularly given the highly complex nature of today’s temperaturesensitive pharmaceutical supply chain. Autumn 2010


Labs & Logistics Clinical studies are now routinely outsourced to multiple and often difficult countries, where fragile infrastructures cannot ensure efficient transit times. Researchers may also be dealing with multiple time zones, extreme climates, lengthy protocol approvals and import timelines, language barriers and local unfamiliarity with the clinical trial process, among other variables. Without experienced in-country partners, it can be extremely difficult to harmonise the goals of the regulated with those of the regulators â&#x2C6;&#x2019; that is, to ensure the smooth flow of materials to and from the research sites (the goal of the pharmaceutical community) without compromising product integrity (the goal of the regulatory agencies). As a result, enforcement of global GxP compliance throughout the entire pharmaceutical supply chain has become more critical than ever, as evidenced by the current environment of increased regulatory scrutiny â&#x2C6;&#x2019; a trend that is expected to intensify. In recent months, for instance, the FDA has stepped up its efforts to identify regulatory offenders, issuing a series of warning letters for non-compliance. Similarly the Health Sciences Authority (HSA) in Singapore is currently transitioning to revised quality standards which will become compulsory in February 2011. Identifying Qualified Suppliers As a matter of course, transportation providers have increasingly gravitated towards the pharmaceutical industry over the past two decades, attracted by the geographical scope and longterm nature of clinical trials. Biological specimens once routinely shipped on dry ice have, over time, given way to the temperature-controlled transport of bulk investigational drugs and ancillary supplies that necessitate ever more sophisticated handling and increasingly stringent regulatory scrutiny. Clinical trials formerly conducted in developing nations with well established infrastructures have been moved further afield to some of the most challenging locations in the world in terms of climate, services, education and facilities. Given the number of variables potentially at play within a single clinical trial, it can no longer be assumed that every supplier can manage every type of shipment to every location, regardless of their claims. 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

What are the key considerations in choosing a transport or logistics supplier? How can you be assured that the supplier of choice has adequate experience and resources to manage the project? How can you ensure that quality guidelines in place at the point of origin extend, without compromise, throughout the entire length of the supply chain to each investigator site? How confident are you that high-value products and supplies will be appropriately managed during periods when they are not in your possession? Pharmaceutical practitioners are advised to review the following qualifications of preferred suppliers in each individual country associated with the trial. GxP-compliance: in todayâ&#x20AC;&#x2122;s exacting regulatory environment, GxP compliance is the cornerstone of responsible pharmaceutical research and development. Virtually every international regulatory agency now calls for GxP compliance throughout the entire

length of the supply chain, applying its criteria to all parties (individuals and organisations) involved in any aspect of the pharmaceutical product distribution cycle, including transport, storage and distribution. Ultimately it is the responsibility of the pharmaceutical company to ensure that its suppliers comply with all applicable regulations. The penalties for non-compliance are severe, and may include warnings, fines, declined new drug applications, and loss of partnerships and professional reputation. Working with a fully-integrated GxP-compliant transport, storage and distribution supplier ensures that the high quality standards demanded by industry are met, assures compliance with all current regulatory and ethical requirements, significantly reduces the number of parties involved in the supply chain, and decreases risk. GxP compliance also ensures that all consignments are handled in Autumn 2010


Labs & Logistics accordance with documented SOPs and with a view to minimising delays and safeguarding the integrity of materials during transit. Only a GxP-compliant service provider can deliver true process control to the pharmaceutical industry, ensure the integrity and stability of investigational drugs and biological samples used globally, guarantee the availability of independently verifiable data, and support the industry’s need to successfully qualify suppliers and sub-contractors participating in their supply chain. A GxP-compliant provider guarantees full accountability, transparency and a documented chain of responsibility including the ability to take corrective actions when required. An established network: in order to effectively establish and monitor GxP standards on a worldwide basis, qualified service providers must have strong and well-established local representation in all site locations associated with the clinical trial, not only in selected countries or cities. Local companyowned offices afford greater control on the ground, including a higher degree of specialisation due to the comprehensive and consistent training of staff; a sharing of common goals, communications and technology; network-wide adherence to standard operating procedures; and the ability to respond to problems and inquiries in a timely fashion, in the same language and within the same time zone. Some transport companies routinely subcontract site work to third-party suppliers and manage operations remotely from Europe or America in a bid to reduce costs. Over time this strategy invariably leads to communications errors, loss of control, compromised integrity of supplies or samples, and a flawed chain of responsibility. Only a well-established network can successfully manage the day-to-day application of systems and processes in every required location – both well established and especially in new growth markets. The alternative of quick-fix ‘bolt on’ solutions in select locations is not sustainable in the long term, nor can it provide the legitimate verifiable control data required by regulators. Local expertise: qualified service providers should also be able to demonstrate a thorough understanding of local regulations, the protocol approval process, import timelines, and 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

customs procedures and facilities − a capability that is particularly important in emerging markets where public agencies may not be easily accessible or formal procedures well documented. As local authorities may lack specific clinical trials knowledge, be dealing with increasing workloads and limited resources, or be hampered by language barriers, it is crucial to have experienced in-country partners working on your behalf. As a rule, conducting clinical trials in emerging markets requires additional planning and extended timelines when compared with most standard markets. A qualified supplier should be seen as a partner in the process, bringing valuable insight and expertise to the planning process and acting as an effective resource in remote locations. Once the trial is underway, its operatives should ensure that all proper import and export permits are in order, facilitate clearance, assist with and resolve customs, temperature-control or local delivery issues, and facilitate any required drug returns. Packaging expertise: depending on the design of the clinical trial, packaging requirements will vary according to temperature requirements. Consignments may need to be shipped in liquid nitrogen (-196°C), on dry ice (-80°C), frozen (-25°C to -10°C), cold (2°C to 8°C), cool (8°C to 15°C), controlled room temperature CRT (15°C to 25°C), or ‘ambient’. There may be specific instructions such as ‘Do not store/ship over/under xx°C’. Depending on the expected length of time in transit and the external temperatures at origin, destination and throughout transit, packaging configurations will vary. A qualified supplier should be able to make packaging recommendations suitable for each shipment and provide the appropriate packaging solutions. They should also be prepared to monitor temperatures both in transit and during warehousing to the degree necessary, replenish refrigerants as needed en route, and independently set and manage any required temperature monitoring devices. In Summary Although the transport and storage of investigational drugs and supplies represents only a small part of the overall quality equation, pharmaceutical

sponsors who take proactive steps to secure their supply chains now may well eliminate unnecessary risk and regulatory exposure later on. Before choosing a supplier, know that GxP guidelines are applicable to all parties involved in the supply chain including transportation providers, that compliance will be enforced by regulatory authorities, and that the pharmaceutical company is ultimately responsible for non-compliance anywhere within its supply chain. Each study is different and must be approached methodically to ensure optimum results. While the shipper must set the priorities, he or she will also need to rely heavily on the off-site expertise of others. There is no ‘cookie-cutter’ approach to clinical research, so it is recommended that pharmaceutical practitioners select their service providers with care n

Dr. Rüdiger Lomb studied Pharmacy at the Philipps University of Marburg, Germany and finished his PhD 1995 at the Christian-Albrechts University of Kiel, Germany. Since 1996 he has held several positions within the Pharmaceutical Industry, working in pharmaceutical production, drug development and Quality Assurance. He joined World Courier 2008 where he is Global Director Quality & Technical Compliance. In his role he develops and maintains the QA organization and procedures to keep World Courier compliant with current and future GxP standards. Moreover, he oversees the company´s ISO program and is responsible for technical compliance within World Courier´s companyowned network of 11 investigational drug storage facilities and more than 140 offices in 50 countries. In his most recent post prior to joining World Courier Dr Lomb was Group Head (Director) of the Global Logistics Clinical Supplies Function for Bayer Schering Pharma AG (Germany). Email: Rlomb@worldcourier.de

Autumn 2010


Company profile and abrasion resistance of novel high-tech materials, e.g. for extremely robust and efficient combustion engines. In life sciences the diagnosis of viruses is one typical application. Both microscopic techniques, light and electron microscopy, ideally complement each other. They can lead to a new depth of information if used as a combined research instrument. This is embraced by correlative light and electron microscopy (CLEM) – an imaging technology which merges the huge variety of imaging modes of optical and electron microscopy, duplicating the advantages of both methods. Practically, a specimen is firstly examined by a fluorescence light microscope. Along the way, specifically interesting sample areas are marked and subsequently probed in detail by a scanning electron microscope. Thus, CLEM enables users to understand in-depth the relation between function and dynamics on the one hand and on the other hand the morphological context of one and the same region of an object with nano-scale resolution – an aspect becoming more and more a central point of interest, e.g. in life sciences. In addition, many questions can only be answered by correlation of these different perspectives. Not least for development and testing of active substances in pharmaceutical research, this unique feature is of exceeding importance.

Joining Two Worlds in Microscopy Since its invention about 400 years ago, microscopy has vastly augmented human knowledge about nature and matter. Today, a variety of different microscopy techniques permit deep insights to diverse facets of living objects, as well as inanimate materials. For scientific and technological development, two types of microscopes are specifically valuable: optical microscopes, including fluorescence light microscopes (FLM) as a special modern type of optical microscopes using visible light for imaging, on the one hand; and scanning electron microscopes (SEM), gauging the objects with a beam of electrons, on the other hand. These instruments are widely used in materials sciences as well as life sciences, such as pharmaceutical research in particular. Each type of microscope has its unique features, enabling users to determine specific attributes of the samples examined. Fluorescence light microscopes, for example, can resolve structures down to some 200 nanometers (0.2 micrometers). The technique is intended to examine living matter, helping biologists and physicians to capture structural and dynamic information. Cells and sub-cellular compartments can be characterised or monitored in movement, delivering information on distance, speed or direction of cell motion. Furthermore, utilizing the technology of fluorescence proteins optical microscopes are used to examine biochemical processes and pathways in cells as well as in whole organisms. In all applications the outstanding benefit of fluorescence light microscopy is the ability to clarify functional and dynamic interactions. Electron microscopes, in contrast, offer an excellent resolution which is up to 100 times better than the resolution of light microscopes. Hence the electron microscopy technique is intended to exhibit subtle ultra-structural details down to just a few nanometers. This is of particularly great interest for the materials researcher, where scanning electron microscopy can act e.g. as a tool to identify small particles on surfaces, or for detailed 3D modelling of surfaces. In some laboratories, materials analysis focuses on microstructures, fractures and particles to examine special attributes like tensile strength

However, so far some serious bottlenecks have limited the operational realisation of correlative microscopy. Such is the lack of easy-to-use handling tools for the specimens examined, as well as reliable software to fulfil the need of precisely relocating regions of interest (ROI) on the sample after changing the microscope system. So far this relocation process is exhausting and time-consuming, and the search procedure for one single ROI often takes up to many hours. “Shuttle & Find”, a unique system for correlative light and electron microscopy developed by Carl Zeiss, is a breakthrough in overcoming these problems. The novel interface between wide-field light and scanning electron microscopes enables researchers to retrieve positions on a fixed specimen which has been electronically marked by one of the two microscopes within a few seconds by the other one. This progress in CLEM technology is provided by two key elements of Shuttle & Find: a transferable sample holder allowing one to smoothly slide the specimen from the light microscope to the electron microscope or vice versa (“shuttle”) in less than a minute, and a software module especially designed by Carl Zeiss for semiautomatic calibration and work routines in system operation. That module controls all functionalities necessary for both of the microscopes and, in particular, automates and accelerates the retrieval of defined regions of interest (“find”). This procedure can be carried out in contrary ways: relocation of interesting sample sites discovered by light microscopy for examination by electron microscopy, or vice versa. The result is an exact reproducibility in imaging of the sample in both microscopic techniques at widely varying resolutions. Alternatively, the images from both systems can be superimposed to an overlay image. Shuttle & Find enables researchers to connect light and electron microscopy, leading to clear time- and cost-saving benefits for users. “The reason why ZEISS could create this unrivalled simple and efficient tool for correlative light and electron microscopy was our extensive know-how as the only manufacturer of light and electron microscopes,” says Ulrich Simon, Managing Director of Carl Zeiss MicroImaging. The tool can be combined with a variety of Zeiss microscope stands. For example, the system connects all upright and inverse optical wide-field microscopes which are equipped with a motorised stage, such as, Axio Imager or Axio Observer, as well as stereo microscopes from the Discovery series with different types of Carl Zeiss electron microscopes: scanning electron microscopes like EVO, SIGMA, SUPRA, ULTRA or MERLIN, as well


Same ROI of a granite rock sample observed by Shuttle & Find with different microscopic techniques (from left to right): light microscope, SEM, and resulting overlay

as the CrossBeam workstation AURIGA. This type of workstation involves a combination of SEM and a focused ion beam to selectively and sensitively process the material under examination. Of particular advantage for the users of Carl Zeiss instruments is that microscopes already in use can be retrofitted with the correlation interface at any time, and directly in the lab. In addition, due to a consequently modular design the complete system can be configured to the specific application needs of the user. The broad spectrum of new features provided by Shuttle & Find – fast and precise superposition of optical and SEM images of functional and structural information – opens new dimensions in microscopy. It dramatically increases the amount of information that can be gained, both in materials and life sciences. After the successful implementation of the innovative CLEM solution for users working on material analysis in the summer of 2009, Carl Zeiss now offers the productive system for life science applications. The first results from researchers in both materials and life science applications illustrate the efficiency of the tool. Carmen Hafner and Timo Bernthaler, two researchers at the Hochschule Aalen, were among the first using the innovative solution in materials analysis. In collaboration with Christian Thomas, an expert at Carl Zeiss Corporate Research and Technology division, they applied the correlative microscopic systems to multimodal imaging of lithium-ion battery materials, which are of specific interest as an energy storage system for next-generation electric cars. By combining the scopes of a light microscope and a scanning electron microscope, Hafner and Bernthaler succeeded in displaying typical structural attitudes of aging and erosion in the battery material. A completely different kind of application of CLEM is shown by the work of Moritz Kirschmann, Daniele Oberti and Richard Hahnloser, researchers at the Institute of Neuroinformatics of the University of Zurich and ETH Zurich. Together with Carl Zeiss scientist Christian Thomas they used Shuttle & Find for examining specific regions in songbird brains. The research team is interested in understanding how the birds learn their songs from a tutor. Because this process is very similar to languagelearning by humans, the new insights gained from songbird neuronal connections with the aid of correlative microscopy promise large steps forward in understanding the human brain. The third example for usage of Shuttle & Find in life sciences is a research project on legume cells, also done by a Swiss team, Miriam Lucas and Roger Wepf of the Electron Microscopy division at ETH Zurich (EMEZ). Legumes are an important source of proteins, especially for people in developing countries. That makes enhancement of efficiency in legume cultivation an important aim in agricultural research, because it promises to improve the food supply in these areas. To achieve this aim, a detailed understanding of symbiotic bacteria living inside socalled root nodules of the legumes is substantially important. The

reason is that the bacteria are essential for serving the legumes with nutrients. Fluorescent light microscopes can give an overview of how many cells are infected with the bacilli, while scanning electron images clearly depict the intracellular distribution and relationship among them. By combining the two imaging techniques, researchers can achieve a lot of valuable new data which is crucial for an improvement in legume cultivation. The feasibilities described above are far from representing all the potential applications of correlative light and electron microscopy. EMEZ scientist Roger Wepf has given a perspective to future developments in this seminal technology, published in a G.I.T. Imaging & Microscopy magazine article: “The availability of tools to easily connect light microscopy and scanning electron microscopy in 2D is a first step to productive CLEM, but many more are needed.” Wepf is convinced that the next step to further establish CLEM applications in science will be 3D imaging. Furthermore, someday researchers will be able to use “software to display ‘Google-earth-like’ the collected multi-scale and multi-modal datasets in an overlay manner to zoom in and out of the virtual datasets”. To put it another way, users of microscopic techniques can look forward to extremely fascinating years to come – not least in pharmaceutics. Correlative Microscopy from Carl Zeiss Carl Zeiss is the sole provider of light and electron microscopes and, thus, dedicated to developing correlative microscopy solutions that enable exciting new insights into the micro and nano worlds. By offering integrated product solutions for easy sample transfer, fast coordinate recovery and powerful image correlation we strive to enable shortest time-to-result and maximum information from your samples. For further information about Correlative Microscopy, please contact: www.zeiss.de/corrmic corrmic@zeiss.de For information about Light Microscopes, please contact: Carl Zeiss MicroImaging GmbH 07740 Jena, Germany BioSciences | Location Göttingen Tel. +49 551 50 60 660 Fax +49 551 50 60 464 micro@zeiss.de For information about Electron and Ion Beam Microscopes, please contact: Carl Zeiss NTS GmbH Carl-Zeiss-Str. 56 73447 Oberkochen, Germany Tel. +49 73 64 / 20 44 88 Fax +49 73 64 / 20 43 43 info-nts@smt.zeiss.com


Manufacturing

Active Pharmaceutical Ingredient (API) Outsourcing – a Perspective from an Integrated Drug Development Solutions Provider The pharmaceutical industry is facing challenging times. Downsizing and rationalisation are daily news stories, and the turmoil of global recession is placing additional stresses on the biotechnology sector.. The traditional drug development challenges of time, cost and attrition remain, and the necessity to add value for investors and shareholders alike adds further pressures. The contract research and manufacturing sector is changing to meet the new demands and opportunities that the marketplace presents. Quality, customer care and delivery are baseline expectations, and new demonstration of additional delivered value at the right price is taking centre stage. In this article, Dr Austin McMordie (Head of Chemistry at Almac) presents the argument for effective integration as a new way to deliver outsourced services. The drug development process is comprised of a wide range of separate but interconnected elements. The traditional outsourcing model relied on an equally wide range of contract research organisations with expertise allied directly to one small part of the development process. For example, a CRO that specialised in API chemical and analytical development offered those services alone without any real involvement in the downstream elements such as formulation or clinical study design. Likewise, formulation specialist companies were supplied with bulk API, synthesised by a separate company, without any real opportunity to share knowledge or experience. Within the client companies the programme managers and directors managed this often complex network of providers, sharing information on a need to know basis only. So, how can the CROs improve the service to their clients?

80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

“Integration” is defined as “the making up or composition of a whole by adding together or combining the separate parts or elements”. It is this act of combining together that is the new paradigm shift in outsourcing. By working with fewer companies that can offer more of the full range of services, timelines and costs can be reduced and attrition of weak clinical candidates achieved earlier. This moves the outsourcing model from the collection of a range of “a la carte” services to a “table d’hote” solution model. A key detail of this new model is the colocation of truly integrated services on a common site, as opposed to an accumulation of the same services as various sites across the world. This colocation supports effective knowledge sharing and enhanced internal and external communication. In this article three areas of integration are considered: (i) Integrated technologies (ii) Integrated services (iii) Integrated project teams

Integrated Technologies There are many available technologies that can be usefully applied to API synthesis. Indeed, many companies have built strong businesses on a single technology. However, to a CRO in today’s climate, the ability to offer the most appropriate technology for the client’s API is of paramount importance. An excellent example of this is biocatalysis. Biocatalysis is a technology whose time truly has come. When correctly applied, it delivers excellent stereocontrol, yield and scalability with superb green credentials . Unlike chemocatalysis, biocatalytic processes do not generate heavy metal waste, often require no functional group protection and deprotection steps, and can often be run in environmentally friendly solvents. The range of chemistry that can be achieved by biocatalysts is wide – this is illustrated on a fictional molecule in Figure 1. Effective integration of biocatalysis with more traditional API manufacture opens new synthetic chemistry possibilities. The use of enzymes for asymmetric chemistry is well known.

Figure 1: Range of API chemistries performed by biocatalysts Oxidise Esterify Add water Add ammonia Epoxidise Reduce Hydrolyse to amide Hydrolyse to acid

OH

NC

S

O

Reduction to -OH Form amine

Oxidise OMe

Demethylate

Hydroxylate Et02C Hydrolyse to acid Esterify carboxyl

NH2 Form an amide Hydrolyse amide From ketone

Hydroxylate Dihydroxylate

Autumn 2010


Manufacturing For example, 1kg of a chiral a-hydroxy acid can be prepared using only 1g of a carbonyl reductase enzyme (CRED) . However, enzymes can also be powerfully used for the scaleable purification of mixtures of compounds by selective “tagging” of either the desired compound or the impurities . One key opportunity for acceleration of API development timelines is the application of new analytical High Performance Liquid Chromatography (HPLC) technologies. Over recent years, column technology has advanced rapidly, leading to dramatic decreases in HPLC run times. Two excellent examples of this are monolithic columns and Kinetex™ columns. Monolithic columns are packed with a monolithic porous rod, rather than individual silica particles. This leads to faster run times, lower back pressures and higher tolerance of pH extremes. Phenomenex recently launched Kinetex™ core shell HPLC columns. The Kinetex™ packing material has a very narrow particle size distribution leading to ultra high column efficiency and excellent reproducibility. Technology can also be applied to accelerate the preparation of the firstin-human (FIH) solid oral dosage forms. One entry route to a FIH study is a simple powder-in-capsule formulation. Traditionally this has been performed by hand filling, a technique that can be time-

consuming and variable, particularly for low dose capsules. The Xcelodose® 600 precision powder dispensing system brings automation to this process, resulting in a faster, more controlled and less wasteful process. Key to the effective integration of technology to API development is using the right technology for the right application. This “project pull” rather than “technology push” delivers the most suitable solution, increasing options for the CRO and decreasing project risk for the client. Integrated Services Acceleration of a drug candidate from the initial chemistry through to the appropriate first-in-human (FIH) formulation is a key element of some of the new integrated solutions models that are now available. Individually, the services of chemistry, analysis, physical form science and preformulation all have relevance to these critical path drug development activities. However, it is in combination that they have their maximum impact. For example, an early understanding of the physical form of the API can direct the studies for API isolation and purification and the design of an appropriate FIH formulation. Further benefits of a truly integrated solution model are as follows: (i) Effective API synthesis batch

API manufacture

Solid State

Analytical services

Integrated services?

Brand

Advinus

4

4

4

Multi-site

-

Almac

4

4

4

4

4

AMRI

4

4

4

4

4

4

Single site

RAPIDDTM

4

Multi-site

Aptuit

4

4

4

4

4

-

4

Multi-site

IndigoTM

Avantium/ Cambridge Major Labs/ Excelience

4

4

4

4

Multi-site consortium

Chemistry Playbook

Carbogen AMCIS

4

4

4

Multi-site

-

Lonza

4

4

4

Multi-site

-

Onyx Scientific Patheon

4

4

4

Single site

-

4

4

4

4

4

4

Multi-site

Quick to Clinic™

Piramal Healthcare

4

4

4

4

4

4

Multi-site

-

Ricerca Biosciences

4

4

4

Multi-site

Non-stop:IP to INDTM

SAFC

4

4

4

4

Multi-site

-

Shasun

4

4

4

4

Multi-site

-

Wuxi Apptec

4

4

4

4

Multi-site

-

82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Formulation

Packaging

strategy. In the integrated model, the clinical testing site and the API manufacturer work together with the client to identify how much API is needed and when. This information allows the chemistry team to identify the fastest batch strategy and brings flexibility if the project needs change. (ii) Early toxicology scope definition in partnership with the client and with Almac. One example of this is the early identification and control of potential genotoxic impurities (GTIs). Depending on the nature of the GTI, the synthesis route can be modified to remove the risk of the GTI forming, or an early start can be made on developing an analytical method to quantify very low levels of the GTI. (iii) Avoidance of repeat activities. For example, in the non-integrated service model, the API analytical method may be transferred several times to disparate sites. In the integrated model, there is a maximum of one method transfer. Any problems with the analytical method are resolved early and the same analysts stay with the method through the development process. (iv) Parallel activity, underpinned by open and regular communication between the API manufacturer, the clinic and the client. This approach allows a more aggressive timeline to be followed without a concomitant increase in risk. Key to the success of any programme

4

4

Distribution/ Logistics

4

4

Autumn 2010


Manufacturing manager or director is excellent communication with all external parties. Working with fewer companies supports better communication through relationship building and through strong project management at the outsourcing company. (v) Savings of time and money and early identification of weak clinical candidates. Through a combination of removal of duplicate activities and joined up programme planning, the total costs and timelines to develop a drug can be significantly reduced. Furthermore, the identification of a weak clinical candidate early in the process can prevent significant waste that can come from unnecessary additional work on this candidate. The full benefits of this integrated services model again come when all of the services are co-located on a single site. This co-location supports more face to face communication both internally within the outsourcing company and with the client. It reduces the time that the client programme manager or director needs to spend on coordination activities, and allows faster escalation and resolution of critical project issues. Several CROs are now embracing this integration approach, albeit not all on a single site (Table 1). Integrated Project Teams Henry Ford, American industrialist and pioneer of the assembly line production method, once said â&#x20AC;&#x153;Coming together is a beginning, keeping together is progress, working together is successâ&#x20AC;?. The contract chemistry, analytical and formulation business truly is a peopledriven business, where integration of technology and of services must be firmly set in the context of integration within working teams. Two of the challenges this presents are the need for clear communication between all parties through the lifetime of the project, and focused ownership of the individual programme components by the relevant scientists. Effective team working is perhaps the most fundamental benefit of a co-located integrated outsourcing company. There are three components to effective teamwork on complex API development projects. (i) Clearly defined roles for all team 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

members. To ensure that all of the project roles are undertaken, without having roles duplicated or missed, it is essential that all of the members of the project team understand their roles at the outset of a new programme. (ii) Experienced programme manager. There are many interconnected tasks that need to be completed during the successful journey of a drug from the initial chemical synthesis through to the FIH study. To successfully identify critical path activities and to make good decisions about how best to mitigate the impact of any delays requires a strong and experienced programme manager. This individual needs to have a good working knowledge of the component tasks, well developed project management abilities and the respect of the team members. The relationship between the client and outsourcing company programme managers is a critical success factor. (iii) Clear communication practices internally and with the client. An essential component of any client-outsourced relationship is clear communication, characterised by accuracy and high integrity. Too much communication is sometimes as problematic as too little. Equally problematic is asymmetric communication, in which one party communicates well while the other party communicates poorly. Conclusion At a time of great change in the global pharmaceutical and outsourcing

markets, true integration of technologies, services and project teams is starting to address some of the most fundamental challenges of the API development process. New relationships are forming and the value of new ways of working is being recognised. True integration requires co-location of the relevant services and people. The highest compliment that can be paid to an outsourcing company comes when the client feels as though the CRO is part of their company. Integration on a single site of high quality technologies, services and people supports such a relationship and will bring benefits to the whole sector for years to come n

Dr Austin McMordie is Head of Chemistry at Almac. After completing a PhD in bio-organic chemistry at Queenâ&#x20AC;&#x2122;s University Belfast, postdoctoral studies at Cornell University and six years as a discovery chemist at Scotia Pharmaceuticals, Austin joined the Almac group in 1999. He has played a key role in the development and growth of chemistry and radiochemistry services at Almac and is the author / inventor of more than 30 papers and patents. Email: austin.mcmordie@ almacgroup.com.

Autumn 2010


Manufacturing

Enabling Technologies for Attractive Paediatric Oral Dosage Forms Formulating oral dosage forms for paediatrics is very challenging due to the specificities of this patient population: - Diversity of the targeted population: ability to take medicines and dosage form preferences vary greatly with age; necessity to adjust the dose to the body weight - Difficulty or impossibility of safely taking traditional swallowable tablets or capsules - Necessity to mask unpleasant taste and odour that would otherwise compromise compliance Depending on the age group, different oral dosage forms are administered: - Solutions, syrups, suspensions, drops for infants (28 d – 23 m) - Solutions, syrups, suspensions, effervescent tablets or granules for preschool children (2 - 5 y) - Orodispersible tablets (ODT), chewable tablets, powders, thin strips, oral granules for schoolchildren (6 - 11 y) - Tablets, capsules, powders, orodispersible tablets, chewable tablets, thin strips, oral granules for adolescents (12 - 16 y) Oral dosage forms are spread in two groups: - Ready-to-use: solutions, syrups, suspensions, tablets, thin strips… - To prepare: powder for reconstitution, tablets to dissolve, concentrated solutions to dilute, effervescent tablets, sachets to dissolve… When dosage form has to be prepared, two main issues need to be addressed: - Access to drinkable water, - Easy dosing for the person administering care, especially in case of multiple unit dosage forms Chemical, physical and microbial stability is also a key issue, especially for liquid dosage forms and multiple unit dosage forms. In any case, the following challenges face the formulators: - Ensure active stability, either in readyto-use dosage forms or reconstituted dosage forms - Improve palatability with a pleasant taste and a smooth texture, often 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

preferred by children -E  ase swallowing with specific dosage forms These issues can be solved with appropriate formulation of attractive dosage forms. Some keys are given in this article. Ensured Stability Stability of the drug has to be ensured whatever the dosage form: liquid or solid, simple or multiple unit formats, readyto-use or extemporaneous prepared dosage forms. Molecular Encapsulation Molecular encapsulation is a simple method to prepare a complex that stabilises and solubilises the drug. Cyclodextrins have long been known and used for that purpose. Of all the cyclodextrins available, hydroxypropyl betacyclodextrin (HPBCD) is the most interesting, as it combines the following properties (Figure 1): - High solubility and low viscosity -S  imple preparation of the complex with the drug - Increase solubility and bioavailability of active ingredients - Quicker onset of action - Increase stability and shelf-life - Reduce side-effects - Mask unpleasant taste or odour - Better compliance - Safe profile Figure 1: Advantages of drug/HPBCD complex

Other high amylose starch derivatives are also being developed as alternative tools for encapsulation, and show tremendous potential. Stabilisation with Specific Excipients Mannitol is a choice excipient for drug stabilisation as it gathers the following advantages: - Exceptional inertness towards drugs - No hygroscopicity - In solution, mannitol is not attacked by cold, dilute acids or alkalis nor by atmospheric oxygen in absence of catalysts - No Maillard reaction - Hydroxyle scavenger Maltitol solution and sorbitol solution also exhibit advantages in syrup formulation as they contribute to a decrease in the water activity of the product and an increase in its stability. Film Coating Film coating is a good tool to isolate the solid dosage form from the atmospheric conditions and increase its stability. In the meantime it also improves palatability and favours compliance. Film coating technology can be developed: - In-house, using a film coating polymer and preparing its own coating solution, or - Ready-to-use coating system can be used Pea starch LYCOAT® film coating polymer has recently been developed to ensure a quicker quality coating. It is also used in a ready-to-use coating system with moisture sealing properties, ReadiLYCOAT™ MS. Dosage Form Choice When developing a dosage form for paediatric use, the stability issue is a key concern. The choice of the dosage form implies specific stability issues. If a multiple-unit liquid dosage form is chosen, then necessarily preservatives will have to be added to ensure the stability and the safety. On the contrary, solid dosage forms are more stable and do not require preservatives. Therefore an appropriate choice of the Autumn 2010


Manufacturing dosage form sometimes permits simpler formulation and a longer stability period. With the development of novel dosage forms such as orodispersible tablets and thin films for example, it is possible to produce a solid dosage form that will show less stability issues than the equivalent liquid dosage form. This has to be taken into consideration in the early stages of the formulation development. Improved Palatability Whoever has administered a medicine to a child knows how critical the palatability is. The dosage form, taste and texture contribute to the general mouthfeel, and consequently, acceptance of the medicine by the child. The choice in excipients and technologies is vast to help formulators improve the palatability of the formulation. Some simple techniques are illustrated hereafter through examples. Judicious Choice of Sweeteners and Flavours The unpleasant taste of drugs can often be masked with an appropriate selection of sweeteners and flavours. This is a rigorous process to carry out, as patient acceptance will depend on the initial taste and the aftertaste. Both are modulated by the sweetener(s) and flavour(s) used in the formulation. Among the sweeteners, three categories exist: - Traditional nutritive sweeteners (sucrose, dextrose, corn syrup…), sucrose being the historical reference for sweet taste - Polyols (mannitol, maltitol, sorbitol, xylitol…), being often preferred to the first category sweeteners as they have greater stability and do not promote tooth decay - Highly intense sweeteners (aspartame, sucralose, neotame…): offering a high concentration of sweetness in a very small amount, they are sometimes advantageous in a formulation, although their taste is often considered as artificial Flavours, either artificial or natural, have to be chosen carefully to mask the taste of the drug, among the wide range available. Some flavours are known to cover specific tastes. For example, bitterness is best covered with cherry, chocolate, grapefruit, liquorice, strawberry, peach, raspberry or tutti frutti. Flavour stability during the product shelf-life needs also to be assessed. The choice in sweeteners and flavours 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY

depends also on the final dosage form, e.g. if it is a liquid dosage form or a solid dosage form, as illustrated with some examples. Syrup impacts the palatability thanks to its sweetness, its taste and its viscosity. The various excipients included in a syrup formulation are often sufficient to mask the poor taste of some drugs. Maltitol solution is generally well accepted in that application due to its nice sweet taste, and also for other benefits such as sugar-free excipient and no cap crystallisation. Chewable tablets need to have not only a good taste, but also a pleasant texture that also contributes to the overall palatability. A directly compressible maltitol (SweetPearl™ P300DC) has been launched recently, and gives exceptional taste and texture to chewable tablets. Orodispersible tablets can easily be produced by direct compression using new PEARLITOL® Flash compound that gives ODT an exceptional creamy and pleasant mouthfeel. Molecular Encapsulation with Cyclodextrin Technology As described in the previous section, cyclodextrins are efficient tools for taste masking. Depending on the drug and the final dosage form, different cyclodextrins are available. Dextrometorphan hydrobromide has been shown to be encapsulated instantly in betacyclodextrin KLEPTOSE® DC. Palatable chewable tablets could be obtained very easily after mixing the drug with DC betacyclodextrin, mannitol, flavour, aspartame and magnesium stearate and direct tabletting. In other cases the complex cyclodextrin/drug will be prepared by a kneading process and incorporated in the formula for any solid dosage form. For liquid dosage forms, the high solubility and low viscosity of hydroxypropyl betacyclodextrin make it a very interesting and simple tool for molecular encapsulation. Film Coating Film coating can be used for a taste masking purpose, either by coating the drug particle itself or by coating the formulated solid dosage form and masking its taste, odour and colour. If coating is applied on the drug particle, it has to be very resistant in order to overcome further processing and avoid any break in the coating that would lead to inefficient taste masking. If coating is applied on the particle,

large quantities of coating polymer are needed and its taste must itself be advantageous. If coating is applied on the final dosage form, efficient taste masking is easier to achieve, with minimum coating polymer requirements. In that case coating will mask the taste and odour not only of the drug, but of all ingredients. It also increases attractiveness with nice glossy colours, and facilitates swallowing of the tablet. Ease Swallowing with Attractive Dosage Forms Children encounter difficulty in swallowing medicines, and if physiological reasons are not obvious, psychological grounds are complicating the issue for the person administering care. Therefore any dosage form that brings safe attractiveness will simplify the drug administration and improve compliance. Novel technologies have been developed and gather all the requirements of palatability, stability and attractiveness. Some of these are described hereafter. Orodispersible Tablets Orodispersible tablets (ODT) are gaining popularity for patients with difficulty of swallowing, including paediatrics. In about one minute the tablet disintegrates on the tongue, without need for water. The child can take it very easily and safely. Numerous technologies have been developed using processes such as lyophilisation and freeze-drying, moulding, cotton candy process and direct compression with specific excipients. This latest technology is the simplest as it does not require specific equipment. The recently developed excipients for direct compression ODT are all based on mannitol and contain other excipients such as superdisintegrant. PEARLITOL® Flash is a dual compound, of two long-established natural ingredients: mannitol and starch. Simplified formulations are possible with PEARLITOL® Flash, as no superdisintegrant is needed and a low level of lubricant is sufficient. It gives robust tablets, with a disintegration time independent on compression force or tablet hardness (Figure 1). PEARLITOL® Flash ODTs melt in the mouth with a very creamy and smooth texture. Orodispersible Thin Films Orodispersible thin films have not Autumn 2010


Oral Granules Oral granules are very easy to administer, but in a different way depending on the age group: mixed with food for toddlers, dissolved in water for children and for adolescents - although this is not exclusive, and a teenager could mix the granules with carrot puree! Again, polyols are much favoured in that application thanks to their appealing sensorial properties (Figure 3) and the wide range of textures they offer. Medicated Confectionery Medicated confectionery is definitely a wonderful vector for drug administration 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

90 70 50 0

20

40 60 80 Tablet Hardness (N)

100

120

Table 1: Tremendous benefits for orodispersible films Care administration benefits

High attractiveness which facilitates the administration to a child • Single unit dosage form • Ready-to-use dosage form •Simplicity of use

Patient benefits

High attractiveness • Easy to swallow • Increases compliance

Process benefits

Liquid process, which increases safety especially for high potency drugs • Liquid process which increases the accuracy • Possibility of drug encapsulation or amorphisation

Laboratory benefits

Innovation • Life cycle management • Range extension

Dosage forms benefits

Solid dosage form • Portable • Novelty • Avoid first hepatic path

LYCOAT® technology benefits

Simple formulation • Robust production process

Figure 3: Polyols offer a wide range of tastes and textures to solid dosage forms TASTE

TEXTURE XYLITOL

Sorbitol

MINT FLAVORS Sorbitol FRUIT FLAVORS MALTITOL MANNITOL

Sweetness

in children, as it favours compliance and palatability is achieved with appropriate flavours and sweeteners. Different forms exist such as candies, pastilles, jellies, chewing gums… For these applications polyols are the best bulk sweeteners to use as they are sugar-free. Numerous products exist to answer all the requirements regarding the processes and the drug properties. Conclusions Formulating paediatric dosage forms is very challenging as for stability, palatability and ease of swallowing reasons. Novel technologies, processes and excipients are being developed to facilitate the formulation. These opportunities should be taken to quickly develop dosage forms suitable for paediatrics. Orodispersible tablets are a wonderful tool to develop stable and palatable dosage forms while securing the ease of administration to children. Liquid dosage form could be reformulated in orodispersible tablets to improve

SMOOTH Dissolution time

Chewable Tablets Chewable tablets are attractive dosage forms particularly suited to the paediatric population, as they combine a nice taste and texture, and they are easy to administer and swallow. Chewable tablets are easily obtained by direct compression. For tablet production, numerous excipients have been developed, among which some are more appropriate for paediatric chewable tablets. That is the case for polyols which combine the following advantages: - Chemical inertness and compatibility with most actives - Low water content - A multitude of tastes and textures can be obtained (Figure 3) - Sugar-free excipients Among all the available polyols, many grades exist, and offer a vast possibility of textures and tastes to be obtained by using them alone or in combination. The latest innovation in this market is the first directly compressible maltitol SweetPearl™ P300DC.

Disintegration time as a function of tablet hardness

100

Disintegration time (s)

yet found the place they deserved for paediatric usage, but should be considered seriously as they combine a multitude of benefits in that application (Table 1). This technology involves the dissolution of the active in a polymer solution, casting of the film and drying. It is therefore a liquid process, with all the linked advantages regarding uniformity that ends up in a solid dosage form. The orodispersible films available on the market are usually complex formulations with numerous excipients and often a combination of several polymers. With the LYCOAT® technology, formulation is simplified as just one polymer is required.

Figure 2: Disintegration time of PEARLITOL® Flash based orodispersible tablets is not affected by tablet hardness

Cooling effect

Manufacturing

XYLITOL CRUNCHY MALTITOL

CREAMY MANNITOL

Hardness

compliance and answer the requirements of the person administering care for simplicity. Film coating technology gives easy access to stable and palatable dosage forms, while improving swallowing and giving attractiveness for teenagers. New directly compressible excipients, such as SweetPearl™ P300DC or PEARLITOL® Flash, are being developed to simplify formulations while taking up the challenges of stability, palatability and ease of swallowing. They also offer high attractiveness for the targeted population and are life cycle management tools n

Cécile Dusautois joined Roquette in 1988 and occupied several positions in R&D. She is now in charge of the Technical Communication for the Applications Division. She has written numerous articles putting forward the company’s products and applications expertise, as well as supporting the major innovations of Roquette. Email: cecile.dusautois@roquette.com

Autumn 2010


92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2010


www.ipimedia.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 93


PACKAGING

Dr. Patricia Lobo, Editor of IPI, speaks with Fran L. DeGrazio of West Pharmaceutical Services, Inc. about reducing the risk of needlestick injuries What technologies have you improved in terms of reducing the risk of needlestick injuries? New technologies include passive systems, such as West’s NovaGuard TM safety needle, that allow for safer injection without altering the caregiver’s administration technique in the hospital and clinical setting. In addition, auto-injectors and other devices that can be used in home care settings, such as West’s ConfiDose® auto-injector system, have focused on developing devices that reduce anxiety for the patient through improved needle technology, and reduce needle phobia by hiding the needle both before and after injection. By coupling the autoinjector with a silicone-free prefillable syringe – such the Daikyo Crystal Zenith® 1mL Insert Needle Syringe system – manufacturers of auto-injectors can create a system that does not require siliconisation, which can affect variability and the gliding performance of the plunger. Gliding force, drug viscosity and siliconisation consistency can be factors in ensuring reliable dosing from an auto-injector or other device. What are the innovations in container closure systems which enable pharmaceutical companies to minimise risk and development costs? From a container closure system standpoint, West’s NovaPure® components can minimise risk and development costs. Through a combination of FluroTec® barrier film, which eliminates the need for silicone oil, and West EnvisionTM automated vision inspection, NovaPure components offer uniformly high quality levels and consistency. Add to that West’s VeriSure® certification process, which assures a consistent, lot-to-lot extractables profile, and drug manufacturers are able to ensure closure consistency while 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

reducing or eliminating the expense and exposure to regulatory risk associated with component preparation and sterilisation. On the container side, Crystal Zenith materials can be used for everything from bulk storage to ready-to-use (RU) vials and syringes systems. Cyclic olefin polymers such as Crystal Zenith can be moulded into complex shapes, so pharmaceutical companies can select a Crystal Zenith containment solution for the lifecycle of their drug – from development through commercialisation. Crystal Zenith resin offers customers additional benefits because the material has very low extractables, is highly break-resistant and can be stored at low temperatures. What is the West Ready Pack® System? The marketplace was desperately in need of a small-volume component system that could be used by pharmaceutical customers in research and development stages. The West Ready Pack® system is the answer. The Ready Pack system includes ready-to-use, sterile stoppers, vials and seals that can be purchased separately or in combination as a container closure system. These components have been tested to assure appropriate fit when assembled properly, and can be easily used in a laboratory setting in clinical trials. Since the vials are available in either glass or Crystal Zenith RU format, there is a Ready Pack system available to meet the needs of any sensitive drug or biologic. In addition, the Ready Pack system allows manufacturers to maintain consistent primary packaging components from the research and development phases through commercial manufacturing. What does the VeriSure® process offer to the medical industry? The VeriSure® process is an industry

leading product for extractables testing. During the last decade, the topic of extractables from packaging components has gone from a guessing game to a science. The VeriSure process brings this to the next level. There are actually two dimensions to the VeriSure process. The first is a technical package that provides customers with a thorough, detailed extractables analysis of a specific elastomeric formulation. This can be used to allow a customer to move directly into leachables studies with a drug product, saving months of time and money for lab testing. The second option is use of VeriSure process certified components – a West product that includes a certified extractable profile. Each shipment of VeriSure components includes an extractables fingerprint and a quantitative Certificate of Analysis. This assures the customer of lot-to-lot closure consistency at a much deeper level than ever before. In addition, the Certificate of Analysis assures customers that no significant changes have occurred during the manufacturing process that could impact the closures’ extractables profile. 5) In what way do LyoTecTM stoppers save time for pharmaceutical manufacturers? LyoTec™ stoppers ensure ease of processing during lyophilisation because they have the demonstrated advantage of not adhering to the pressure plates of lyophilisation chambers. A coating of FluroTec® barrier film on the top of the stoppers also helps to prevent clumping in sterilisers and feeding bowls. Thus, LyoTec stoppers allow manufacturers to gain efficiencies and no product is wasted. What do NovaPure® components offer in terms of quality assurance? Autumn 2010


PACKAGING West NovaPure® components help customers meet quality requirements because they can be certified for an extractable profile and are available in ready-to-sterilise or ready-to-use formats. The RU format has specifications for particles, endotoxin and bioburden removal. In addition, NovaPure components are manufactured to uniformly high quality levels with a product-specific subvisible particle specification. This assures the customer that the closures they receive are consistent from lot to lot, with minimum variability. 7) What anti-counterfeiting solutions do you offer at West? West currently offers West SpectraTM ID, which enables manufacturers to emboss urgent safety or cautionary statements on our tamper-evident Flip-Off® seals. Use of distinct colours and cap/seal colour combinations can also differentiate a product. In addition, West has several different counterfeiting technologies that can be applied to the seals used to keep stoppers on vials. These technologies are constantly changing and evolving based on industry demands and regulatory requirements. 8) What products of West would highlight the importance of improved patient safety? Ultimately, all of West’s products serve the purpose of improved patient safety because the pharmaceutical industry is first and foremost concerned with the patient. The regulatory framework revolves around minimising risk to the patient, and quality enhancements and new technologies are designed with that critical attribute in mind. Because every drug arrives on the market in a container or delivery system, primary packaging and secondary closures are essential in keeping drugs pure and patients safe. West’s delivery systems such as the NovaGuard safety syringe and the ConfiDose auto-injector system are also critical to patient safety since these types of products help to minimise needle-stick injuries. In addition, our administration systems, such as needleless transfer devices or vial adapters, can help deliver a medicament safely. While West’s first point of contact is the drug manufacturer, it is the patient – and ultimately improved patient safety – that drives our innovations n 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Frances L. DeGrazio - Vice President, Marketing & Strategic Business Development West Pharmaceutical Services. Fran DeGrazio has been with West since 1983. Throughout her tenure she has served in various functions with the analytical laboratory and research and development areas. She is a member of the Parenteral Drug Association (PDA), American Chemical Society (ACS) and the American Association of Pharmaceutical Scientists (AAPS). Fran holds a B.S. degree in Chemistry from Cabrini College in Radnor, Pennsylvania, USA. E-mail: fran.degrazio@westpharma.com

Autumn 2010


PACKAGING

How can intelligent packaging best aid patient compliance?

Patient non-compliance (not taking the right medication at the correct time) causes thousands of deaths and costs the healthcare industry billions of pounds per year. Innovative medical packaging can combat non-compliance and so is an area which is likely to see considerable emphasis in the next few years. Already, advanced technology is being incorporated into packaging which allows links between medicine removal from packaging and the client’s overall treatment plan to help improve this situation. New areas of development like smart materials and nanotechnology will add to the possibilities of smart packaging but it has to be recognised that in many areas of the world, the absence of the otherwise ubiquitous internet and mobile phone technologies, will mean that the most sophisticated packaging advances will not be applicable. However, there will still be a need for some levels of sophistication to combat the increasing problems with counterfeiting and to implement other aspects of brand protection. Those involved in the pharma industry will need to be up to date, not only on the latest developments in drugs but also in the latest development in drug packaging. 1. Patient non-compliance, risks, causes and costs Every day millions of patients fail to take their medications as prescribed by their doctor. Medication non-adherence is a problem that disrupts the healthcare system in many ways, leading to patients failing to receive full treatment benefit. Non-adherence can lead to hospitalisation and even death. The root of this problem is human behaviour. Even though we are “creatures of habit”, we often lose 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

momentum when taking medications, or do not always understand or appreciate the benefits. Subsequently, patients often tell an ‘untruth’ to mask the fact and avoid embarrassment, whether noncompliance was accidental or planned. Causes of Non-Compliance Potential causes of non-compliance are numerous, some accidental and others pre-meditated; the latter being attributable to a number of psychological issues. In his article ‘Confidence in Compliance’, Tassilo Korab, Healthcare Compliance Packaging Council (HCPC - Europe) postulated that there were four causal factors: 1. Type, Seriousness and Duration of Illness (Spilker 1991) demonstrated that compliance is low in less serious illness cases, increases with medium level cases and drops-off again for serious cases. Also, (Heuer 1999 ) that compliance reduces substantially the longer an illness persists. 2. The Complexity of Therapeutic Regimen “Compliance is inversely related to the number of prescribed medications”, but the frequency of the daily intake of medication also reduces the rate of compliance (Murray 1993). Ideally, medication should be taken once daily (morning). More daily intakes cause

deterioration and provoke sharp decline in compliance rates (Haynes1979). 3. Information about Health Condition and Trust Between Patient and Healthcare Provider Compliance depends largely on health condition information and patient/ Health Care Provider (HCP) trust. Generally, practitioners spend under 60 seconds per prescription conveying compliance-related information to patients. Consultations usually result in a prescription but most patients are left alone with therapy questions/concerns regarding: medication benefits/risks, other drug interaction and side-effects (Heuer 1999). 4. Health Belief Model The lay patient’s perception of treatment’s necessity can differ completely from diagnosis and recommendations by HCP. Sometimes patients see their condition as a threat, and other times might not even accept illness existence - period. Fears regarding treatment and possible side-effects will influence patient behaviour. So various patterns of noncompliance equal -a complex situation. Risks and Costs The risks of non-compliance can be listed on a scale of increasing negative consequence: 1. A  ilment prolonging because

Figure 1: Cost of nona-compliance (Source: Rosa 2009) 77 Billion US$ for health insurers p.a. USA*, 47 Billion US$ Life Sciences Industry p.a. USA*, 13 Billion EURO in Germany** p.a., 9.7 Billion EURO in France p.a., 6.5 Billion EURO in Italy p.a., 10 Billion EURO in UK p.a. 4.3 Billion EURO in NL p.a. * 125.000 Deaths Annually: Smith D., Compliance Packaging, a Patient Education Tool, American Pharmacy volume NS29, nr.2., Feb 1998 * Non-compliance leads to 10% of hospital admissions, Schering Report IX: The Forgetful Patient, the high cost of improper patient compliance *S  tanberg L.R., Drugs as a reason for Nursing Home admissions, American Healthcare Association Journal, 10, 20, 1984 ** 1  3% of all Healthcare Expenditure is related to non-compliance: Sonnenmoser M.,Compliance in der Arztneimitteltherapie, ABDA, Dezember 2002

Autumn 2010


PACKAGING ineffective efficacy levels reached 2. Building resistance through prolonged drug exposure leading to complete medication failure 3. Ailment worsening 4. Hospitalisation 5. Death The cost, both in human lives and monetary terms, is considerable. Evidence collated by Rosa (Figure 1) estimate US and EU costs amounting to £100’s Billions. 2. Current packaging approaches to limit non-compliance It is widely recognised that packaging has the capability to improve noncompliance and advancing technology allows increasingly sophisticated efforts to achieve this, many approaches have been taken over the years, including: (1) Medication reminders that beep at medication time. (2) Devices that track the number of dosages removed from an opened medication pack/container, collect statistics, download and check at doctor’s office or pharmacy. (3) Devices reminding patients to take medications and confirmation by button pressing to send data. (4) Miscellaneous alarmed reminder devices, like automated pill boxes or wrist watches. Whilst these devices can never guarantee that patients have taken their correct medicine or taken at the right time, good packaging in this area has a number of common attributes, including: effective colour use, icons & reminder aids, accessibility, portability & robustness, plus more objective features such as ‘intuitiveness’. Effective presentation of pack information can greatly ease patient use and hence encourage compliance. (Thomas Dries, 2010) Examples of excellent packaging developed over recent years include: The Zacpac, launched 2001 for H-Pylori patients, having to take 3 different tablets/doses per day. The solution was a single blister containing 5 tablets (of 3 different varieties) held in a ‘calendared’ dispensing pack. The combination of detailed instructions, therapy visualisation, plus 1 x mixed blister per day, was a real ‘step forward’. It was also easier for 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY

pharmacists because it involved only one prescription, one dispensing and one explanation. In 2008 Stora Enso launched its DDSi (Discrete Dose Slider), a solution based on a carton with embedded Cypak Radio Frequency Identification (RFID) microchip. Supported by software enabling compliance monitoring, authentication, tracking and tracing of products, it records precise date, time and specific pill removal information. The Near Field Communication (NFC) technology is that used in mobile phones and allows wireless communication between devices over a short distance, enabling functions such as electronic medication diary or SMS reminder. This pack won the HCPC Europe 2008 Packaging Award. Cypak, which provides the aforementioned chips, have been instrumental in developing and setting global IEEE standards for wireless technology in healthcare. They have also created secure contactless technology to compete with traditional RFID systems, using conductive ink and adhesives to print electronic circuits and antennas on paper and plastic. Stora have recently developed a pack called ‘Memori’, which also uses a microchip embedded into the paperboard but uses conductive print. Protomed, a pharmaceutical design company, have developed Biodose™ Total Medication Management System (ToMM™), which consists of patented pod & tray dispensers, sealers, alarmed cabinets, trolleys, mini-packs for community use and pharmacy software. It provides the ability to dispense and monitor medications, aimed primarily at compliance in institutions such as carehomes, hospitals and even prisons. Dutch DSM TCG have developed the OtCM™ (Objective therapy Compliance Measurement) system which measures and monitors patient medication compliance whilst interacting wirelessly with home diagnostic devices, correlating compliance with drug therapy. It monitors each individual dose taken, providing real-time data, graphs and combines medication intake and diagnostic outcomes. The technology: • Includes RFID labels applied to existing standard medication blisters which records pill removal

•C  ompliance information read via mobile phone, transferred to central database, then sent wirelessly to caregivers, who analyze, offering patient feedback These examples show the huge innovative development that has been taking place over recent years, all relying heavily on technology. So where is all of this going? 3. Opportunities for further developments–technology convergence The packaging developments above are leading-edge and demonstrate that there is a growing convergence between technology and internet. Fiction often prefigures reality and in the movie, Minority Report, a future was depicted, where visual objects are manipulated by hand, newspapers have sound & moving pictures, billboards change & interact (depending on who is viewing them) and cereal packs ‘talk’. Remarkably much of this technology already exists. Touch-screen technology is rapidly developing and ‘talking’ newspapers with moving pictures are close, as printing & polymer science catches up in devices like flat-screen televisions, where Sony launched “the worlds first OLED TV” in Japan 2007. In ‘Web squared’, (O’Reilly 2009), the author refers to exponential Internet growth, as objects/devices increasingly go online, applications reside on the ‘net’ remotely in a ‘cloud computing’ environment, and the Web ‘learns’ by itself. Objects, devices, people/things will get online directly & indirectly via vision recognition & tagging. New ‘crowd sourcing’ opportunities will emerge as Smart packaging, devices and internet further interact to provide a more holistic approach to healthcare and wellbeing.A further result will be increasing usage of ‘Augmented Reality’ (AR), a physical real-world environment whose elements merge with (are augmented by) virtual computer-generated imagery, creating a mixed reality. Elon University made broad predictions for the future: 2010-2014: RFID tied to GPS everywhere. Super supercomputers. Intelligent materials. 2015: Adaptable materials. Genetic Autumn 2010


PACKAGING profiling. Human cloning. 2016-2025: VR immersion. Ubiquitous robots. Emotion-control devices. Painton power. 2026-2045: Space elevator. Moon base. A “singularity” due to accelerating change. 2046-2150: Mars colony. Time travel. Brain downloading. Humans assimilated into the internet So what opportunities will emerge for healthcare packaging? Certainly, it will need to be ‘smarter’, not only in terms of technologies and materials but also: • supporting changing lifestyles • Providing greater consumer & patient convenience • lower environmental impact Packaging will also need to communicate better (on-shelf & at home): • ever-more information required on ever-smaller packs • traditional printed packaging will not cope • use of low-cost printed displays & electronics Some AR technology is already used in consumer packaging, such as Lego Point-of-Sale packaging that gives a 3D visual rendition of the assembled contents within. AR needs to help solve problems for the end-user and medical packaging (patient compliance) is an avenue through which to exploit the technology benefits, help save lives and ultimately save £billions per year. However, Dries 2010, recognised that there is “no one fits all” effective compliance solution. He emphasises that patients have many concerns over packaging used in this field, such as: “over-engineered”, “too-expensive” “not very environmentally friendly” and “very hard to recycle”. There are also concerns about the ‘Big Brother’ nature of this intrusion, personal data-capture and information sharing, no doubt highlighted in healthcare due to patient information sensitivities. 4. Developing World Issues The preceding devices and technologies, by their very nature, are comparatively expensive. So how could they be used in ‘Developing World’ countries, where mobile phone & internet access is limited and cost 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

is a major factor in medicine use? The answer is that the very sophisticated solutions are probably not appropriate for these environments but this is not to say that there is no role for packaging development in the distribution of medicines in less developed nations. Non-compliance in developing nation environments has its own peculiarities/ issues, often resulting in greater fatalities than the ‘West’. Correct medication/ dosage is one issue but there are others such as counterfeiting, corruption and expired products which also affect a patient’s compliance and recovery. In a report published by the World Health Organisation (WHO) in 2003, following a study on patient knowledge & compliance in Ethiopia, it was found that: •T  he percentage of patients demonstrating adequate knowledge (ability to tell dose, frequency of administration and length of therapy) about drugs dispensed was only 67.4%. •A  dequate availability of EDLs (Essential Drugs Lists) in health facilities for six disease conditions, namely, Tuberculosis/Leprosy, Sexually Transmitted Diseases, Malaria, Acute Respiratory Tract Infection, diarrhoeal diseases, and opportunistic infections related to HIV/AIDS was present in only 39% of 108 health facilities surveyed. So the majority of health personnel are working without standard guidelines, providing huge opportunity for incorrect drug use. Furthermore, in one region almost 50% of the medications in hospitals were found to be ‘out of date’! The findings, albeit from only one African country, demonstrate a clear need for enablers, such as better packaging, to impart knowledge, promote understanding and lead ultimately to greater compliance. It is interesting to see that the winner of the recent HCPC Compliance packaging awards was the Novartis Coarthem Malaria treatment, for a disease that kills over 863,000 Africans annually, many children, costing USD 12 billion in lost African GDP (Source: Novartis). It demonstrates that this area of concern is being addressed, but I’m sure that there is ‘room for improvement’. Key to Coartem’s efficacy is specially designed packaging to maintain compliance via

pictograms and colour coding. This is a great initiative, but if you take into account that apparently over 10% of drugs worldwide are counterfeit, and in some countries over 50% of the drug supply is counterfeit, it opens up a number of questions. In 2003, WHO cited estimates that annual earnings of counterfeit drugs were over US$32 billion. As well as copies of real drugs, counterfeit legal drugs can include falsely-labelled drugs that were previously expired, drugs where the active ingredient is fraudulently diluted, adulterated, substituted, completely misrepresented, or sold with false brand name. As things stand, there is a chance in developing nations that upto 50% of the products reaching patients aren’t what ‘it says on the box’ - a horrifying thought. It is quite possible, therefore, that the challenge in the developing world will not be sophisticated packaging to improve patience compliance but more likely packaging designed to combat counterfeiting and brand fraud. According to Pira International (Packaging World, 2010), the global brand-protection market will exceed $11.4 billion by 2014, up from $6.7 billion in 2009. Pira defines brandprotection as the use of tamper-evident, anti-counterfeiting, anti-theft, or trackand-trace technology to prevent or limit damage from brand attacks occurring through product counterfeiting, parallel trading, product tampering and theft. Smart packaging solutions will be the main vehicle for this. 5. Leveraging smart materials for smart packaging ‘Smart’ materials are those that display ‘Smart behaviour’, sensing stimuli from their environment and reacting in useful, reliable, reproducible and usually reversible ways. Their development means continually evolving and improving capabilities. Examples are ‘thermochromic’ materials that change colour at a particular temperature. (Materials KTN) Affiliated is ‘Nanotechnology’ and ‘Nanomaterials’, involving materials at the atomic/molecular level, that can be engineered, ‘designing-in’ required properties – ‘smart chemistry’ This includes thin-film structures Autumn 2010


resulting from deposition of multiple material layers onto surfaces to create transparent, self-assembling coatings – giving multifunctional benefits by exploiting optical, magnetic, electronic and catalytic effects. Imagine a scenario where a pack could recognise its position (internet connection through the packaging itself), talk to patient in their own language and explain, using sound and moving pictures, how to self-medicate. Additionally, alerting pharmacists and nurses when nearing shelf life end, to improve management of stock rotation and replenishment. It may sound like ‘science fiction’, but much is probably already possible, although possibly not on a commercial basis. Organic, plastic or polymer electronics, is a branch of electronics that deals with conductive polymers, plastics, or small molecules, which are carbon-based, like molecules of living things, as opposed to traditional electronics (or metal electronics) which rely on inorganic conductors such as copper or silicon. All-organic electronic devices could be very versatile (flexible and stretchable), and because they can be deposited/printed using ink-jet or other printing technologies, could be extremely robust and low cost, providing potential to be integrated into everyday packaging. Whereas silicon chips are cost-effective only when small and produced in vast numbers, plastic electronics should be cost-effective to produce in small numbers. It should also be possible to print organic circuits on top of each other and produce large area devices like flexible electronic sheets made with roll-to-roll processes. (Source: Faraday) Areas of particular interest necessary to provide organic electronic functionality into medical packaging include: • Moving (plastic electronic) displays • Power (organic printed batteries or photovoltaic devices) • Printed sensors • Memory (organic flash memory like that used in a USB pen drive) • Transponders or tags like RFID tags • Logic processors Things are moving forwards in all areas, but some are experiencing more R&D effort than others. Sony’s New www.ipimedia.com

Sony’s New OLED Screen is ultrathin (Source: www.psfk.com)

Lego AR interactive POS terminal (Source: Augmented Reality Blog)

OLED screen is ultrathin (thinner than a strand of hair at 80 μm-thick) and a great example of leading-edge developments in moving displays. (Source: www.psfk. com) 6. Conclusions Medical packaging is an area which is likely to see considerable emphasis in the next few years. Already, advanced technology is being incorporated into packaging which allows links between medicine removal from packaging and the client’s overall treatment plan, allowing patients, carers and practitioners to confirm that the right medication is being taken at the correct time. The enormous costs of noncompliance both in terms of health and health service costs will mean that considerable investment in these areas can be justified and we can expect to see continuing developments into areas such as AR, which at present seem to be simply the ‘stuff of’ science fiction.

New areas of development like smart materials and nanotechnology will add to the possibilities of smart packaging but it has to be recognised that in many areas of the world, the absence of the otherwise ubiquitous internet and mobile phone technologies, will mean that the most sophisticated packaging advances will not be applicable. However, there will still be a need for some levels of sophistication to combat the increasing problems with counterfeiting and to implement other aspects of brand protection. The pharmaceutical industry is not always the most progressive in the uptake of technology but demand from health services looking to save on non-compliance costs, marketers looking to minimise on brand fraud in the developing world, and from health professionals looking to ensure good communication of necessary drug information to users, will ensure that there will be a continuing revolution in the packaging used for the full range of drugs on the market. Those involved in the pharma industry will need to be up to date, not only on the latest developments in drugs but also in the latest development in drug packaging n References:Figure 1. ‘Confidence in Compliance’, Tassilo Korab, HCPC– Europe, Packing, Packaging & AntiCounterfeiting, PMPS Spring 2009 p90, ,www.samedanltd.com (a). Spilker – methods of assessing 1991 (b). Heuer – Compliance in der Artzneittherapie 1999 (c). Murray – The annuals of Pharmaco Therapy – 1993 (d). Haynes – Determinants of compliance 197 PC –Europe Newsletter 17 - Spring 20109. Image 1.Pira International via Packaging World – May 2010 Image 2. Plastic Electronics and the FMCG consumer report - www. faradayknowledge.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 103


ExHibition Previews & Reviews

CPhI Worldwide, along with its co-located events ICSE, P-MEC and BioPh 2010, Surpass All Expectations Hosted in Paris Nord Villepinte, Paris, France, CPhI Worldwide 2010 significantly exceeded expectations with visitor numbers topping last year’s event in Madrid, Spain. Projections by organisers UBM Live had predicted numbers similar to the 2009 event which hosted 25,500 visitors and 1,808 exhibitors. However, CPhI Worldwide 2010, along with its co-located events, saw an increase in visitors of over 14%* and more than a 6%* increase in exhibitors. Similarly, co-located events ICSE, for contract services and clinical trials and P-MEC, for pharmaceutical equipment and machinery, saw record years, with ICSE featuring 100 new companies and over 50 new packaging exhibitors. The fourth event, BioPh for the converging pharma and biotech industries, was also a notable success and despite only being in its second year, had 300 exhibitors either in BioPh or on the BioPh trail. At the 2010 event, the overwhelming message expressed by the organisers, exhibitors and attendees alike was maintaining a focus on how to move forward in a global market that has seen some sluggish returns over the past few years. When asked about growth over the 2009 event, Annemieke 104 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Timmers, Brand Director for CPhI noted, “The show has continued to expand which reflects the market’s transition to a positive outlook for the industry as a whole.” The optimistic sentiment was shared throughout the show floor and the consensus among attendees was that the industry was on the upturn. For the second year, CPhI offered a pre-show conference series the day before the show got underway. The series focused on ‘Global Sourcing and Contracting Strategies’ with a multi-track format that offered 30-minute seminar modules of the following themes: API sourcing in India and China, market opportunities in biosimilars, CMO selection and relationship management, CRO partnership and risk management, new innovations in excipient sourcing and generics, super generics and post-patent outlook. This series saw a 45% increase in attendance over 2009 numbers. In addition to promoting a positive industry focal point, the show also showed a commitment to enhancing the visitor experience with some well received logistical improvements. The most notable was the introduction of zoning, whereby the CPhI event was broken up into six zones which aided

“more talking, less walking” time. Similarly, ICSE featured a Packaging Zone and a Clinical Trials and Contract Research Zone, offering a layout that was easily navigable and allowed for more efficient communication. Another offering new to the 2010 event was the introduction of a mobile website for Blackberry, iPhone and other web-enabled mobile phones. The new mobile website allowed visitors to look up exhibitors, check event schedules and get the latest news updates during the event while on the go. As excitement for next year’s events ramps up for the 2011 dates at Messe, Frankfurt, Germany, from October 25th to 27th UBM Live has already announced two new co-located shows for 2011. Launched to offer the Pharma community innovative and diverse packaging solutions to satisfy the changing ways in which medication is packaged and delivered, InnoPack reflects an organic evolution from the ICSE Packaging Zone, following its successful introduction in Paris. The second new event, LABWorld will cover the laboratory, analytical and biotech equipment markets, and will cater for the increasingly sophisticated new technologies in the pharma and biopharma laboratory space n Autumn 2010


ExHibition Previews & Reviews Participants at the round table discussion at the 1st Baltic Biotech Forum

1st Baltic Biotech Forum from research to commercialization ScanBalt BioRegion is composed of life science stakeholders in the Nordic/Baltic Countries, Poland, North Germany and North western Russia. The Groningen area in the Netherlands is affiliated. The concept of ScanBalt BioRegion was formed following a round table discussion at the 1st Baltic Biotech Forum in Mecklenburg-Vorpommern (GE) September 2001. ScanBalt BioRegion has: • More than 2500 Life science and life science related companies including over 700 research based biotech SME´s • More than 1000 academic institutes and institutions • More than 230 hospitals and clinics • More than 100 Life science investors ScanBalt ScanBalt™ fmba (in short ScanBalt) is a not-for-profit member association serving as a service provider for the members. The regional/national networks, clusters and regions together 106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

with public authorities, industries and hospitals constitute the member basis. The secretariat is located in Copenhagen (DK) while regionally financed liaison offices are located in Tartu (EE), Gdansk (PL) and Rostock (GE). The key tasks are to: • promote projects, business and research • promote visibility and branding • promote policy issues, regional innovation and cluster development Fig 1: the development of ScanBalt BioRegion and ScanBalt The ambition is that ScanBalt BioRegion becomes a globally leading bioeconomy based on sustainability and “smart growth”, fundamental principles laid down in the statutes of ScanBalt back in 2004. ScanBalt Academy ScanBalt Academy (SBA) consists of distinguished and prominent life scientists from academia as well as industry and government. Purposes of SBA:

• Add credibility to the scientific quality of ScanBalt projects and initiatives • SBA or SBA committee’s serve as external advisory boards to ScanBalt activities • SBA Fellows gives lectures or teach courses in ScanBalt BioRegion • SBA Fellows act as ScanBalt Ambassadors. • SBA Fellows act as evaluators on proposals for new ScanBalt activities and projects. • SBA assists to reverse brain-drain from ScanBalt BioRegion, and help to engage expatriates in ScanBalt activities. From research to commercialisation – A case story The major problem in the EU for the competitive development of life sciences is the transfer of ideas from academic research into products or commercialisation . Another challenge is a low level of interregional cooperation within research and development and among companies and institutions from Autumn 2010


ExHibition Previews & Reviews different regions of several states . This holds true also for ScanBalt BioRegion. The project Bridge-BSR (coordinated by ScanBalt) got co-funded by EU FP 7 (Capacities) and was finalized September 2009. The following was achieved: - Assisted to establish the triple helix cluster BioBaltica in Gdansk - Initiation of shared SME services between clusters in ScanBalt BioRegion - Integration of an Innovation Agenda “Smart Growth” into regional strategies - Assisted to initiate the process towards a Baltic Sea Fund for Innovation - Launched ScanBalt Health Region (see below) official kick-off in Brussels June 2010 - Integration of IP-management into project activities - Development of regional scoreboards Bridge-BSR is one example of how ScanBalt BioRegion as a concept and ScanBalt as an organisation work to promote regional development and affront societal challenges. ScanBalt Health Region – Health and Health Economy ScanBalt Health Region is a flagship in the action plan of the EU Baltic Sea Region strategy. Health Region affronts the growing challenges to the health of the population in the EU member states well described in the EU white paper “Together for Health – A Strategic Approach for the EU 2008-2013” . These are: 1. Demographic changes including population aging are changing disease patterns and putting pressure on the sustainability of EU health systems. 2. Pandemic, major physical and biological incidents and bioterrorism pose potential major threats to health. 3. Recent years has seen a great evolution in healthcare systems in part as a result of the development of new technologies revolutionizing prediction, prevention and treatment of illness. Health Region promotes a sustainable growth of Health Economy in the Region, which is facing opportunities 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Fig 1: the development of ScanBalt BioRegion and ScanBalt

and challenges within for example: -H  ealth preservation and prediction, prevention and treatment of diseases, and fighting of the major health threats. -D  isparities and differences exist in the economic power of the countries in the Region. -w  eak trans-national and transinstitutional coordination of the whole innovation chain -L  ack of experienced teams to realize proof-of-concept, as well as lack of understanding of the market opportunities and exit possibilities. -S  carcity of early financing for highly innovative ideas blocks development of innovations and growth of start-up companies -P  rocurement practices hinder SME access to the regional health care market. ScanBalt Health Region sets up crosssectoral and transnational reference projects for collaboration and innovations in both health and in life sciences in order to promote public health on a high and sustainable level and to make the region a globally leading and prosperous Health Region. This can only be achieved by enhancing the convergence between EU, national and regional policies within e.g. health, research and industry. HealthPort – first success of ScanBalt Health Region The project HealthPort September 2010 was approved in the Baltic

Sea Region programme 2007-2013. HealthPort will: - Transfer ideas from clinics into business - Enhance Innovation competencies at health care providers and SMEs - Improve SME acess to BSR health care market - Open access to international markets - Integrate regional innovation agendas towards a BSR health economy strategy - Support match making between health care prviders and SMEs - Promote SME access to financing - Support SMEs in procurement practises - Disseminate best trans-national practises for knowledge transfer from health care providers to SMEs - Promote public dialogue on innovation issues Partners in HealthPort are MedCoast Scandinavia (SE/NO), North Denmark Region (DK), Oulu Innovation Ltd (FI), Entrepreneurship Development Centre for Biotechnology and Medicine (EE), BioCon Valley (DE), Turku Science Park (FI), BioBaltica (PL), Vilnius University (LT) and the coordinator ScanBalt (DK). September 2011 ScanBalt BioRegion has 10 years jubilee. On the occasion Mecklenburg-Vorpommern organises the 10th annual ScanBalt Forum coorganised with the annual ScanBalt Academy meeting to take place in Poland. ScanBalt BoRegion is today widely seen as the leading model for macroregional collaboration n Autumn 2010


IPI NEWS

“Smart Pill” from Novartis According to Reuters, Novartis AG plans to seek regulatory approval within 18 months for a pioneering tablet containing an embedded microchip, bringing the concept of “smart-pill” technology a step closer. The initial program will use one of the Swiss firm’s established drugs taken by transplant patients to avoid organ rejection. But Trevor Mundel, global head of development, believes the concept can be applied to many other pills. “We are taking forward this transplant drug with a chip and we hope within the next 18 months to have something that we will be able to submit to the regulators, at least in Europe,” Mundel told the Reuters Health Summit in New York. “I see the promise as going much beyond that,” he added. Novartis agreed in January to spend $24 million to secure access to chip-in-a-pill technology developed by privately owned Proteus Biomedical of Redwood City, California, putting it ahead of rivals. The biotech start-up’s ingestible chips are activated by stomach acid and send information to a small patch worn on the patient’s skin, which can transmit data to a smartphone or send it over the Internet to a doctor. Biodegradable Drug Delivery Innovations For patients with ongoing medical conditions that require consistent treatment with injections, the hassle and discomfort of treatment can be as much of a drain as the ailment they are trying to manage. But researchers are working on a whole new concept of drug delivery, leveraging biodegradable polymers and supercritical fluid technology to make new advances in sustained-release medication. The basic aim is to wrap drug doses in non-toxic, biodegradable, biocompatible materials that allow the drug to be released over an appropriate period before the “wrapper” dissolves into the body. Novartis Discontinues ASA404 Trial Novartis announced today that the clinical trial program for the investigational cancer treatment ASA404 (vadimezan) will be discontinued and resources will be reallocated to other compounds in the oncology pipeline. The decision was made after interim results from a Phase III trial showed that ASA404 would not likely meet the primary endpoint of significantly extending overall survival when used in combination with chemotherapy for the second-line treatment of patients with advanced non-small cell lung cancer (NSCLC). The study, called ATTRACT-2 (Antivascular Targeted Therapy: Researching ASA404 in Cancer Treatment), included patients with advanced (stage IIIb/IV) NSCLC of squamous or nonsquamous histology who experienced disease progression on or following an initial chemotherapy regimen. The trial has been stopped early based on a recommendation from an independent data monitoring committee. Investigators involved in the study and regulatory agencies have been notified of the decision to stop the trial. Novartis does not plan to proceed with regulatory filings based on these data. 110 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Professor Howdle, here posing with a supercritical fluid vessel, is a professor at the University of Nottingham’s School of Chemistry as well as founder and CSO of Critical Pharmaceuticals. For patients and healthcare professionals, this could mean the difference between daily and monthly injections. There is also exciting work being done to apply these biodegradable materials to implants, allowing for devices to be implanted without the need for surgical removal, simply dissolving after therapy has been provided. Successful trials have already been carried out on biodegradable drug-eluting stents, septal occluders and eye implants for the treatment of posterior uveitis. Howdle is the founder and chief scientific officer of Nottingham-based biotechnology company Critical Pharmaceuticals, which is developing a number of biodegradable drug delivery systems for the pharmaceutical market. Although these devices are some way away from commercial production, Howdle seems confident that they will bring huge benefits to patients and doctors alike. Autumn 2010


IPI NEWS

Biowisdom extends partnership with Astrazenca for safety intelligence program BioWisdom Ltd (BioWisdom), the market leader in delivering healthcare intelligence to the pharmaceutical industry, today announces a further 3 year agreement with AstraZeneca. AstraZeneca has been a major partner in the development and exploitation of BioWisdom’s Safety Intelligence Program (SIP) since the program initiation in 2007. Since then, the Safety Intelligence Program has become a key tool for predictive toxicology at AstraZeneca, and the implementation of the Program won the BioIT Best Practices award in 2009. The Safety Intelligence Program applies state-of-the-art technology and methodology to derive highly structured information from publicly accessible sources, which enables more effective searching, retrieval and analysis of prior knowledge in toxicology. The Program is used to support drug safety risk assessment at various stages of the drug discovery process. BioWisdom also applies this same technology to AstraZeneca’s own internal toxicity reports, allowing AstraZeneca scientists the best views of public and proprietary safety knowledge for compounds in both the clinical and preclinical settings. “Implementation of the Safety Intelligence Program at AstraZeneca is delivering real value in drug research and development.” said Dr David Cook, Global Safety Assessment, AstraZeneca. “Providing AstraZeneca’s scientists with desktop access to both internal and public toxicology information and knowledge is a key part of our strategies to improve the early identification and understanding of safety in our projects. Working with BioWisdom and the Safety Intelligence Program enables us to do this in a highly integrated and effective way and we look forward to continuing our strong collaboration with BioWisdom in this important area.” Thermo Fisher Scientific Launches Mass Frontier 7.0: the Chemically Intelligent Small Molecule Structural Elucidation Software for Mass Spectrometry Thermo Scientific Mass Frontier 7.0 software offers a confident path from spectra to structure SAN JOSE, CA (November 10, 2010) - Thermo Fisher Scientific Inc., the world leader in serving science, today announced Mass Frontier 7.0, the newest release of its small molecule structural elucidation software. The software simplifies the management, evaluation and interpretation of mass spectral data and can be used for metabolism, metabolomics, forensics, natural products, impurities and degradants research. Thermo Fisher will showcase the software within its booth during the 27th Montreux Symposium on LC/MS, being held November 10th – 12th, in Montreux, Switzerland. Thermo Scientific Mass Frontier 7.0 software delivers unique features that improve ease-of-use, increase throughput of compounds analyzed, reduce potential for false results and offer more confident structural elucidation. For a demonstration of Mass Frontier 7.0 software, visit the Thermo Scientific booth during the 27th Montreux Symposium www.ipimedia.com

on LC/MS. For further information, call +1 866-463-6522, e-mail analyze@thermofisher.com or visit www.thermoscientific.com/ massfrontier Biotec makes significant appointment to management team Bridgend-based pharmaceutical services company, Biotec Services International, has appointed a new head of project management to its team. Amanda Furnell, 37, joins the business with more than 13 years experience in the pharmaceutical and healthcare industry and an MSc in clinical research from Cardiff University. Now head of project management at Biotec Services International, Ms Furnell will be responsible for managing the import, qualified person certification, labelling, packaging, storage and worldwide distribution of materials for use in clinical trials and commercial supply. On her appointment, Ms Furnell said: “This is an exciting opportunity to join a company which is very much a leader in its field. I look forward to further developing my role within the industry and am confident that my experience in working with a diverse range of pharmaceutical clients on an international level will serve as a real benefit to Biotec”. Bristol-Myers Squibb Foundation Launches $100 Million Initiative Targeting America’s Type 2 Diabetes Crisis The Bristol-Myers Squibb Foundation announced Together on Diabetes®: Communities Uniting to Meet America’s Diabetes Challenge, a 5-year, $100 million initiative to help patients living with type 2 diabetes better manage their disease beyond the doors of their doctor’s office - in their homes and communities - and for the course of their disease. The largest corporate philanthropic commitment to fighting type 2 diabetes in the United States, Together on Diabetes® will draw upon the Foundation’s deep experience supporting community-based, non-medical support services that complement medical care and improve health outcomes. This approach - first employed by the Foundation in 1999 as part of its groundbreaking $150 million SECURE THE FUTURE® initiative to fight HIV/AIDS in Africa - helps remove barriers to diagnosis and care while empowering patients to understand their role in managing their disease and reducing the risks it can pose to their health. Together on Diabetes® is the Foundation’s first large-scale diabetes initiative. Working with a wide variety of communitybased, regional and national partners, Together on Diabetes® will support efforts to develop and expand effective patient self-management programs and broadly engage affected communities in the fight against type 2 diabetes. The initiative’s “innovation fund” will encourage and test new ideas for controlling type 2 diabetes, which today affects about one in 12 Americans and could affect as many as one in three Americans by 2050. Together on Diabetes® also released its first request for proposals, which focuses on African American women. Source: World Pharma News INTERNATIONAL PHARMACEUTICAL INDUSTRY 111


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Page 81 Almac Group Page 21 Amphora Research Systems Page 7 Amsterdam BIO Page 3 Analytical Biochemical Laboratory BV Page 48 & 49 Astra Biotech GmbH Page 77 Berlinger USA LLC IFC BIOCLINICA Page 19 BioM Biotech Cluster Development Page 61 Biotec Services International Ltd Page 91 Biovian Page 23 BIOWIN – health Cluster of Wallonia Page 55 Bioskin GmbH Page 42 & 43 BMG Labtech Ltd. Page 99 BOBST Group Page 101 Brecon Pharmaceuticals Ltd. Page 26 & 27 Cardio3 BioSciences S.A. Page 78 & 79 Carl Zeiss SMT GmbH Page 59 Center For Applied Nanotechnology Page 5 Centrical Global Ltd. Page 51 Chiltern International Ltd. Page 85 Christian Bürkert GmbH & Co. KG Page 47 Domainex Ltd. Page 83 ELPRO – BUCHS AG Page 69 Envirotainer AB Page 63 ERT Page 39 Eurofins Page 65 Excard Research GmbH Page 29 Forresters Page 37 Glycotope Biotechnology GmbH Page 9 Goeteborg BIO Page 25 Health Protection Agency Page 97 Körber Medipak GmbH Page 13 Life Sciences Health Page 31 Ludger Ltd. Page 89 LYOFAL S.A.S. Page 15 Medilingua Medical Translations B.V. Page 17 Miller Insurance Services Limited Page 92 & 93 Moorfields Pharmaceuticals Page 107 12th Annual CTS Europe - Clinical Trials Supply (VIBpharma) Page 109 20th Annual Partnership In ClinicalTrials (Informa LifeSciences) Page 87 Patheon Inc. Page 75 PDP Courier Services Page 33 RANDOX Laboratories Ltd IBC SCA Cool Logistics Page 67 Sensitech Page 105 Scientific Update OBC Swiss World Cargo Page 57 Vaccibody AS Page 45 Vindon Scientific Page 95 West Pharmaceutical Services Page 53 Woodley Equipment Company Ltd. Page 71 & 73 World Courier

Autumn 2010



IPI - International Pharmaceutical Industry