IPI - International Pharmaceutical Industry

A Highly Regulated Environment for Biomarker and Biopharmaceutical Testing Helping to Drive the Global Drug Development Process

Insect Models for Drug Discovery

Recent Trends in Manufacturing Deals and Alliances What’s the Buzz on Pharmaceutical Packaging?

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Volume 3 Issue 2

International Pharmaceutical Industry Supporting the industry through communication


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INTERNATIONAL PHARMACEUTICAL INDUSTRY 1www.ipimedia.com

ContentsPublisher’s letter

regulatory & MarketPlace

risk Management of Drug safety: Pre-approval Planning and research will ensure successDr William C. Maier and Dr Carl de Moor of Registrat-Mapi explain that the last decade has witnessed an increase in the power of national regulatory authorities to require explicit programmes to control and mitigate risks related to the use of new and existing drugs. The impact on the pharmaceutical industry is substantial, because these new laws and regulatory powers will require a significant change in the way drugs are developed and supporting research is done prior to the filing of new drugs. This detailed article concludes that this new era of risk control and accountability requires that companies obtain evidence of the likely effectiveness of their proposed risk control programmes prior to the submission of an application for drug marketing.

the challenges of e-Publishing in regulatory affairs: obstacles to overcome on the Way to “Veni Vidi Publicati”The change to e-publishing has brought about many challenges for regulatory affairs professionals. Conventionally, the end result was the focus of consideration – the electronic submission, and therefore the capability of a company to submit electronically. But e-publishing is much more. As an end-to-end process, it defines the critical capability a company needs to create and fine-tune. The move towards e-publishing has come in waves, and went hand in hand with the advancements in technology and the evolution of standards. Raoul-A. Lorenz, CEO of LORENZ Life Sciences Group, expands further in this article.

recent trends in Personalised Medicine: oncology Deal-MakingSteve Poile, the founder and chief executive officer of Wildwood Ventures Ltd explains in this article that personalised medicine has recently grown in importance as drug companies and regulators alike come to terms with optimising resources on the right interventions for responsive patients, as well as improving early diagnosis of those patients susceptible to certain diseases before they become manifest.

Drug DiscoVery/DeVeloPMent & DeliVery

insect Models for Drug DiscoveryIs the insect hemolymph-fat body-Malpighian-metabolising-excretion system a relevant model for highly efficient documentation of some key ADMET parameters in the early drug discovery phase? Peter Aadal Nielsen, CEO at EntomoPharm, and Gunnar Andersson, CSO at EntomoPharm, answer this question and direct us to how in the future insect models could potentially be used as a filter between in vitro and in vivo models, filling the gap between the ‘quick’ in vitro models and the ‘slow, expensive but more reliable’ in vivo models.

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6Directors: Martin Wright Mark A. Barker

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PrinteD by: SW TWO UK www.swtwo.com

PublisheD by: Pharma PublicationsBuilding K, Unit 104Tower Bridge Business Complex,100 Clements Road, London, SE16 4DG, UK

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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 August 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.

2011 PHARMA PUBLICATIONS


Volume 3 Issue 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

a highly regulated environment for biomarker and biopharmaceutical testing: helping to Drive the global Drug Development ProcessNicola Gaskell, Client Manager in Bioanalytical Sciences at Quotient Bioresearch, explains that this article provides a current overview of how high throughput diagnostic analyser platforms and research-based analysis within a regulatory environment can be used to seamlessly deliver high quality data to the pharmaceutical industry, helping to drive the drug development process for the pharmaceutical industry.

improving the human relevance of Preclinical trials: technologies to replace animal testingA fundamental of drug development is the provision of safe and effective medicines. The safety and efficacy of a drug can only be demonstrated through large-scale trials in humans. However, as Emma Sceats, Business Development Manager at Zyoxel Ltd explains, using humans as test subjects for drugs whose safety is unknown would be unethical. Instead, legal and regulatory guidelines require a plethora of studies to be conducted prior to clinical trials, so that all reasonable steps have been taken to mitigate risk to trial participants. Drug developers are also expected to give evidence of the expected effectiveness of the drug for treating human disease. Scientists have therefore needed to develop non-human models that can help to predict how patients will respond to a drug.

rgcc: a leading company in analysis of cscs as Progenitors of all cancer relapsesIoannis Papasotiriou explains in this article that RGCC Ltd is a leading company in analysis of circulating tumour cells (CTCs) as well as cancer stem cells (CSCs). Through their analysis, the organisation is able to offer services in the clinical field as well as in R&D in the pharmaceutical industry. By using the most advanced and innovative technologies of molecular and cellular biology, RGCC Ltd manages to overpass several restrictions and difficulties that the analysis of CTCs and CSCs involve. Through such an approach a massive amount of information and data has been generated in order to be used for identifying new «druggable» targets as well as offering methods in clinical practice like new and precise assays, risk scale and classification of cancer patients.

Fighting rare Diseases: Pathway from orphan Drug Development to Market accessShirley Johansson of Midfield Media estimates that 6%-10% of the world’s population will suffer from a rare disease at one point in their life, and approximately one out of five people personally know an individual suffering from a rare disease. She goes on to explain that finding a cure or improved treatments for such patients is fundamental, not only to their lives, but also to society as a whole. The journey has begun, and there is great potential to improve the work amongst all stakeholders: patient organisations, governmental authorities, health technology assessment organisations, payers, and orphan drug developers. On 14th–16th September 2011, many of the key stakeholders will be represented at the Orphan Drugs Summit in Copenhagen, a hub for pharmaceutical development, to discuss challenges and

Contentsalternatives to support the fight against rare diseases.

Promotion of aggregation via agitation as a Means of assessing the stability of antibody MoleculesAlison Turner, Principal Scientist at UCB (Celltech), explains in this detailed article how in the process of antibody candidate selection it is important that during manufacture and shelf-life the antibody shows aggregation stability. Hence it is necessary to be able to measure and predict the propensity of aggregation of different antibody molecules in a pre-screening assay.

clinical research

Flexible Phase i study Designs: expediting early clinical Drug DevelopmentValerie Harding, Quanticate’s Communications Account Director, explains that Phase I marks a significant milestone in the development of any new medicinal product. A target has been identified, a compound has been discovered that hits the target, and it has been refined to ensure it has good properties for development. In-vivo safety pharmacology and toxicology studies have been conducted and the compound has been tested in pre-clinical models of the disease. This process will have taken many years. A multi-disciplinary team has evaluated all the data, and decided to take the plunge and invest in clinical development. And now, the drug is ready to be tested in humans.

ePro technology enables reliable, real-time suicidality Monitoring in clinical trialsMichael Federico, Vice President at ePRO, ERT Inc., states in this article that increasing concerns regarding treatment-emergent suicidality have prompted the US Food and Drug Administration (FDA) to issue draft guidance for prospective assessment of suicidal ideation and behaviour in clinical trials. The Columbia-Suicide Severity Rating Scale (C-SSRS), a free-form clinician-administered interview, is an accepted instrument for meeting this requirement. However, procedural variance in the way this and all clinical assessments are performed by human raters has been a shortcoming for many years, negatively impacting the reliability of results. Electronic patient-reported outcome (ePRO) solutions can effectively address this limitation.

implementing the Voluntary harmonisation Procedure for accelerated clinical trial approvalTraditionally, clinical trial application (CTA) approval in EU member states has been subject to national legislation. As a result, the assessment of a CTA that was filed simultaneously in several member states often resulted in varying final decisions and unnecessary delays. Country-specific modifications to the application often occurred due to changes requested by the different competent authorities and ethics committees. In some cases, a clinical trial might even be approved in one member state and rejected in another. The entire procedure could be extremely time-consuming and the country-specific modifications risk jeopardising the scientific value of clinical trial results. Dr Franz Josef Buchholzer, Vice President, Regulatory Operations Worldwide at PharmaNet, concludes in this article that in Europe, the voluntary harmonisation procedure (VHP) is a new

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method to obtain clinical trial approval across multiple European countries in a timely manner. In comparison to the traditional standard national submissions, which must be completed in parallel and submitted to each of the different European agencies, the VHP consolidates these activities into a single submission.

adaptive Designs: a Method for the Future of cancer researchThomas Zwingers, Chief Operating Officer for CROS NT, explains that, in the past few years, we have witnessed an exponential increase in costs for research and development of new cancer drugs: it has been estimated that the average expenditure in R&D for new drugs has doubled in the last decade. Consequently, the question pharmaceutical companies continue to face is: “How can we make a study more efficient while maintaining the validity and integrity?” Sponsors, clinical researchers and biostatisticians are becoming more interested in designs with greater flexibility than the standards and procedures that anticipate “go/no-go” decisions.

Dermatological Models: a sound basis for early Decision-MakingBetsy Hughes-Formella, the Director of Business Development and Consulting at Bioskin GmbH, explains that, in dermatological models, discrete evaluation of treatment effects may be possible following simultaneous application of multiple formulations/actives to small treatment areas in parallel in one individual, without risk of cross-over effects. By making intra-individual comparisons between treatments, the inter-subject variability is reduced, allowing meaningful interpretation of results with smaller panel sizes. Further, in these models non-invasive biophysical measurement and imaging methods to monitor skin function and structure provide alternative objective endpoints to support clinical evaluation, delivering additional information on structural and functional changes in the skin.

labs/logistics & colD chain suPPly

good clinical laboratory Practice: an introductionTim Stiles, Director of Qualogy Ltd, introduces Good Clinical Laboratory Practice (GCLP). GCLP is a quality system for laboratories designed to provide a strong framework to those individuals and organisations that undertake the analyses of samples from clinical trials, specifically on the facilities, systems and procedures that should be present to assure the quality, reliability and integrity of the work and results generated during the organisation’s/individual’s particular contribution to a clinical trial.

it’s a risky business Sue Lee of World Courier (UK) Ltd examines the issues of risk. Risk is a part of life, and will never go away, as we might tell the small child finding out what happens if he sticks his fingers into the electric socket. However, we should remember that if companies decided to take no risks at all then the world of commerce would grind to a halt. It is possible to circumvent almost anything if you are prepared to spend a great deal of money on shipping, chartering flights, driving to the other side of Europe, using hand-carriers and flying people to remote

destinations, but these are normally extreme measures. Perfection can be achieved but is a very expensive commodity, and so a balance must be struck. We should consider the advice of General Patton, who said: “Take calculated risks. That is quite different from being rash.”

ManuFacturing

recent trends in Manufacturing Deals and alliancesOutsourced manufacturing has long been a key component of the pharmaceutical industry, whether it is to overcome internal capacity issues or exploit external expertise and cost advantages. Steve Poile of Wildwood Ventures Ltd explains that in recent years, the trend towards outsourcing manufacturing to India and China has increased, enabling significant cost savings. However, manufacturing is often just a component of a wider deal where the product or technology is being developed, and future manufacture for clinical or commercial use is anticipated within the agreement.

Packaging

in-line Qc - the key to ‘Zero Fault’ Pharma Packaging Production.Until five or ten years ago, companies supplying packaging to the pharmaceutical industry delivered their cartons several days or weeks before they were needed. The cartons went into the stores at the packing and filling plant, where white-coated quality control (QC) people would descend on the job to check that they met with the brand specifications. But this all changed with the arrival of leaner than lean, just-in-time manufacturing. Nowadays the same packaging is delivered not to a warehouse but straight to the filling line itself, and not days or weeks in advance but instead when it is actually needed, almost to the minute. Maryline Strasser of Bobst Group explains how In-Line QC is the Key to ‘Zero Fault’ Pharma Packaging Production.

What’s the buzz on Pharmaceutical Packaging?Gonçalo Poças, the Marketing Manager at Neutroplast and the Director of Neutrodevices, explains that an important – if not essential – part of any pharmaceutical product is its packaging. Nevertheless, it has almost always been seen as an outsourcing need, due to its distance from the core business of pharmaceutical companies. This is ever more present if one takes into consideration that in the development of a new drug, the production of the drug itself, regulatory concerns and its marketing and commercialisation, there are already many physical infrastructures, human resources and other investment involved, which in turn form very heavy and costly structures.

innovative Protection against counterfeiting: a Q&a with richard burhouse at Payne security In this Q&A, Neil Ivey, Sales Development Manager, at Payne Security provides a brief history of Payne Security and answers questions such as: How big a problem is counterfeiting in the pharmaceutical industry? And how can covert technologies work in conjunction with overt technologies such as holograms?

eVents PreVieWs & reVieWs

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Publisher’s letterWelcome to Volume 3 issue 2, of IPI. I take this opportunity to thank all my colleagues within the industry who have helped support us for the last three years to make IPI an informative Journal.

We at IPI have been making some incredible developments too. IPI now has its Weekly Newsletter. Packed with recent news sourced by our staff reporter, extracts of various articles we publish within IPI, and independent company news and banners, this weekly newsletter will keep you abreast of the current trends within this industry. So visit www.ipimedia.com and sign up now for the newsletter.

I and my editorial team bring you a wide selection of interesting and informative series of articles in this issue.

On the Regulatory & Marketplace front, Dr William C. Maier and Dr Carl de Moor of Registrat-Mapi cover the areas of risk management, drug safety and the Pre-Approval Planning and Research processes. The last decade has witnessed an increase in the power of national regulatory authorities to adopt programmes to control and mitigate risks related to the use of new and existing drugs. The impact on the pharmaceutical industry is substantial because these new laws and regulatory powers will require a significant change in the way drugs are developed and supporting research is done prior to the filing of new drugs. Change is fundamental to the pharmaceutical industry and new systems developments are inherent as witnessed in IPI through the article on the challenges of e-Publishing in regulatory affairs by Raoul-A. Lorenz, the CEO of Lorenz Life Sciences Group. IPI always seeks to highlight pharmaceutical trends, and in this issue the focus is on recent trends in personalised medicine in the area of oncology deal-making where Steve Poile, the founder and chief executive officer of Wildwood Ventures Ltd explains further in this article that personalised medicine has recently grown in importance as drug companies and regulators alike come to terms with optimising resources on the right interventions for responsive patients, as well as improving early diagnosis of those patients susceptible to certain

diseases before they become manifest. Insects lend a hand in IPI’s Drug

Discovery, Development & Delivery section, evaluating parameters in the early drug discovery phase with Peter Aadal Nielsen the CEO at EntomoPharm and Gunnar Andersson, CSO at EntomoPharm. In the future insect models could potentially be used as a filter between in vitro and in vivo models. Nicola Gaskell, client manager in bioanalytical sciences at Quotient Bioresearch explains that this article provides a current overview of how high throughput diagnostic analyser platforms and research-based analysis within a regulatory environment can be used to seamlessly deliver high quality data to the pharmaceutical industry, helping to drive the drug development process for the pharmaceutical industry. A fundamental of drug development is the provision of safe and effective medicines. The safety and efficacy of a drug can only be demonstrated through large-scale trials in humans. This topic and related issues are examined by Emma Sceats, business development manager at Zyoxel. Analysis of circulating tumour cells (CTCs) as well as cancer stem cells (CSCs) is an area well known to Ioannis Papasotiriou, head of RGCC, a leading company in analysis of CSCs as progenitors of all cancer relapses. In the section on fighting rare diseases, Shirley Johansson of Midfield Media covers pathway from Orphan Drug Development to Market Access. On 14th–16th September 2011, many of the key stakeholders will be represented at the Orphan Drugs Summit in Copenhagen, a hub for pharmaceutical development, to discuss challenges and alternatives to support the fight against rare diseases. Needless to say, IPI will also be present.

In the section on Clinical Research, Valerie Harding of Quanticate explains that Phase I marks a significant milestone in the development of any new medicinal product. While ePRO Technology Enables Reliable, Real-Time Suicidality Monitoring

in Clinical Trials is a topic tackled by Michael Federico, Vice President at ePRO, ERT Inc. Other vital topics covered in this section include Implementing the Voluntary Harmonization Procedure for Accelerated Clinical Trial Approval, while Thomas Zwingers, the Chief Operating Officer for CROS NT covers Adaptive Designs: a method for the Future of Cancer Research. Dermatological Models, a Sound Basis for Early Decision-Making is an area for Betsy Hughes-Formella, the Director of Business Development and Consulting at Bioskin GmbH.

In the Labs, Logistics & Cold Chain Supply section, Tim Stiles introduces the Good Clinical Laboratory Practice, while Sue Lee of World Courier (UK) Ltd examines the issues of Risk in “It’s a Risky Business“.

In IPI’s Manufacturing section, Steve Poile of Wildwood Ventures Ltd explains that in recent years, the trend towards outsourcing manufacturing to India and China has increased, enabling significant cost savings. However, manufacturing is often just a component of a wider deal where the product or technology is being developed and future manufacture for clinical or commercial use is anticipated within the agreement.

Other topics covered in the Packaging section include, In-Line QC - The Key to ‘Zero Fault’ Pharma Packaging Production, What’s the Buzz on Pharmaceutical Packaging, Innovative Protection Against Counterfeiting: A Q&A with Richard Burhouse at Payne Security.

IPI looks forward to meeting all readers at DIA Annual Meeting in Chicago & ECCP 2011 Toulouse, The ECCP event is the oncology-partnering meeting in Europe for biotech, pharma, investors, clinicians and academia n

Clive BaigentPublisher IPI - International Pharmaceutical Industry

REGULATORY & MARKETPLACE


risk Management of Drug safety: Pre-Approval Planning and Research will Ensure Success

the last decade has witnessed an increase in the power of national regulatory authorities to require explicit programmes to control and mitigate risks related to the use of new and existing drugs. the impact on the pharmaceutical industry is substantial because these new laws and regulatory powers will require a significant change in the way drugs are developed and supporting research is done prior to the filing of new drugs.

National regulatory agencies in the US and Europe have adopted similar approaches to enacting risk control programmes. In the US, the FDA has developed the concept of Risk Evaluation and Mitigation Strategies (REMS). The guidance (FDA, 2011) outlines the requirements and expectations, but not the explicit approach that companies will need to use. The basic elements of the REMS programmes include mechanisms to inform healthcare providers about appropriate use of medications, describe product risks to patients and control access to products through risk screening (i.e. questionnaires), diagnostic testing and use of national speciality pharmacies. Companies selling products with a REMS programme also have to commit to the evaluation of the effectiveness of these risk control measures at regular intervals following the launch of the drug.

The European approach (EMA, 2008) requires that a formal risk control plan (called an EU-RMP) be submitted with each new drug approval application at both a pan-European and national level. This plan outlines both the known and potential risks, and all required methods designed to monitor and control these risks. Within this document, which is finalised at the time of product approval, the sponsor makes explicit

commitments to complete the activities outlined in the document. Like the US approach, there is also a requirement for detail on the effectiveness of the risk control activities, and efforts must be made to change the plan if this effectiveness evaluation indicates the risk control goals are not being met.

The additional complexity in Europe is the multi-layered pharmaceutical regulatory environment. The EMA has responsibility for the approval of most new products in the European Union and will approve a specific risk control programme, but the implementation of this programme will occur and be regulated separately by each individual European Union country. The practical result is that additional risk control activities may be required at individual EU country level. In addition, several EU member state regulatory agencies are questioning the value of educational programmes designed to control risk, as they see these as often relating to promotional activities.

The primary common element of both the US and EU approach is the increased desire to ensure that the proposed risk control methods will be effective prior to approval of the product. Both regulatory agencies have adopted the approach of having additional risk management review committees specifically review the proposed programmes separately from the routine drug approval process. In addition, both regulatory agencies have secured increased regulatory powers to require these programmes and levy substantial fines if post-marketing commitments related to risk control programmes are not completed according to schedule. This increased pre-approval scrutiny, and the increasingly punitive aspect of failing to deliver upon a promised programme, means the pharmaceutical companies need to ensure that they

can prove that their proposed risk control programmes will work following approval of the drug. They also need to ensure that they understand and can prove the feasibility of post-marketing commitments.

The traditional approach of pharmaceutical companies to risk control programmes has been to propose a very minimal risk control programme as part of a new drug application. The goal is to learn what regulatory agencies want by getting them to voice objections as part of the review process and negotiate the final programme. In the new environment, this is unlikely to be a successful strategy because regulatory authorities have adopted a systematic approach to risk control and are looking for proof of effective risk control techniques being proposed.

A similar approach has often been taken by companies in the design of post-marketing commitments. The goal has generally been to secure product approval by promising studies without any assessment regarding the feasibility of actually completing these activities in a reasonable amount of time. In the new environment, regulatory authorities are less likely to be sympathetic and more likely to fine companies with substantial penalties for these failures.

Fortunately, it is possible for companies to generate this additional proof in the pre-approval stage of drug development with a relatively small investment. The proof of likely risk control plan effectiveness is based on: 1) description of current medical practice in a given therapeutic area; 2) sufficient information from practitioners in this therapeutic area to demonstrate that the proposed risk control methods can be enacted and; 3) the efforts to communicate them will be well understood. The feasibility of post-






marketing study commitments can also be understood relatively inexpensively by doing small-scale surveys of a few of the likely recruiting physicians in multiple countries to identify regulatory hurdles, patient enrolment rates, and any issues related to implementation of the study protocol.

In order to illustrate these concepts in a practical setting, I have worked through an example using a hypothetical drug profile for a new drug for multiple sclerosis (MS). MS is an autoimmune condition characterised by recurrent episodes of loss of motor function, progressing to permanent disability and death. This disease area has seen extensive drug development in recent years due to the severity and progressive nature of the disease and the relative lack of therapies to address both acute and progressive elements of the disease in a safe and effective manner. Because the pathophysiology of MS involves an autoimmune process, immunosuppressive or immunomodulatory agents are commonly used and evaluated as therapies. The potential problems associated with this pathway of activity are increased risk of opportunistic infections and cancer.

In the hypothetical example, the company has determined that there are few patient history factors which increase the risk of these adverse events, and as a result the goals of its risk management plan (RMP) are to provide information to physicians and patients about potential risk factors which may increase the risk of opportunistic infections. The company has proposed a set of educational tools to help achieve these goals. These tools include a patient education guide, letters to healthcare providers about the details of the RMP, and a healthcare provider RMP training kit. In addition, the company has proposed a risk evaluation programme including a multi-national post-authorisation safety study of drug users to estimate the incidence rates and risk factors for identified and potential risks as described in the EU-RMP.

The patient education guide would provide the patient with information about the effect of the drug. This will also provide some detail on activities that the patient’s physician will do to monitor for potential adverse effects, symptoms that the patients might observe if they are

developing an opportunistic infection and what a patient should do if any of these symptoms are observed. The healthcare provider (HCP) letters would provide a summary of the rationale and goals of the RMP and describe the communication tools being used to achieve these goals. It would also mention that a training kit is available for healthcare providers. This training kit would provide detailed instructions targeted at different types of healthcare providers that may be involved in patient care. It would describe how the drug acts to improve MS and the potential adverse events of this therapy. For each of these potential adverse events, it would list potential risk factors and signs that may indicate the development of these conditions. It would list any routine monitoring that may be carried out within the primary care setting and describe what physicians should do if they suspect one of these adverse effects is developing within a patient.

The pre-approval approach to development of these tools would involve a process of qualitative focus groups to develop the content of each of these tools. The goal of the pre-filing qualitative testing would be to evaluate the appropriateness and readability of the material from the perspective of healthcare providers. This would involve the conduct of multiple focus groups of physicians and non-physician healthcare providers. Multiple focus groups would be conducted in an iterative fashion to allow for revision of materials between focus groups and for confirmation of any trends observed. Focus groups have the advantage in this application because a large amount of information can be collected in a short period of time. An additional advantage is the sponsor can also attend these focus groups, as long as participants are notified before attending, behind an opaque glass and request the moderator to gain more information on specific topic areas that arise during the meeting. Regulatory guidance indicates that multiple interviews or focus group testing can assist in determining acceptance or comprehension of a risk control tool by major stakeholder groups. These focus groups would involve 5-10 participants per group and could be organised and conducted within a short period of time

to allow for them to be conducted in the year prior to submission of the drug marketing application.

Post-authorisation safety studies (PASS) are challenging to conduct because of frequent difficulties related to the recruitment of physicians and patients. Unlike clinical studies, PASS studies usually involve physicians with limited research experience, thus the sponsor of the studies will usually have to provide support services to secure ethical approval and data collection from the site. These studies are observational studies of marketed products so no drug has to be distributed, and physician payments tend to be low because of the relatively limited procedures performed for each patient. In addition, these studies usually involve large sample sizes (>1000 patients), and large numbers of sites are generally needed.

Pre-approval feasibility assessments based on short interviews and questionnaires sent to a small number of physicians in the major countries expected to be included in the study can provide evidence to understand the feasibility of a proposed PASS study. The information requested in

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these feasibility assessments includes expected rate of patient enrolment at each site, any likely problems associated with conducting the research, and the willingness of the site to participate in the research. These can usually be conducted within two to four weeks and can be easily conducted in the year prior to submission of the drug marketing application.

The new era of risk control and accountability requires that companies obtain evidence of the likely effectiveness of their proposed risk control programmes prior to the submission of an application for drug

marketing. Failure to provide this information is likely to lead to either longer approval times or increased failures during the drug approval process. However, the information on programme effectiveness is relatively easy and inexpensive to obtain prior to submission of a marketing application. As a result, companies can ensure the success of their new medications by conducting this research n

Reference:1. Draft Guidance for Industry Format and

Content of Proposed Risk Evaluation and Mitigation Strategies (REMS),

REMS Assessments, and Proposed REMS Modifications. 2011. FDA www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory

Information/Guidances/ UCM244570.pdf2. Volume 9A of The Rules Governing

Medicinal Products in the European Union Guidelines on Pharmacovigilance for Medicinal Products for Human Use. 2008 EMA http://ec.europa.eu/heal th/ f i les/eudralex/vol-9/pdf/vol9a_09-2008_en.pdfGuidanceComplianceRegulatoryInformation/Guidances/UCM244570.pdf

Dr William C. Maier, is Vice President Epidemiology, Drug Safety, and Risk Management at Registrat-Mapi the industry’s largest clinical research organization (CRO) dedicated solely to real-world clinical research.Dr Maier has over 20 years of experience in drug development and commercialization at pharmaceutical companies in Europe and the United States. He was previously Senior Director of Epidemiology at GlaxoSmithKline and Elan Pharmaceuticals and led research groups conducting observational research using registries, databases, chart reviews and field research to support reimbursement, marketing and

drug safety investigations of pharmaceuticals throughout the world. He has worked on over 50 observational studies in several disease areas including respiratory, neurology, psychiatry, autoimmune, cancer, endocrinology, cardiovascular, cerebrovascular, urology, opioid dependency and vaccines. He routinely provides training seminars to pharmaceutical, biotechnology and medical products companies in Europe and the US on the use and development of real-life data for use in health technology assessment, drug safety and risk management. In July 2007 he presented the Tysabri Risk Management Plan at an FDA advisory committee meeting. Dr Maier is editor of the quarterly PharmacoEpi and Risk Management Newsletter, (http://www.prmnewsletter.org/) which publishes articles on applications of methods, development of new tools and reflections on regulatory developments in product safety, pharmacoepidemiology and risk management. He is also involved with the International Society of Pharmacoeconomics Research (ISPOR) project to develop a global database of real-life health care information (www.ispor.org/Intl_Databases/) and is a member of the EMEA’s European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (www.encepp.eu). In addition, he is a frequent speaker at medical conferences and has academic appointments in the UK (Dundee) and the USA (North Carolina). Email: [email protected]

President Dr. Carl de Moor brings a wealth of Medical Research and clinical research organization (CRO) experience in the areas of epidemiology, biostatistics, & health outcomes. He collectively has 24 year of experience in consulting and research in epidemiology, biostatistics, and health outcomes including retrospective and prospective observational studies, secondary database analyses, clinical and patient reported outcomes studies, economic analysis, and design of registries. He also has extensive experience in the design of Phase I-IV clinical trials. Beginning his career as a Research Assistant Professor at the

University of Texas Health Science Center, Carl has served as Chief, Behavioral Statistics & Associate Professor of Biostatistics at the University of Texas M. D. Anderson Cancer Center; Associate Director of Design & Analysis and Associate Professor, Division of Biostatistics at the University of Texas Health Science Center at Houston, School of Public Health; Director, Data Management Core, Clinical Research Program, Children’s Hospital Boston and Associate Professor, Department of Psychiatry, Harvard Medical School. Most recently, he served as Executive Director, Epidemiology & Health Outcomes at PPD where he was responsible for pharmacoepidemiology, safety registries, health outcomes, and pharmacoeconomic consulting and studies in the late stage research. Prior to this position he was Vice President Health Outcomes and Pharmacoeconomics for Supportive Oncology Services, Inc. in Memphis, responsible for direction of all health outcomes, pharmacoeconomic, and pharmacoepidemiology post marketing observational studies. Dr. de Moor has been published in more than 95 peer-reviewed publications in clinical, epidemiological and health outcomes studies, has served as biostatistician co-investigator and co-principal investigator on 40 funded grants and contracts, and performed article reviews for 12 industry publications. He has performed grant review committee service for the NIH, Lance Armstrong Foundation, California Tobacco Control Initiative, CDC, and American Cancer Society. He received his PhD and MS in Biostatistics from the University of Washington and a BS in Biology from San Diego State University.Email: [email protected]

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the challenges of e-Publishing in regulatory affairs – Obstacles to Overcome on the Way to: “Veni Vidi Publicati”

the Move towards e-PublishingThe change to e-publishing has brought about many challenges for regulatory affairs professionals. Conventionally, the end result was the focus of consideration – the electronic submission, and therefore the capability of a company to submit electronically. But e-publishing is much more. As an end-to-end process, it defines the critical capability a company needs to create and fine-tune.

The move towards e-publishing has come in waves, and went hand in hand with the advancements in technology and the evolution of standards.

In this context, we will refer to e-publishing as the creation of a submission for regulatory filing. The submission itself may in the end then be in paper or electronic format, but the source documents for either output will be electronic.

a “bolt-on”When e-publishing gained more momentum in the early to mid-nineties, engaging in this luxury for regulatory affairs departments meant spending considerably more time and effort. The reason for this was simple: the entire

document and submission creation value chain remained unchanged, and it was left up to regulatory affairs to “bolt on” electronic publishing at the end of this process.

Usually, every department delivered their results on paper. The regulatory affairs departments then made scans of these results to convert them back into an electronic format, in order to then create an electronic output. In essence, the result was an exact digital version of the paper format that existed.

The result of the above process was that electronic publishing was regarded

as time-consuming and expensive. It delayed the potential submission date, and at the same time it made those working in the value chain prior to regulatory affairs work harder to complete tasks faster - ultimately, to leave time for the e-publishing “bolt-on”.

However, with time came greater insight into the organisational document creation processes. Some companies began to see e-publishing as a means to streamline their entire document creation value chain – and in fact looked at e-publishing not as an end, but merely as a means to an end.

shift in Focus: Digital Value chainWith a shift in focus from “How do I get an electronic submission to an agency?” to “How can I digitise and optimise my entire document and submission creation value chain?”, the electronic submission in itself became less important: no matter whether the output is paper or an electronic document, the succeeding process is the same. So the importance of the electronic compilation increased, with the whole submission process now starting with electronic documents. The publishing process can then create an electronic as well as a paper output.

Some companies used this technique to significantly reduce the time needed to create their submissions. For example, companies such as Berlin-Chemie AG (Berlin, Germany), today a part of the Menarini Group, significantly increased their capabilities in generating submissions: from 1995 to 1999, they compiled and submitted 29 submissions. In 2000 alone, they compiled and submitted 21 submissions. According to Berlin-Chemie, this goal would not have been achieved without the rigorous implementation of a digital process for the compilation of submissions.

By 2000, the US Food & Drug Administration had also spent two years experimenting with standardised electronic submission formats. By then it had become obvious that e-publishing to generate an electronic output was no longer just an option and a means to generate more efficiency in the document and submission creation processes, but that in fact “e-submission” was well on its way to becoming a mandatory format in the near future.

change ManagementToday, this vision has become clearer, and most regulatory agencies participating in the International Conference on Harmonization (ICH) have made statements confirming

The industry challenge:

eCTD Submission Management

Key areas: Life Cycle Management High Performance and

Scalability in formats and devices

Multi Document Management System Support Compability in current and future global standards

Submitting eCTD‘s & NeeS?Reduce your risk!Download our FREE Basic LORENZ eValidator 3.0!www.lorenz.cc

The solution:LORENZ docuBridge is a regulatory submission management system designed to create, publish and review eCTD, NeeS, PDF and paper submissions.

Your contact: LORENZ Archiv-Systeme GmbHEschborner Landstrasse 7560489 Frankfurt/MainGermanyTel.: +49-(0)69 78991 - 901Fax: +49-(0)69 78991 - 129

[email protected] – www.lorenz.cc



that electronic submission is the way forward, some of them even making it a prerequisite.

However, many companies still struggle to make the transition from a paper-based to an electronic-based publishing approach. There are several reasons for this:1. A different set of skills is required in

regulatory affairs in order to operate in an electronic environment. Regulatory affairs managers today need to have a solid understanding of IT and technical guidelines, while in the past their focus was only on content and understanding the scientific guidelines and interpretations. In order to overcome this hurdle, many companies have set up dedicated e-publishing departments that work closely together with regulatory affairs and focus solely on compiling electronically and publishing electronically.

2. Many companies still fail to look at the entire document and submission creation value chain. Electronic publishing is still treated as a “bolt-on” and seen as an additional expense, rather than an investment in the submission infrastructure capabilities of a company. Furthermore, the concept of submission lifecycle, defined as the history of changes to an original submission over time, is still underestimated. While many accept that a document has a lifecycle which must be controlled, few understand the exponentially greater complexity (measured in numbers of hyperlinks, pages and documents) of managing the lifecycle of a submission.

3. Continuous education is critical. Publishing according to digital standards and specifications means that companies are subject to constantly changing requirements. This is the nature of technology: nothing remains constant. Specifications are like software development, they are constantly upgraded or improved to iron out weaknesses. Companies that do not keep their regulatory affairs or publishing staff up to date may find they are publishing to old and outdated standards rather than current ones. Understanding where standards are going is equally vital: it may well have an impact on the document creation strategy for

submissions several years down the line.

4. Misaligned expectations can cause a sense of frustration. Regulatory affairs may have unreasonable expectations of what an electronic publishing process can do for them – forgetting that technology and software are meant to support the process rather than replace it. In part, software vendors in this area may also have contributed to building up an unreasonable expectation to win a customer.

5. Finally, investments in the wrong type of products and services to realise the e-publishing capabilities may also cause a problem. It is vital for companies when investing in e-publishing capabilities to fully understand their requirements in order to be able to distinguish between the different solutions on the market. Vendor selection cannot be based on superficial knowledge, and being dependent on one vendor only may lead to costly mistakes. Talking to user groups, references and attending relevant conferences is a vital component of research that needs to be done prior to any vendor selection.

Future challenges – and benefits: ectD, Foreign reviewMore challenges are about to come in the future, as e-publishing is entering yet another transition stage. Current standards like the electronic Common Technical Document (eCTD) will soon be replaced by a new one in the upcoming years, the Regulated Product Submission (RPS). The eCTD currently only allows for a one-way communication between sponsor and agency, and is very much focused on human drugs. RPS is will not only allow for a two-way communication, but it will also make it possible to handle more submission types. For some vendor technologies, this could mean a change or delay in e-publishing capabilities adherent to the RPS standard, and could necessitate new hardware/software/training investments by purchasing companies.

Secondly, as can be seen from standards such as the US Structured Product Labeling (SPL), the exchange of information is increasingly based on

data, rather than on documents. This will have a significant impact all the way back to the authoring process: companies who believe that they can “bolt on” the data submission types at the end of the submission process will find themselves in a costly no-win situation similar to those companies which chose the “bolt-on” route when the concept of electronic submission was first gaining momentum. Again, the same case for action and the same criteria for success apply even as e-publishing enters a new phase: Embracing e-publishing means facing the necessity to look at the complete publishing process and re-engineering the value chain with a holistic view, as opposed to living with band aid solutions which cover up fundamental process flaws.

Finally, the output that is generated by e-publishing processes – the “electronic submission” – is currently stimulating a new round of discussions amongst regulators: reducing workload and accelerating the ability to bring medicines to the market faster through “foreign review”. The ability to share information more easily in a digital world can bring together experts in a number of fields from a number of different regulatory agencies. Global regulators working together virtually on the same dossier can prove beneficial not just for the sponsor, but in particular for the most important stakeholder as well: the patient n

Raoul-A. Lorenz, CEO, LORENZ Life Sciences Group graduated with a B.A. (Hons) in European B u s i n e s s Administration from the European Business School of London, UK. Raoul joined LORENZ in 1996 and held various positions including directorships of the LORENZ UK, US, Canadian, German and Indian divisions before he was assigned CEO in 2006. Raoul regularly runs workshops and gives presentations on electronic submissions, DIA, BIRA/TOPRA and related topics at European, North American and Australian conferences.Email: [email protected]

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recent trends in Personalised Medicine: Oncology Deal-MakingPersonalised medicine has recently grown in importance as drug companies and regulators alike come to terms with optimising resources on the right interventions for responsive patients, as well as improving early diagnosis of those patients susceptible to certain diseases before they become manifest.

Much has been driven by a tightening of budgets and closer regulatory scrutiny of new products and their worth. As a result, opportunities have emerged to use new technologies to better match patients with the best interventions leading to better outcomes. Consequently over the past few years there has been a growing frequency of personalised medicine-focused partnering.

In 2010, a total of over 200 personalised medicine deals were announced (source: Current Agreements) of which about half had an oncology focus. This is nearly double the number of personalised medicine deals seen in 2009 and suggests that there has been a significant increase of interest in this field.

The lead oncology indications for personalised medicine since 2005 have

included breast, colorectal and lung cancer.

Big pharma companies play a minor but emerging role in deal-making in emerging personalised medicine R&D. Of the over 200 personalised medicine partnering deals announced in 2010, only 36 deals, or just fewer than 20%, had a big pharma company as a party to the deal. Many are in partnership with small diagnostic or biomarker companies in order to develop companion diagnostics, either for use during a clinical trial to enable more ready determination of clinical endpoint, or to accompany a new product launch into the market where reimbursement may be aligned to clinical outcome.

What makes personalised medicine partnering particularly interesting is the number of deals between small biotech, diagnostic and research tools companies – representing over 80% of deals in 2010. This is often a feature of a new exciting and emerging technology area, and it is being played out in the personalised medicine arena.

The following table provides a listing of recent personalised medicine deals of note where the parties to the deal are smaller biotech, diagnostic or research tools-focused. The data has been selected for oncology-focused deals.

The number of oncology-based personalised medicine deals so far in 2011 (42 by mid-April 2011) suggests that this continues to be a very active area for the future. We expect to see a growing number of deals, as both

smaller companies partner to bring new biomarkers and diagnostics forward, and larger companies increasingly participate to accelerate new drug discovery, development and drug treatment-companion diagnostic linked products enter the market.

*Current Partnering has recently published a series of Personalised Medicine partnering reports: Personalized Medicine Partnering Terms and Agreements, Biomarker Partnering Terms and Agreements, Companion Diagnostic Partnering Terms and Agreements, and Pharmacogenomic Partnering Terms and Agreements.

Current Agreements is a premium subscription database providing comprehensive business information and intelligence with access to thousands of contract documents, giving coverage of all deals and alliances across the life sciences sector n

Steve Poile is the founder and chief executive officer of Wildwood Ventures Ltd., the publisher of CurrentPartnering, the online provider of best practice, business information and intelligence for deal-makers, and Current Agreements, premium subscription database providing comprehensive business information and intelligence with access to thousands of contract documents, giving coverage of all deals and alliances across the life sciences sector. Steve has over 20 years’ experience in the life sciences sector, having previously founded Pharmalicensing and co-founded Bridgehead International. Prior to his entrepreneurial career, Steve was both a business development manager at Reckitt Pharmaceuticals and development scientist at GlaxoSmithKline.Email:[email protected]

Figure 1: Recent oncology partnering activity

year number oncology deals

2009 529

2010 556

2011 to date* 162

Figure 2: Recent oncology partnering by therapy target Jan 2010 to Apr 2011

Date Parties stage therapy area Value us$m

upfront us$m

royalty rate %

subject

16/02/2011 AVEO Pharmaceuti-cals, Astellas

Phase III Kidney cancer, Oncology

1425 75 50 Collaborative R&D and com-mercialisation agreement for tivozanib

24/01/2011 Amgen, Biovex Phase III Head and neck cancer, Melanoma

1000 425 Licensing agreement for OncoVEX(GM-CSF)

10/01/2011 Epizyme, GlaxoSmithKline

Discovery Oncology 650 20 n/d Development and licensing agreement for epigenetic enzymes for the treatment of cancer and other diseases

19/01/2011 Pfizer, Theraclone Sciences

Discovery Infectives, Oncology 632 n/d Collaborative R&D agreement for I-STAR technology in infectious disease and cancer antibody discovery

04/01/2011 Servier, Xoma Phase III Cardiovascular, Diabetes, Inflammatory, Oncology, Ophthalmics

555 35 n/d Development, licensing and option agreement for XOMA 052 for multiple indications

16/03/2011 Five Prime Therapeutics, Human Genome Sciences

Phase I, Phase II, Preclinical

Oncology 495 50 n/d Development and licensing agreement for FP-1039

25/02/2011 Quintiles Transnational, Samsung Electronics

Oncology, Rheumatoid arthritis

265.5 Joint venture agreement for biomedicals

06/01/2011 Pfizer, Seattle Genetics Discovery Oncology 208 8 n/d Licensing agreement for antibody drug conjugate technology for oncology target

22/03/2011 Abbott Laboratories, Seattle Genetics

Discovery, Preclinical

Oncology 208 8 n/d Collaborative R&D agreement for antibody-drug conjugate (ADC) technology with antibodies to a single oncology target

10/03/2011 Eisai, Epizyme Preclinical Lymphoma, Oncology 206 6 50 Collaborative R&D, development and licensing agreement for therapeutics targeting EZH2

31/01/2011 Eisai, H3 Biomedicine Discovery Oncology 200 Collaborative R&D agreement for oncology treatments

14/04/2011 4SC, Yakult Honsha Phase II Colorectal cancer, Lymphoma, Oncology

189.8 5.8 n/d Licensing agreement for Resminostat

07/04/2011 Boston Biomedical, Dainippon Sumitomo Pharma

Phase I, Phase II

Colorectal cancer, Oncology, Solid tumors

170 15 n/d Licensing agreement for BBI608

06/01/2011 Chiva Pharmaceuticals, Ligand Pharmaceuticals

Discovery Hepatitis B, Hepatitis C, Liver cancer, Liver disease

101 1 n/d Development, licensing and sub-licensing agreement for hepatitis programs

30/03/2011 Gilead Sciences, Yale University

Discovery Oncology 100 Collaborative R&D agreement for oncology research

Figure 3: Recent oncology deals of note – 2011 1



of Life Sciences Health

Dutch Masters

Cooperation is in our genes

Life Sciences Health and Amsterdam BioMed Clusterare pleased to welcome the 6th edition of BIO-Europe Spring 2012 to Amsterdam.

The Netherlands is one of fi ve European countries characterized by the EU as ‘having a high number of high-impact universities’. Indeed, 11 out of the country’s 14 universities ranked within the fi rst 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.

Small country, world-class researchIn 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.

Adding to reputable universities are about one thousand life science-related companies and eight top-quality university medical centers, 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.

Science shapes our minds

Trends in citation impact scores

(1993-1996 vs 2003-2006)*,**

Source: CWTS/Thomson Scientifi c Web

of Science fi le. Adaptation: CWTS.

* Area-normed citation impactscores

(global average = 1,0).

Figuur 3.9 Trends in citation impact scores (1993-1996 vs 2003-2006)*,**

% increaseimpact score

Switz

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Net

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35 Impact 1993-1996

Impact 2003-2006

Change in impactbetween ‘93-’96 and ‘03-’06 (%)

More informationTo fi nd out more about Dutch life sciences and potential life sciences partners, please visit www.lifesciences.nl or email [email protected]

To get information on the many advantages of setting up or expanding business operations in the Netherlands, please visit www.nfi a.nl or email info@nfi a.nl

[email protected] +31 (0)71 332 2025F +31 (0)71 332 2026

“In Holland all major players are just a stone’s throw away: 11 universities with biomed research 8 university medical centers Up to 300 innovative SMEs, multinational med- & biotech and Pharma 120 mile radius”

Thr

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Impact 2003-2006


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Through the ages, the Dutch have always been masters of innovation, not just in the arts but in science and business as well. Creativity, entrepreneurship and a strong inclination to reach across boundaries enabled a small low-lying country to become a world player.There are many good reasons why any search for European life sciences partners should begin in The Netherlands.

The Dutch are world champions in seeking consensus and collaborationToday, the Netherlands stands out for its collaborative research and development programs, especially in the life sciences. Among major research-oriented EU countries, the Netherlands ranks number one in the number of international collaborations per scientist. In Europe’s collaborative Research Programs, Dutch leadership often proves benefi cial for success. In The Netherlands, the public and private sectors have joined their efforts on a huge scale. The country has invested billions of Euros in public-private life

sciences partnership programs, their scopes ranging from basic genomics research to developing medical, agricultural and industrial applications.

In other words, The Netherlands is built upon people working together, so anyone in search of collaborators should really start with the Dutch.

1006040200 80 120 160 180140

Number of participations in European programmes per thousand researchers

Netherlands

Belgium

Switzerland

Austria

Denmark

Sweden

UK

Finland

France

Germany

Top-ten European research countries, ranked according to participations

in European research programs per thousand researchers (2008-2009).

Source: European Commission.

of Life Sciences Health

Dutch Masters

Cooperation is in our genes

Life Sciences Health and Amsterdam BioMed Clusterare pleased to welcome the 6th edition of BIO-Europe Spring 2012 to Amsterdam.

The Netherlands is one of fi ve European countries characterized by the EU as ‘having a high number of high-impact universities’. Indeed, 11 out of the country’s 14 universities ranked within the fi rst 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.

Small country, world-class researchIn 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.

Adding to reputable universities are about one thousand life science-related companies and eight top-quality university medical centers, 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.

Science shapes our minds

Trends in citation impact scores

(1993-1996 vs 2003-2006)*,**

Source: CWTS/Thomson Scientifi c Web

of Science fi le. Adaptation: CWTS.

* Area-normed citation impactscores

(global average = 1,0).

Figuur 3.9 Trends in citation impact scores (1993-1996 vs 2003-2006)*,**


Switz

erla

nd

Uni

ted

Stat

es

Net

herl

ands

Den

mar

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UK

Nor

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0.40

0.60

0.80

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1.40

1.60

−10

−5

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5

10

15

20

25

30

35 Impact 1993-1996

Impact 2003-2006


More informationTo fi nd out more about Dutch life sciences and potential life sciences partners, please visit www.lifesciences.nl or email [email protected]

To get information on the many advantages of setting up or expanding business operations in the Netherlands, please visit www.nfi a.nl or email info@nfi a.nl

[email protected] +31 (0)71 332 2025F +31 (0)71 332 2026

“In Holland all major players are just a stone’s throw away: 11 universities with biomed research 8 university medical centers Up to 300 innovative SMEs, multinational med- & biotech and Pharma 120 mile radius”

Thr

ee S

pher

es II

, 194

6, M

C E

sche

r, The

M.C

. Esc

her

Com

pany

B.V

. - B

aarn

- H

olla

nd.


Switz

erla

nd

Uni

ted

Stat

es

Net

herl

ands

Den

mar

k

UK

Nor

way

Belg

ium

Ger

man

y

Fran

ce

0.40

0.60

0.80

1.00

1.20

1.40

1.60

−10

−5

0

5

10

15

20

25

30

35 Impact 1993-1996

Impact 2003-2006


Ana

tom

y Le

sson

of D

r. N

icol

aes T

ulp,

, 16

32, R

embr

andt

van

Rijn

, Roy

al P

ictu

re G

alle

ry M

aurit

shui

s The

Hag

ue

Through the ages, the Dutch have always been masters of innovation, not just in the arts but in science and business as well. Creativity, entrepreneurship and a strong inclination to reach across boundaries enabled a small low-lying country to become a world player.There are many good reasons why any search for European life sciences partners should begin in The Netherlands.

The Dutch are world champions in seeking consensus and collaborationToday, the Netherlands stands out for its collaborative research and development programs, especially in the life sciences. Among major research-oriented EU countries, the Netherlands ranks number one in the number of international collaborations per scientist. In Europe’s collaborative Research Programs, Dutch leadership often proves benefi cial for success. In The Netherlands, the public and private sectors have joined their efforts on a huge scale. The country has invested billions of Euros in public-private life

sciences partnership programs, their scopes ranging from basic genomics research to developing medical, agricultural and industrial applications.

In other words, The Netherlands is built upon people working together, so anyone in search of collaborators should really start with the Dutch.

1006040200 80 120 160 180140

Number of participations in European programmes per thousand researchers

Netherlands

Belgium

Switzerland

Austria

Denmark

Sweden

UK

Finland

France

Germany

Top-ten European research countries, ranked according to participations

in European research programs per thousand researchers (2008-2009).

Source: European Commission.

DRUG DISCOVERY/DEVELOPMENT & DELIVERY


insect Models for Drug Discovery

Currently, it takes from $800 m to $1 bn and 10-16 years to bring a new drug to market. It is estimated that only four in 5,000 - 10,000 compounds that begin preclinical testing will progress to human testing, and only one of those will be approved for human use. About 40-60% of the compounds fail due to absorption, distribution, metabolic, elimination and toxicological (ADMET) properties in clinical development where the cost per drug candidate is the most expensive1. Thus, it is essential for the pharmaceutical companies to reduce the costs and the time to market for new drugs. To succeed in doing this more and more complex in vitro models are developed and applied as filters to select the most suitable compounds for the in vivo models. However, the gap between in vitro and in vivo models is still large and this may introduce problems when linking in vitro findings to in vivo readouts. Hence, there is demand for intermediate models that give a better prediction of in vivo ADMET parameters than in vitro models, and at the same time are faster and cheaper than traditional vertebrate in vivo models. There are strong indications that insect models may fill the gap between in vitro and in vivo.

Certain invertebrates have served as useful models for understanding many different biological processes. In particular, the fruit fly, Drosophila melanogaster (Dm) is a well-recognised model research organism, which has already made significant contributions to the understanding of, e.g., genetics, neurobiology, and molecular biology2. Generally, insects and vertebrates have many physiological features in common. They are all multi-cell organisms, but the anatomy of insects is relatively simple and the physiology is well-studied. Moreover, there are remarkable molecular and functional similarities with mammals, and this suggests that insects may be relevant as models in drug discovery research.

Transgenic models of Dm have been developed to imitate neurodegenerative human diseases. Some of these models have demonstrated their

efficiency for testing relevant drugs, and concordance of drug efficacy in flies and mammals is seen for diseases like Huntington’s, Parkinson’s and Alzheimer’s3,4. In addition, Dm has been used to provide model systems for research on drug abuse5. In fact, such studies led to identification of genes required for cocaine sensitisation in mammals. Hence, insects have proved their potential as experimental models in drug discovery. The homologies between insects and vertebrates also allow studies of ADMET properties of chemicals. Thus, insects are potential new model organisms for studying blood brain barrier (BBB) permeability, pharmacokinetics (PK), intestinal absorption and transporter mediated efflux/influx of chemicals.

insect PhysiologyIn contrast to vertebrates, insects do not have a blood vessel-based circulatory system. Instead the body fluid (i.e. the hemolymph) circulates (by aid of a dorsal beating tubular heart) throughout the insect body. In the hemolymph nutrients are transported to the various organs while waste products are transported to the excretory organ, i.e. Malpighian tubule. An optimal internal environment is obtained by regulation of hemolymph osmotic pressure. This regulation is executed by the Malpighian tubule, long thin blindly ended tubes arising from the posterior end of the midgut, exhibiting a most efficient capacity to exchange material with the hemolymph and maintain a proper internal environment (Figure 1).

The principal cells of the Malpighian tubule are enriched with closely packed microvillus, and the cells contain numerous mitochondria indicating metabolically very active cells. The principles for water and molecular entry to the Malpighian lumen are the same as that for primary urine formation in vertebrates. In vertebrates the liver is very important for a first pass metabolism of orally-administered drugs. Metabolisms in insects occur in a number of organs, mainly the intestinal mucosa, the fat body (a specialised tissue consisting of cells with enormously increased

outer membrane surface area and high capacity for uptake and metabolism similar to that of vertebrate hepatocytes) and the Malpighian tubule. In Dm it has been shown that there is a remarkable enrichment of detoxification genes (e.g. cytochrome P450 (CYP450) enzymes and glutathione-S-transferases) in the Malpighian tubule6. Furthermore, microarray studies have shown that nearly every subclass of the huge ABC transporter gene family, as well as the OAT, OCT, OATP, sugar and amino acid transporter families, are highly expressed in the Malpighian tubule7.

Pharmacokinetics To make a successful drug, displaying a therapeutic effect, the drug must pass all pharmacokinetic hurdles in order to reach the target organ and exert its pharmacological action. Thus, it is important to investigate to what extent compounds permeate cellular membranes, how they are distributed, the rate and extent of metabolism, etc. The metabolism is usually addressed in vivo by measuring the compound concentration in the blood over time. It is known that insects are able to metabolise xenobiotic compounds, e.g. pesticides, in a similar manner to mammals. This is the basis for adding compounds like piperonyl butoxide to

Figure 1. The Malpighian organ in insects consists of long blindly ending tubular structures that arise at the junction between the midgut and the hindgut, and functions as an excretory organ maintaining the homeostasis in the hemolymph. The functional similarities between human and insect primary urine formation and its neuroendocrine control combined with the metabolic capacity of the Mapighian organ makes insects excellent models for basic and applied pharmacology research in drug metabolism and clearance.

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insecticide mixtures, as these potentiate the effect of the toxic pesticides through inhibition of CYP450s in the insects. In a recent study we injected Quinidine into six grasshoppers and hemolymph samples were extracted from each insect at five different time-points. From this study it was seen that Quinidine is metabolised by insects over time as shown in Figure 2.

intestinal absorptionThe vertebrate intestine is known for its absorptive function because of the presence of large numbers of microvilli and the expression of several physiological relevant uptake carriers for nutrients. In addition there is a high expression of both phase I and phase II metabolising enzymes contributing to the so-called first pass metabolism. Furthermore, the high abundance of the efflux transporters like P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) severely limit the absorption of numerous drugs. Much attention has been given to the dynamic interaction of metabolism, secretion and the role of transporters on drug absorption. Because of the significant role of the intestine in the first pass metabolism and permeation of drugs a number of models have been established from cellular in vitro models (e.g. CaCo-2) via intestinal tissue preparation (Ussing chamber) to in vivo techniques. However, factors affecting drug absorption include drug permeability, metabolism, transporters and interaction between these factors, and this is difficult to model in vitro8. On the other hand from traditional vertebrate in vivo ADMET models it is difficult to distinguish the effect related to the actual intestinal absorption from the metabolising effects in the liver.

In insects the alimentary midgut cells are tall, columnar and morphologically very similar to vertebrate enterocytes and exhibit huge numbers of microvilli towards the luminal side. Also similar to the vertebrate intestine there are proliferative zones with the same stem cell principles of reproduction and differentiation as in vertebrates. The presence of the CYP450 system in the insect midgut cells has been shown, but there is sparse information on the presence of transporters, though an

unexpected similarity between intestinal sugar absorption in vertebrates and insects has been reported9.

bbb PermeabilityThe vertebrate BBB represents the physiologic barrier between the brain tissue and blood vessels, which restricts the exchange of solutes and regulates absorption of exogenic agents (e.g. drugs) from the blood into the brain. Penetration of the BBB is one of the major hurdles in the development of successful CNS drugs. The insect BBB has largely been ignored as a model system for the mammalian BBB, because it was for a long time assumed that epithelial barrier junctions in insects and vertebrates were analogous rather than homologous structures. However, identification of homologous proteins, i.e. claudines, at the epithelial junctions of both septate junctions in flies and tight junctions in mammals10 has led to a re-evaluation of this view11.

The insect brain is bathed in hemolymph. This is in contrast to the vertebrate brain which contains a huge number of blood vessels. Consequently, the insect brain surface and thereby the exposure to the hemolymph is thus expected to be much lower than the mammalian brain surface. However, as in vertebrates, insects have complex compartmentalised nervous systems for specialised functions like vision, olfaction, learning, and memory (Figure 3)3.

Transmembrane permeability in

the vertebrate BBB is limited by the presence of efflux transporters that actively block the passage of drugs or endogenous compounds from the blood to the brain. The most important efflux transporters expressed in the membrane of endothelial cells are Pgp, BCRP, and MRP2.

In a recent study using the grasshopper (Locusta migratoria) it was found that a number of CNS active test compounds crossed the locus brain barrier, whereas peripherally acting non-CNS compounds were excluded from the brain. Furthermore, it was found in an ex vivo locust model that treatment with a human Pgp inhibitor facilitated the uptake of a typical Pgp substrate12.

transportersDuring the last decades, numbers of in vitro and animal studies have shown that multidrug-transporting proteins (MDTP) are important for drug absorption and excretion. Moreover, these proteins affect drug disposition and pharmacological activity at the cellular target site. Most MDTP research has so far been focusing on the efflux transporters e.g. Pgp and other multidrug resistance proteins (MRPs). During recent years the importance of other cellular membrane transporters has been investigated. Of main interest have been the studies of the organic anion and cation transporters (OATs and OCTs) but also the organic anion transporting polypeptides (OATPs). The major interest in these studies has

Figure 2. The utility of insects in pharmacokinetic studies is illustrated by the time course concentration of Quinidine in the hemolymph of the locust after a single injection of the compound into the hemolymph.



CellGro® is a registered trade mark of CellGenix in several European countries and Japan.In the USA and Canada CellGro® products are distributed under the name of CellGenix™


been focusing on transporters in the BBB, intestine, liver and kidney tissues and cells since this is important in drug absorption, metabolism and excretion and consequently the disposition, therapeutic efficacy and adverse effects. Transporter proteins may also cause safety issues related to drug-drug interactions. Thus, the identification of membrane transporters influencing the disposition and safety of drugs is a new challenge in drug discovery. Of the numerous drug transporters identified so far, their importance in drug absorption (e.g. intestinal Pgp and BCRP), in drug distribution (e.g. Pgp at the BBB and OATPs in hepatocyte uptake) and in drug excretion (OATs and OCTs for renal elimination) have been considered. It has been shown that insects have OATPs and Pgp in the intestinal wall, while the Pgp function has been shown in both Dm and locusts12. This indicates that insects may be useful as in vivo systems in the early drug ADMET characterisation.

Thus, taken together, there are many reasons to believe that the insect hemolymph-fat body-Malpighian- metabolising-excretion system could be a relevant model for highly efficient documentation of some key ADMET parameters in the early drug discovery phase.

FutureInsect models could potentially be used as a filter between in vitro and in vivo models, filling the gap between the ‘quick’ in vitro models and the ‘slow, expensive but more reliable’ in vivo models. In vitro models are used for high- or medium-throughput screening, but it may be difficult to judge which compounds have the highest probability of successfully passing mouse studies. In contrast to in vitro models, the insect models are based on more complex biological organisms that comprise many parameters not present in in vitro models. Moreover, many homologies on molecular as well as functional levels are reported, and the data generated from using insects have so far been very promising. This, in combination with the fact that insect models have been shown to be both cost- and time-efficient, imply that insect models may be useful as intermediate screening models in the drug discovery phase.

Another interesting feature is the fact that insect models only require tiny amounts of compound material; existing DMSO stock solutions are suitable, i.e. re-synthesis is not needed.

It is obvious that insects are not substituting in vitro or in vivo models, but used in the right way insect models could potentially enhance the drug discovery phase and reduce the number of traditional animal studies. So far, the research performed on insects indicates that insects could be a new model species in ADMET profiling of chemical compounds n

References1 Charles River Laboratories, Annual Repot

(2009)2 Gullan, P.J. & Cranston, P.S. The insects.

An outline of entomology. Blackwell Science Ltd. (2000)

3 Marsh, J.L., & Thompson, L.M. Can flies help humans treat neurodegenerative diseases? Bioessays 26, 485–496 (2004)

4 Marsh, J.L. & Thompson, L.M. Drosophila in the Study of Neurodegenerative Disease. Neuron 52, 169-178 (2006)

5 Wolf, F.W., & Heberlein, U. Invertebrate Models of Drug Abuse. J. Neurosci, 54, 161-78 (2003)

6 Dow, J.A.T. Insights into the Malpighian tubule from functional genomics. J. Exp. Biol. 212, 435-445 (2009)

7 Wang, J., Kean, L., Yang, J., Allan, A.K., Davies, S.A., Herzyk, P., & Dow, J.A.T. Function-informed transcriptome analysis of Drosophila renal tubule. Genome Biology, 5, R69.1-R69.21 (2004)

8 Pang, K.S. Modeling of Intestinal Drug Absorption: Roles of Transporters and Metabolic enzymes (For the Gillette Review Series). Drug Metab. Disp. 31, 1507-1519 (2003)

9 Caccia, S., Casartelli, M., Grimaldi, A., Losa, E., de Eguileor, M., Pennacchio, F. & Giordana, B. Unexpected similarity of intestinal sugar absorption by SGLT1 and apical GLUT2 in an insect (Aphidius ervi, Hymenoptera) and mammals. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R2284-R2291 (2007)

10 Wu, V.M., Schulte, J., Hirschi, A., Tepass, U. & Beitel, G.J. Sinuous is a Drosophila claudin required for septate junction organization and epithelial tube size control. The J. Cell Biol. 164, (2), 313–323 (2004)

11 Daneman, R. & Barres, B.A. The Blood-Brain Barrier—Lessons from Moody Flies. Cell 123, 9-12 (2005)

12 Nielsen, P.Aa., Andersson, O., Hansen, S.H., Simonsen, K.B. & Andersson, G. Models for predicting blood-brain barrier permeation. Drug Discov. Today (in press)


Peter Aadal Nielsen is CEO at EntomoPharm. He received his PhD in Computational C h e m i s t r y from University of Copenhagen. He has worked as senior scientist at AstraZeneca R&D and 7TM Pharma. During his work he has been focusing on developing computational models for prediction of ADMET properties. Email: [email protected]

G u n n a r A n d e r s s o n is CSO at EntomoPharm. He received his PhD in Animal Physiology from University of Lund. He has worked as Head of Department of Experimental Animal Pharmacology at various pharmaceutical companies. He has been Adj. Professor at University of Lund with a main focus on cell proliferation and differentiation.Email: [email protected]

Figure 3. Main structure of the locust brain consisting of three fused ganglionic masses, the protocerebrum, the deutocerebrum and the tritocerebrum. The protocerebrum is a major integrative centre receiving information from many sensory sources like the compound eye and the ocelli. This part is also believed to be involved in olfactory learning. The deutocerebrum receives input from mechano- and chemosensory receptors on the antenna and the tritocerebrum integrates the signals that are sent to various muscles in the insect body.






a highly regulated environment for biomarker and biopharmaceutical testing: Helping to Drive the Global Drug Development ProcessabstractThis article provides a current overview of how high throughput diagnostic analyser platforms and research-based analysis within a regulatory environment can be used to seamlessly deliver high quality data to the pharmaceutical industry, helping to drive the drug development process for the pharmaceutical industry.

introductionA basic requirement in pharmaceutical clinical research is to meet the needs of the drug development process in an efficient and cost-effective manner. A firm understanding of the regulatory standards and guidelines, particularly before analytical outsourcing, deciding who is a best fit to provide the services required, all add to the complications of maintaining a drug development pipeline. Significant investment of time is required from first concept to market, with the constant threat from competitors whose aim is to realise approval of similar compounds in a shorter timeframe and get to market quicker.

The US Food & Drug Administration (FDA) recognised the need to facilitate the progression of drug compounds to market1, and prime the translation of scientific innovation into clinic. They identified the significant role for biomarkers, specifically in their ability to highlight efficacious drugs, or pinpoint those that were a risk to patient safety. Biomarker evaluation can achieve this more quickly than historically seen for compounds in development. This (indirectly) would help to reduce costs in the early phases, and may allow patients to benefit from treatments earlier as investment would be directed into projects containing the relevant lead compound(s). The FDA, being under pressure to improve safety, published the FDA Critical Path Initiative in 19881. This article discusses the strategies needed to deliver biomarker analysis in a highly regulated and competitive environment using a variety of analytical platforms.Pharmaceutical analysisWhether methods are developed by pharmaceutical companies or

outsourced to contract research organisations (CROs), guidelines support the development of novel assays for biomarker detection in conjunction with the regulatory guidelines such as chromatographic, ligand binding assays and more recently multiplex assays which increase throughput and the number of tests accessible2,3,4,5,6. The focus more recently has been the value of panels of biomarkers in preference to a single analyte. For example, mass spectrometry (MS) is perfect to deal with the complexities of a plasma matrix. Various combinations of MS and affinity chromatography (AC) or liquid chromatography (LC) aim to identify or quantify signatures of peptides. The advantage of MS is its ability to track complex biomarker sets virtually without limitation, but also with greater sensitivity whilst having the ability to detect subtle protein changes. However, multiple fractionation steps may be required experimentally before the analysis to detect even medium abundance proteins. Furthermore, these multiple extractions make the process challenging to validate rapidly.

In addition to MS, ELISA can specifically detect proteins at low concentrations in a mixture of abundant proteins, but these assays can be difficult to develop in a multiplexed format. They depend upon raising capture or detection antibodies, increasing the time required to develop novel assays. Both techniques however are of significant value to the drug development process in their own right, and applied within the framework of GLP-accredited facilities.

advancing new technologyMaintaining a leading-edge position and providing expertise in analytical capabilities to meet the requirements of sponsor studies can be a challenging task requiring substantial investment and risk. Timing is essential in order to identify new technologies early, and establish, validate or optimise the instrumentation before trials begin. This requires foresight, adaptation, and a clear understanding of emerging

biomarkers of interest. Several initiatives from the US FDA, including the Drug-Diagnostic Co-Development Concept Paper8 and the Critical Path Initiative1 promote biomarker evaluation to speed the drug development process. The Drug-Diagnostic Co-Development Concept Paper attempts to provide a model for combination product submission9, (e.g. HLA B1502 and Carbamazepine) but does not seem to be a sustainable business model due to timing between clinical development studies and diagnostic device trials.

In 2009 the FDA formed a multi-centre, multi-disciplinary working group to discuss potential guidance on Rx/Dx co-development, and it is anticipated that more comprehensive white papers will be issued in the future on this topic. The challenge is to know which biomarkers are valuable to a compound early in the development process to obtain the clinical validation of the biomarker itself. Once data has been compiled, prioritising the biomarker(s) within an in vitro diagnostics (IVD) company’s pipeline is another hurdle – hence availability of diagnostic grade technologies is likely to be negligible, especially for novel biomarkers. This means alternative guidelines for demonstration of biomarker assay performance is required. Laboratories have generally adopted assay validation and acceptance policies to comply with pharmaceutical industry guidelines and expectations, such as those referenced earlier.

the Diagnostics industryA recent report published in May 2009 analyses the global IVD market comprehensively10 . This report provides sales forecasts and discussions of emerging technologies. The global IVD market generated sales of over $40bn in 2008 and the report predicts that the market will generate nearly $60bn in 2014.

IVD platforms were traditionally not recognised within the drug development scene but they have become increasingly more important. IVD tests

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historically provided information about pathology, aiding diagnoses and choice of treatments in clinic. Their usefulness in the drug development process, especially via biomarker panels, constitutes a major advance and an expanding market opportunity for diagnostics assay manufacturers. It is believed that from 2009 worldwide investment in IVD testing will increase, particularly of value as theranostics (also know as companion diagnostics), as well as medical research.

So how do you specifically decide which quality system is the right one at a specific point in the process? Knowing the important questions to ask requires a basic knowledge of what underpins the specific standards. We can discuss one question in particular – can biomarker or biopharmaceutical laboratories work in a way that adheres to all quality systems and standards that are relevant in drug development, or alternatively employ a tiered system, where careful evaluation of the analytical requirements allows a pragmatic and tiered approach depending upon the needs of the research stage, the tools (assays) available, and the costs? Figure 2 shows the overlaps in quality systems, and shows the key areas to address within a regulated project.

Assay ValidationOne area in particular which can lack clarity is the context of validation, or the assay validation process required for ‘novel’ versus ‘known’ biomarker assays. The European Bioanalytical Forum (EBF) defines a novel biomarker as ‘an analyte that is measured as an in-vitro test or specialised technology which is not available as a routine clinical lab test’. The definition for ‘known’ biomarker is ‘an analyte that is measured as an in-vitro test or specialised technology which is available as a routine clinical lab test’14. Therefore a reasonable position on validation requirements for known biomarkers is to evaluate the framework already in place via the ligand binding assay guidelines2,5 for novel biomarkers, using assay kits designated ‘for research use only’, or novel chromatographics. Further expert guidance for immunogenicity assay validation (novel biomarker analysis) is available for immunoassay validation, and regulatory considerations15,16.

A sound knowledge of the available guidelines can be applied in most assay validation scenarios to ensure any assay is fit for purpose throughout sample analysis13.

However for ‘known’ biomarkers where assays are supported by preceding (manufacturing) quality assurance, for example, diagnostic IVD grade17 or CE-marked assay kits18 either for manual or automated use (and providing the manufacturer of the assay provides performance data relating to the assay), the validation process which may consist of an instrument validation phase, and a short period of assay qualification, where the user demonstrates that in their laboratory, and the assay performs over several batches at least to the standard described by the manufacturer. For diagnostic grade assay kits the focus is on following the manufacturer’s instructions for use, and maintaining consistency of analysis, thus the manufacturer shares responsibility for reagent performance.

Furthermore, where other assays are implemented (for example for novel biomarkers) there may be a need to enhance the performance of an existing assay, optimise, or even evaluate the assay for a non-intended purpose e.g. measure a biomarker in an alternative matrix. These circumstances warrant full and possibly extended feasibility and validation processes, supported by the accepted guidelines, and the provision of extensive data supporting performance of the assay. Once implemented, however, it may be challenging over time to demonstrate continued performance from year to year unless the laboratory implements a local internal quality assurance (IQA) scheme to show consistency of performance longitudinally.

Needless to say, the qualification or ‘method transfer’ approach for the better characterised diagnostic grade assays lends itself well to continual monitoring of performance post-implementation, for example using external quality assurance schemes (EQA) such as NEQAS (UK), Bio-Rad EQAS, Accutest (US) where schemes are available. These schemes add no value though, unless review of the scheme provider reports are carried out and actioned on a regular basis by the laboratory, and scheme peer groups evaluated after each exercise.

One of the positive aspects of CE marking in Europe, which was enforced in December 2006 for all diagnostic assays (19), was that this move supported standardisation across Europe, not only by enforcing the assay manufacturers to be regulated and monitored, but also encouraging users to follow the manufacturer’s instructions to perform the assay. Where separate laboratories previously had chosen to optimise these assays as they saw necessary, other users of the same assay may have performed it differently. This led to lack of standardisation across laboratories for the same test. (This can be a significant risk in a diagnostic environment, for example PT/ INR testing in anticoagulant therapy.)

The pitfalls, however, are the rigidity and lack of ability to optimise currently available manufactured IVD assays that are of interest in a research environment. Also, these assays can sometimes be within closed systems, where the operator cannot specifically alter the technology or process method. Nevertheless, some IVD assay kits have a significant role in the research environment. For example they may be evaluated for a different (non-intended) purpose, and although the CE mark is invalidated, there is still scope for valuable research data to be generated, providing that suitable guidelines are followed for validation of the assay, as would be followed for other assays (such as ‘for research use only’), where the components do not fall into the CE / IVD catchment.

standardisationEnsuring the quality of biomarker assays may include a level of standardisation. Pharmaceuticals are developed on a global scale, with the global footprint seeming to shrink in the pursuit of patient populations in sufficient numbers to evaluate, and economics often influences the geography of studies. This causes problems ensuring consistency of sample processing and analysis. Where the global footprint of a clinical trial spans continents, the logistics of this can be highly challenging, and the stability of biomarkers may compromise the value of a study. Networked, high quality laboratories with excellent logistical support, who invest in a programme of cross-standardisation by using parallel instrumentation and assay


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platforms, followed up by standardisation experiments, can provide a solution to these issues, and provide consistency without compromising biomarker stability.

hybridisationAn important role for industry is to embrace new models for diagnostics and drug development. Three key industry players — diagnostics, pharmaceutical and genomics / biotech / contract research firms — a shift towards more collaborative business models that focus on co-developed products. The FDA also has the important role of facilitating a streamlined approval process that provides clarity; coordination across centres; cooperation and collaboration with other stakeholders outside the FDA; facilitating a solution for data approval; setting standards; and refining approaches for review of co-developed drugs / diagnostics20. The integration of diagnostic platforms into the drug development business can be embraced to deliver cheaper mechanisms for cohesive biomarker analysis, promote technical innovation, and apply pharmaceutical regulatory experience to provide sound sample analysis based on the solid quality standards germinated in the pharmaceutical sector. Significant savings in the development process will directly benefit patients immediately, and post-marketing.

conclusionHaving multifaceted platforms for biomarker discovery will become critical to keeping up with the rapidly changing world of drug development, and allow the delivery of hundreds of markers within single projects. Drawing on knowledge in various arenas can guarantee the rapid delivery of high quality data, with significant cost savings. The key for the sponsor is to understand the performance and quality standards required. There is unlikely to be one detailed ‘one size fits all’ set of guidelines in the short term for laboratory standards.

Overall, the benefits of a hybridised system (using the principles underpinning the common quality systems) ensures that biomarker or biopharmaceutical data will be held in the highest regard in the critical late stages, and support progression and

regulatory acceptance. Organisations such as Quotient Bioresearch, who provide a variety of analytical platforms and the ability to apply quality systems effectively to the requirements of the sponsor or project, ultimately support study managers to meet the needs of drug development in an efficient and cost-effective manner.

References1. Innovation or Stagnation: Challenge

and Opportunity on the Critical Path to New Medicinal Products. <http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html>, s.l. : US Department of Health and Human Services, Food and Drug Administration, 2004.

2. Recommendations for the Bioanalytical Method validation of Ligand-Binding Assays to support Pharmacokinetic Assessments of Macromolecules. De Silva, B. et al. 11, November 2003, Pharmaceutical Research, Vol. 20, p.

Figure 1: Simplified Overview of Clinical Development Phases and Quality Systems

Figure 2: To Illustrate the Basic Components of an Integrated / Hybridised Quality System for

Biomarker Analysis

Table 1: Diagnostics Companies with IVD Biomarker Assays

Abbott Diagnostics

De code Genetics Inc.

Ortho Clinical Diagnostics (OCD)

Vermillion/Ciphergen Biosystems Inc.

Beckman Coulter Inc

Genomic Health Qiagen N.V. Nanogen

Becton, Dickinson and Company (BD)

Gen-Probe Inc. Quidel Corporation

Clarient Inc.(ChromaVision)

bioMerieux Inc. Immucor, Inc. Roche Diagnostics

Sysmex Corporation

Celera Corporation

Inverness Medi-cal Innovations

Seegene, Inc. Cellestis Ltd

Siemens Medical Solutions Diagnostics

Luminex Corporation

Sequenom, Inc Cepheid



1885.3. Workshop on Bioanalytical Methods

Validation for Macromolecules: Summary Report. Miller, K.J. et al. 9, s.l. : Plenum, September 9, 2001, Pharmaceutical Research, Vol. 18, p. 1373.

4. Workshop / Conference Report: Bioanalytical Method Validation - A revisit with a decade of progress. Shah, V. P. et al. 12, 2000, Pharmaceutical Research, Vol. 17, p. 1551.

5. Workshop / Conference Report - Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays. Viswanathan, C.T. et al. 1, 2007, AAPS Journal, Vol. 9, p. E30.

6. Guidance for Industry and FDA Staff Class II Special Controls Guidance Document: Instrumentation for Clinical Multiplex Test Systems. s.l. : U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Office of In Vitro Diagnostic Device Evaluation and Safety, Division of Chemistry and Toxicology Devices, March 2005.

7. Validation and comparison of two multiplex technologies, Luminex and Mesoscale Discovery, for human cytokine profiling. Chowdhury F, Williams A, Johnson P. 1, Southampton : Elsevier, January 2009, Journal of Immunological Methods, Vol. 340, pp. 55-64.

8. Drug-Diagnostic Co-Development Concept Paper. www.fda.gov/cder/genomics/pharmacoconcept fn .pdf>, s.l. : Department of Health and Human Services, Food and Drug Administration, 2005.

9. FDA.www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/UCM116689.pdf. [Online] April 8, 2005.

10. Visiongain. Market Analysis: In Vitro Diagnostics 2009-2024. 2009.

11. Abbott Laboratories US. Abbott Molecular. [Online] Abbott Laboratories. Abbott Park, Illinois, U.S.A., November 2009. http://www.abbottmolecular.com/AbbotttoCollaboratewithPfizerInconCompanionDiagnosticTest_105213.aspx.

12. Roth, M. FDA Draft Guidance Concerning Specific Companion Diagnostics. US Food And Drug

Administration. 2007.13. An Approach to the Validation of

Flow Cytometry Methods. Jo Cunliffe, Nicola Derbyshire, Sue Keeler and Ruth Coldwell. 12, Loughborough : SpringerLink, December 2009, Pharmaceutical Research, Vol. 26, pp. 2551-2557.

14. Amsterdam, Peter van. EBF Survey: Quality Systems in Macromolecule Analysis. Seattle : European Bioanalytical Forum, 2009.

15. Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. Shankar G. et al. Radnor : s.n., Dec 15, 2008, J Pharm Biomed Anal., Vol. 48, pp. 1267-81.

16. Scientific and regulatory considerations on the immunogenicity of biologics. Shankar G, Shores E, Wagner C, Mire-Sluis A. Radnor : s.n., Jun 2006, Trends Biotechnol., Vol. 24, pp. 274-280.

17. FDA Medical Devices: Overview Of IVD Regulation. Food & Drug Administration. [Online] June 2009. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/I V D R e g u l a t o r y A s s i s t a n c e /ucm123682.htm.

18. MHRA: How we regulate devices. MHRA (UK). [Online] April 2009. http://www.mhra.gov.uk/Howweregulate/Devices/index.htm.

19. Directive 98/79/EC Of the European Parliament and the Council of 27 October 1998 on the in vitro diagnostic medical devices. 1998, Official Journal of the European Communities.

20. Diagnostics and biomarker development: Priming the pipeline. Phillips, K.A. June 2006, Nature Reviews Drug Discovery, Vol. 5, p. 463.

21. Integration and use of Biomarkers in Clinical Practice: A US regulatory perspective. Amur, S. et al. 2008, Biomarkers Med., Vol. 2, pp. 305-311.

22. (MHRA), Medicines and Heathcare Products Regulatory Agency. Guidance notes on In Vitro Diagnostics Medical Devices Directive 98/79/EC. Revised February 2006.

23. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic

medical devices. 24. Clinical Laboratory Improvement

Amendments (CLIA) 24 CFR Part 493. 1988.

25. ICH Harmonized Tripartite Guideline, Validation of analytical procedures: Methodology. ICH.

26. The Good Clinical Practice Concept Paper. Ezzelle, et al. 2008, J Pharmaceutical and Biomedical Analysis, Vol. 46, pp. 18-29.

27. Presentation - EBF Quality Survey: Quality Systems in Macromolecule Analysis. Seattle : s.n., 2009.

28. Guidance on the maintenance of regulatory compliance in laboratories that perform the analysis or evaluation of clinical trial samples.www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/

Nicola Gaskell has more than 12 years experience working as a B i o m e d i c a l Science, and as a qualified State Registered Biomedical Scientist (Transfusion Science & GMP) in the diagnostics sector, also draws on experience of working to relevant quality systems in diagnostic & biomedical testing laboratories (National Blood & Transplant Authority, L&S East Zone). With a special interest in haemostasis, and whilst working with the University Of Cambridge Dept of Haematology, Nicola gained her MSc developing flow cytometry techniques for quantification of glycoproteins on platelet membranes to aid clinical diagnosis of inherited disorders of the platelet type. After joining Quotient Bioresearch in 2005, Nicola became a GLP Study director, established a LIMS & automated platform for high throughput analysis of biomedical samples from clinical trials, and thrives on project management, currently steering an operational team to deliver high quality biomarker and biopharmaceutical services to large Pharma.Email: nicola.gaskell@ quotientbioresearch.com

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improving the human relevance of Preclinical trials: Technologies to Replace Animal TestingA fundamental of drug development is the provision of safe and effective medicines. The safety and efficacy of a drug can only be demonstrated through large-scale trials in humans. However, using humans as test subjects for drugs whose safety is unknown would be unethical. Instead, legal and regulatory guidelines require a plethora of studies to be conducted prior to clinical trials, so that all reasonable steps have been taken to mitigate risk to trial participants. Drug developers are also expected to give evidence of the expected effectiveness of the drug for treating human disease. Scientists have therefore needed to develop non-human models that can help to predict how patients will respond to a drug.

An ideal model would exactly predict human responses. However, human drug responses are complicated by factors such as age, sex, health status (including diet, lifestyle and medical conditions) and the co-administration of drugs. A universal model that incorporates these complex factors does not exist, so scientists have needed to be creative in developing models that assess certain aspects of drug response. Several such models are used in pre-clinical studies and the data generated from the models is collated to assess the overall risk-benefit profile of a drug.

animal ModelsAnimals have been used extensively in pre-clinical testing since laws were passed in the United States (1938 Federal Food, Drug and Cosmetic Act) requiring their use in the safety assessment of drugs prior to market approval. The complex biology of a whole living organism cannot be recreated in a petri dish so animals are used as surrogates to understand how a drug works in vivo.

The use of animals in drug toxicity assessment has played a crucial role in preventing unsafe drugs from entering the market. Animals have also directly contributed to the development of

vaccines for smallpox, polio, tetanus, rubella and rabies, and the development of insulin for diabetes. However, it is the case that many substances that are safe and effective in animal studies are of limited therapeutic benefit or toxic in humans. The drugs rofecoxib (Vioxx) and troglitazone (Rezulin) passed through rigorous pre-clinical checks before their association with elevated risk in humans of myocardial infarction and liver toxicity, respectively, was established. The converse of this – substances that are safe and effective in humans are ineffective or toxic in animals – is also true. The antibiotic drug penicillin, one of the most important medical discoveries of the 20th century, might never have reached market had it been put through modern pre-clinical testing (penicillin is ineffective in rabbits and toxic in guinea pigs and hamsters).

Limited concordance of the toxicity and efficacy of drugs in humans and in animals has contributed to declining productivity in the pharmaceutical industry, and the withdrawal of several approved medications from the market. Costs associated with animal experimentation, the questionable scientific value of certain animal experiments, ethical issues surrounding animal testing, legislation preventing animal tests where alternative methods are available, and education of researchers in the 3Rs (reduction, refinement and replacement) have all contributed to a decline in the use of animals in testing.

Scientists are unanimous that they would not use animals if alternative models were available for their research. In a survey of more than 1300 scientists conducted by the UK National Centre for the 3Rs (NC3R), the availability of more relevant cell cultures and human tissues, technical advances in tissue engineering, and more predictive computer models were the principal technologies that respondents thought would enable them to address their research objectives without the use of animals. The following paragraphs

highlight some emerging technologies that could revolutionise pre-clinical testing and potentially replace or reduce the use of animals by providing more clinically relevant models.

Primary cells and cell linesIn vitro assays using human immortalised cell lines (HICL) and primary cells are an important tool in pre-clinical drug screening. Primary cells are desirable because they can most closely recapitulate in vivo characteristics. However, their high cost, limited supply, short term viability ex vivo and donor-specific issues make these cells unsuitable for routine use.

HICL are cells that have undergone mutations to allow a cell type which would not normally be able to divide to proliferate in vitro. Cell lines provide an unlimited and relatively homogenous supply of cells and have proved valuable for research in several fields. However, cell lines are not without their own limitations. Many commonly used cell lines are derived from cancerous tumours and have undergone significant mutations so that they divide indefinitely. As a consequence these cell lines cannot fully recapitulate characteristics of the healthy adult cell types from which they were derived. For example, hepatocarcinoma cell lines do not typically express the full range of metabolising enzymes in adult hepatocytes, and so these cells must be used with caution when studying metabolism-mediated drug toxicity.

Stem cells, including human embryonic stem cells (hESC) and human induced pluripotent stem cells (hiPSC), potentially offer a ‘best of both worlds’ alternative to primary cells and cell lines. Stem cells are immortal, thereby avoiding the supply issues associated with primary cells, and pluripotent stem cells have the capacity to give rise to any cell type in the body, which could have important implications for research on cell types that are in limited supply (e.g. pancreatic beta cells for diabetes research). hiPSC are less controversial



14th – 16th September, 2011, Copenhagen, Denmark

THE INTERNATIONAL EXCHANGE OF KNOWLEDGE FOR TREATING RARE DISEASES

In what area do YOU play? Dutch Health Care Insurance Board (CVZ)Ad Schuurman Head of the Business Contact Center & International Affairs

Surrey & Sussex NHS TrustOmar Ali Formulary Development Pharmacist

PfizerAdam Heathfield Director of Policy

Merck SeronoTom Bols VP Health Policy and Market Access

GlaxoSmithKline Rare DiseasesPierrick Rollet VP, Global Market Access/Advocacy/Communications

MEET THE SPEAKERS:

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Shire, Gary Clements Director, Senior Director Business Development

Genzyme Wills Hughes-Wilson Senior Director & Health Policy Europe

TopoTarget A/S François Martelet CEO

AMT Jörn Aldag CEO

GlaxoSmithKline Andrea Rappagliosi VP European Government Affairs and Head of Brussels Office

Swedish Orphan Biovitrum ABBo Jesper Hansen Chairman of the Board

ZymenexJens Fogh CEO

Actelion Otto Schwarz President Business Strategy & Commercial Operations

Kakkis EveryLife FoundationEmil Kakkis President

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than hESC because they can be created from adult cell types via a genetic reprogramming step that returns them to an embryonic state.

Stem cells can provide a closer phenotypic match to human cells than animal material. Recent studies have also shown the potential for hiPSC to provide in vitro models of inherited diseases. The ability of hiPSC to recapitulate pathological tissue formation in vitro could open new avenues of research into diseases where suitable animal models do not exist. hIPSC might also be used to generate patient-specific in vitro disease models for personalised medicine approaches, such as the models of inherited metabolic disorders of the liver that were reported by Rashid et al. in 2010.

Aside from the moral and ethical issues surrounding the use of hESC, several challenges remain before stem cells achieve widespread use in the laboratory. Methods for the expansion and reliable differentiation of hESC into desired adult cell types need further development to provide appropriately scaled and reproducible production systems. Further research must also be done to establish whether stem cell-derived adult cells reliably mimic in vivo cellular characteristics and responses.

advanced in Vitro Models for the Prediction of Drug toxicityDrug induced liver injury (DILI) is the leading cause of approved drugs being removed from the market. Drugs that cause dose-dependent, reproducible DILI (e.g. acetaminophen) can typically be identified using current pre-clinical models. The challenge lies in identifying drugs that do not produce dose-dependent effects and only give rise to DILI in susceptible patients. The incidence of idiosyncratic DILI can range from 1 in 100 patients to 1 in 10,000 patients, so a major concern is that DILI will only be identified once a drug has reached market and is given to large numbers of patients. It has been calculated that in order for a clinical study to detect a single case of DILI (with 95% confidence) the study would require 30,000 patients, which would make drug development economically unfeasible. If clinical studies cannot be used to identify patient susceptibility, more effective pre-clinical screens must

be sought.The development of advanced

in vitro assays, including three-dimensional (3D) cell cultures and co-cultures of human cell lines and primary cells, might offer one solution. 3D liver models, such as those developed by Zyoxel (TissueFlex®) and Regenemed (RegeneTOX), and micropatterned co-culture systems developed by Hepregen (HepatoPac™), enable hepatocytes to be cultured in a more in vivo-like environment. This enables cells to be cultured for much longer periods (weeks) while remaining highly metabolically competent.

Hepatocytes in monolayer cultures tend to dedifferentiate and exhibit declining metabolic competence over 24 hours, so 2D cultures can only reliably be used in acute drug toxicity studies. 3D and co-culture systems can be used in long-term (chronic) drug toxicity studies and in the evaluation of drug effects at concentrations more comparable to therapeutic in vivo levels. Such studies could be important for drugs that are only slowly metabolised or demonstrate unusual dose-responses. These cultures could also be useful for studying certain types of DILI such as cholestasis which can only be modelled in long-term cultures that develop the correct morphological features (canaliculi and associated transporter proteins).

Advanced cell culture models are being used more frequently in drug development. However, these systems are relatively low throughput and work must be undertaken to upscale and integrate with high-content imaging platforms to enable their more routine use at the front end of drug screening. If higher throughput can be achieved, and in combination with human induced pluripotent stem cell (hiPSC) techniques described in the preceding paragraphs, then these systems could potentially be used in large-scale studies to understand patient DILI susceptibility. The influence of environmental factors such as diet, smoking, alcohol and chemical exposure on DILI susceptibility is not well understood and cannot be replicated in animal models. Thus, hiPSC-based studies could be useful for the identification of ‘at risk’ individuals and in the design of safer drugs.

in Vitro tumour ModelsPre-clinical tests have historically been very poor at predicting the efficacy of anti-cancer drugs. Many cancer drugs have progressed into human trials only to reveal that they offer no clinical benefit. This high failure rate and the huge cost of drugs failing in the clinic means that fewer drugs are available to patients and less money is available to develop new drugs.

Tumour xenograph models, which involve the transplantation of human tumour cells or cell lines into immunocompromised animals, are the gold-standard method for testing the efficacy and toxicity of anticancer drugs. However, these models are time-consuming, expensive and technically challenging to develop, making them unsuitable for routine testing. Also, low throughput xenograph models are unsuitable for testing the large number of tumour lines which are necessary for understanding the relevance to patient populations. Two-dimensional cell cultures are also used in anti-cancer drug screening; however these simple systems neglect the cell-cell and cell-matrix interactions that have been shown to play a critical role in tumour drug response.

Advanced in vitro models aim to replicate the structural, functional and mass transport properties of tumours by culturing (and co-culturing) cells in three dimensions. 3D models, including multicellular tumour spheroid (MCTS) models, can reproduce many characteristics of the in vivo tumour microenvironment and better replicate the barrier to drug penetration which is presented by dense tumours. Companies including Precos have developed co-culture 3D microtumour models and these have been shown to more closely replicate characteristics of tumours in vivo.

A growing number of studies have examined the effects on anti-cancer drug efficacy of tissue architecture and extracellular matrix. Significant differences in efficacy emerge when drugs are tested in 2D or 3D cultures, with no clear pattern of improved or reduced chemoresistance of cells in one system over the other. That there is no obvious trend for changes in drug efficacy between 2D and 3D culture suggests that different signalling pathways and






mechanisms of action may be important in 3D cell cultures. More research using these models is required in order to understand differences in cellular behaviour and mechanisms of disease progression in three-dimensional tissues and to validate in vitro observations of anti-cancer drug efficacy with clinical outcomes.

in silico Models for Drug DiscoveryThe declining cost of high performance computing platforms and the availability of improved in silico biological models have contributed to the growing use of computational models in drug discovery and development. In an age of declining productivity it is hard for drug companies to ignore any technology that could potentially reduce pharmaceutical research and development costs by up to 50%, as was suggested in a 1999 report by Pricewaterhouse Coopers. This is an innovative and growing market segment with many established companies, including Entelos, Pharsight and Simluations Plus Inc, as well as smaller incumbents such as Physiomics and Simugen, offering software products and services.

Computational systems biology is being used in a wide range of settings in drug discovery and development. These tools are being used in drug discovery to model mechanisms of action and thus to validate drug targets and drug candidates. Other software tools are being applied to simulate drug pharmacokinetics and pharmacodynamics to predict drug absorption and in vivo bioavailability and toxicity, providing useful supplementary information in lead selection and optimisation programmes. In silico tools can also be used to optimise dose schedules and drug combinations because, unlike animal or clinical studies, it is possible to simulate many thousands of potential drug regimes. Cohorts of virtual patients are used to optimise clinical trial design by predicting clinical outcomes for patients with differing disease status or patients on different drug doses, and by identifying clinical biomarkers that are indicative of drug efficacy or toxicity.

Several large collaborative programmes are underway to develop disease-specific and patient-specific in silico models, which should ultimately

assist in the development of novel medical devices and drugs. For example, researchers involved in the euHeart project (www.euheart.eu) are developing computational cardiac physiology models to facilitate the understanding of cardiovascular disease (CVD) progression and to improve the diagnosis and treatment of CVD.

For the increased utilisation of in silico techniques in drug development further validation studies must be performed. Ideally this would be achieved via comparison with clinical trial data for a large group of drugs with different mechanisms of action in blinded studies. Such studies should expose any weaknesses in the underlying mathematical models or model parameters, which are only as good as the experimental data on which they are based.

conclusionThe development of non-animal models that can accurately predict human drug responses is a major challenge. Fortunately, this has been an active area of research and product development and many new technologies including stem cell-derived cell lines, advanced in vitro cultures of healthy and diseased tissues, and computational tools, have emerged. These technologies promise to improve the success rate of drug development programmes while reducing the cost of bringing new drugs to market. For this promise to be realised it will be important for academics, pharmaceutical companies and technology providers to work together to develop, refine and validate these new technologies. Funding initiatives, such as Europe’s Innovative Medicines Initiative, are welcomed in this regard because the consortium-based approach should bring together all of the necessary stakeholders for the successful development of these important enabling technologies.

References1. In the UK there has been a decrease

of 30% over the past 10 years in the numbers of animals used by the pharmaceutical industry. Source: UK Home Office.

2. Views on the 3Rs: Survey Report 2008. National Centre for the Replacement, Refinement and Reduction of Animals

in Research. Copyright 2008. 3. Evolution of induced pluripotent stem

cell technology. Zhou H, Ding S. Curr Opin Hematol. (2010) 17(4):276-80.

4. Modelling inherited metabolic disorders of the liver using human induced pluripotent stem cells. Rashid ST et al. J Clin Invest. (2010) 120(9):3127-36.

5. Drug-Induced Hepatotoxicity. Lee WM. N Engl J Med. (2003) 349:474-485.

6. What’s wrong with our cancer models? Kamb A. Nat Rev. (2005) 4:161-165.

7. Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies. Weaver VM et al. J Cell Biol. (1997) 137:231-245.

8. Activity of anticancer agents in a three-dimensional cell culture model. Nirmalanandhan VS et al. Assay Drug Dev Technol. (2010) 8(5):581-590.

9. Pharma 2005. Silicon Rally: The Race to e-R&D. Pricewaterhouse Coopers. Copyright 1999.

Emma Sceats is Business Deve lopmen t Manager at Zyoxel Ltd (Oxford, UK), a spin-out company from the University of Oxford. Zyoxel provides pre-clinical drug testing products and services based on TissueFlex®, a proprietary bioreactor technology for three-dimensional perfused cell culture. Prior to joining Zyoxel, Emma was Licensing Manager at Isis Innovation, the University of Oxford’s Technology Transfer Office, with a specialisation in enabling technologies for pharmaceutical research and development. She holds an M.Sci. in Chemistry from the University of Bristol (UK), an M.S. in Chemistry from the Massachusetts Institute of Technology (USA) and a D.Phil. in Chemistry from the University of Oxford (UK).Email: [email protected]

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rgcc: A Leading Company in Analysis of CSCs as Progenitors of All Cancer RelapsesRGCC Ltd is a leading company in analysis of circulating tumour cells (CTCs) as well as cancer stem cells (CSCs). Through their analysis, RGCC Ltd is able to offer services in the clinical field as well as in R&D in the pharmaceutical industry. By using the most advanced and innovative technologies of molecular and cellular biology, RGCC Ltd manages to overpass several restrictions and difficulties that the analysis of CTCs and CSCs involves. Through such an approach a massive amount of information and data has been generated in order to be used for identifying new «druggable» targets as well as offering methods in clinical practice like new and precise assays, risk scale and classification of cancer patients.

By answering the question: “Which is the best pool of data harvested from tumours”, RGCC Ltd was able to develop a target technology in order to generate the best options and pure data which will reflect clinical reality, and at the same time these data will include most of the relevant information about the risk of relapse and repeatable patterns of gene expression. Specifically, it is well known that in a primary tumour there are two major classes of cells. The first one is the stroma, which includes normal cells like endothelial cells, monocytes, fibroblast etc., and they support the existence and feeding of the tumour. The second group of cells includes the malignant cells. However, this last group of cells is NOT homogenous. It is composed of several subpopulations with different genotypes and phenotypes, with different behaviour and abilities due to the genetic instability of cancer cells. Only very few subpopulations of those cells have metastatic features which they can enter from an epithelial to mesenchymal transition (EMT). These cells will invade and enter into the circulation and they will become circulating tumor cells (CTCs). These cells include the progenitor of

every micro-metastasis. These cells are known as cancer stem cells (CSCs). Hence, CTCs and CSCs have all the necessary information for colonisation and engraftment to distant organs as micro-metastases, causing relapse of the disease.

RGCC Ltd has developed an innovative method in order to identify, isolate and sort these cells from the most appropriate sample (mainly blood). By using flow cytometric methods as well as powerful sorters it is possible to identify, enumerate and isolate the CTCs and CSCs.

But even from CTCs, only those who have CSC phenotypes have the ability to engraft and generate distant micro-metastases. Hence, by using negative and positive selection, RGCC Ltd has developed assays in order to identify and isolate CTCs. Sequential to that, an additional innovative method has been generated in order to expand the CSC from the CTCs. The risk of changing the genotype of the cultivated cells has been minimised by using the appropriate media and by performing this method for a short time window.

These cells are expanded and they enter into an exponential phase of growth. Then the cells are analysed in an all-genome gene expression profile in order to:• Analyse the up and down regulation of

genes;• Identify stable patterns of aberrant

expressed genes which may become «druggable» targets.

These «druggable» targets are validated by RGCC Ltd through knock-down methods like antisense of RNAi. Additionally, more protein-based methods have been used in order to down-regulate the expression level of protein.

The kind of genes that RGCC Ltd is interested in are related to the cell

cycle, metastases, neoangiogenesis, apoptosis etc.

Parallel to that, RGCC Ltd has developed several viability and cytotoxicity assays in order to assess and validate a candidate drug against cancer cell lines. By that method the candidate drug is validated in order to proceed further in trials and gain a license for daily clinical use.

RGCC Ltd has generated several human cancer cell lines and also CSC cell lines in order to generate a huge cell line bank that can be used for identifying patterns, as well as for using the different cell lines for viability assays, in order to establish whether a candidate drug is effective. Finally, RGCC Ltd has developed a repeatable and comparative analysis in order to compare the expression profile on time. Specifically, a comparison analysis between samples from the same patient provides us with an advantage in preventing relapse.

In a few words, RGCC Ltd, as a clinical company and a CRO, has generated new assays and methods in order to help clinicians to deal easily with difficult cases. The methods that RGCC includes and performs in its facilities are:• PCRs (endpoint, gradient and qPCR)• Flow cytometry-sorting• Micro-array gene expression analysis• Cell culturing• Blotting• Viability-cytotoxicity assays (MTT, CVE,

SRB, etc)• Spectroscopy • Microscopy

All these issues make RGCC Ltd a leading CRO, as well as a company providing clinical services. The expertise of this company is expanding, with branches and distributors in Europe, Asia, Africa, and the USA, as well as in Oceania. Additionally, RGCC Ltd has

developed strong cooperation and collaboration with local and foreign universities and companies in order to participate in larger projects and R&D programmes. RGCC Ltd is a company you can choose as a CRO in order to validate «druggable» targets, to assess candidate drugs, or to perform high-throughput screening of a substance when it is exposed to cell lines in order to verify the possible effect.

For all these reasons RGCC Ltd has become the most effective CRO in order to generate data and validate candidate drugs in the field of oncology n


Ioannis Papasotiriou I was born in Germany in 1973 and after years I return in childhood in Greece where I studied in Medical school of Thessaloniki and I specialized in Human Genetics in Switzerland. Two master degree rewards have been obtained in molecular biology in Medicine from the Westminster University (UK) and in oncology from the University of Nottingham (UK). A promotion have been performed (MD) in MLU in Germany under the field of evaluation of TKIs in human cancer cell lines. Since 2004 I am the director and founder of RGCC Ltd which is activated in both areas of services (Research and Clinical). Email: [email protected]

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Fighting rare Diseases: Pathway from Orphan Drug Development to Market Access

It is estimated that 6%-10% of the world’s population will suffer from a rare disease at one point in their life and approximately one out of five people personally know an individual suffering from a rare disease. Finding a cure or improved treatments for such patients is fundamental not only to their lives but also to society as a whole. The journey has begun, and there is great potential to improve the work amongst all stakeholders: patient organisations, governmental authorities, health technology assessment organisations, payers, and orphan drug developers. On 14th–16th September 2011, many of the key stakeholders will be represented at the Orphan Drugs Summit in Copenhagen, a hub for pharmaceutical development, to discuss challenges and alternatives to support the fight against rare diseases.

background & successful initiativesOver 55 million people are estimated to suffer from rare diseases in Europe and the US. Global estimates suggest that there are between 5000 and 8000 rare diseases. New rare conditions are discovered frequently and many are without treatment. Until recently, drug companies lacked the incentive to invest in this field, due to the high cost of bringing a rare-disease medicinal product to market. Furthermore, the high cost to the end consumer did not justify the financial investment to ensure commercialisation.

It can take ten to fifteen years, with an average cost of 800 million Euros, to develop a new drug, therefore traditional pharmaceutical companies have historically prioritised drug development for diseases that affect a greater percentage of the population.

In order to encourage pharmaceutical companies to invest in the development of this niche sector, governments have established regulatory incentives,

with the US being the original pioneer twenty-five years ago. Fifteen years later, the European Union enacted similar orphan drug legislation (EC 141/2000). Legislations differ, but they all have common ground such as market exclusivity, reduction or waivers of fees, and tax credits. Additionally, the governments of Japan and the US, as well as the EU, have made substantial research grants available to further

encourage orphan drug development.

challenges ahead, to name a Few:Research gathered from interviews with delegates attending the Summit cited challenges with European market exclusivity, finding creative solutions to source trial participants and the desire to combine or shorten phases in the clinical trials to reduce the cost of development as key concerns. Small



biotech and pharmaceutical companies were quick to mention that they are now feeling the crunch with larger pharma now entering this potentially lucrative market.

Pharmaceutical companies encounter difficulties at the development phase and also with the recruitment of patients for clinical trials, as the pool of patients to draw from is rather limited. On average, Phase

III trials of orphan drugs only recruit 124 patients compared to the many hundreds that are typically recruited for trials of non-orphan drugs or so called blockbuster drugs. This of course is due to the low prevalence of the disease amongst populations and the challenge of diagnosing a rare condition.

In addition to these difficulties, there is the uncertainty as to whether reimbursement will be made available, which consequently impacts the affordability and patient access to new drugs. Even when clinical trials are successful, there is no common policy when it comes to pricing, reimbursement and technology assessment of drugs in Europe, which is mostly decided on a member state level. In Europe alone, there are 27 different procedures for marketing authorisation of new drugs.

Over the lifecycle of new orphan drug development towards medical treatment, other potential uses may be identified as a result from the increasing knowledge of the disease mechanism or the drug itself. As a consequence, an orphan drug may gain a new status when multiple indications are possible and cross the non-orphan/blockbuster boundaries. These developments, although beneficial as they provide new treatments to other diseases, can prove to be difficult as they may also create uncertainty for the developer of the “designated” orphan drug. Consequently, these new findings may affect the drug status and the linked benefits.

Historically, small and medium enterprises (SMEs) as well as pioneer orphan drug developers were the only companies willing to embrace the challenges to establish themselves in the orphan drugs sector. Due to the nature of this niche market segment, companies have become flexible and agile to better engage with authorities in order to mitigate risks with development and clinical trials. They have also

been quite pro-active with patient organisations and patient partnership schemes to increase the awareness of rare diseases.

Recent FDA and EMA regulations concerning orphan drugs are changing the landscape of this niche market, as it is now generating high interest from large pharmaceutical companies. This is due to their desire to add orphan drug products to their existing blockbuster portfolios in order to strengthen their competitive edge in certain diseases fields, such as oncology, the highest recipient of orphan drugs funds. For such companies, establishing alliances, licensing agreements, partnerships or even the acquisition of companies developing orphan drugs are all alternatives to entering this new market. For both SMEs and large pharma companies, the potential rewards outweigh the risk.

The orphan drugs legislation and patient organisations initiatives have certainly opened the eyes of private stakeholders to this neglected field of diseases. However, the economic return of such investments is still uncertain and despite positive estimates, there are many improvements which need to be made concerning the harmonisation of the regulatory landscape to ensure broader patient access to medicines. This is the reason for setting up the Orphan Drugs Summit 2011 in Copenhagen, Denmark, where these areas will be addressed by; patient organisations such as Kakkis EveryLife Foundation and Sjaeldne Diagnoser, pioneers in orphan drug development such as Shire, Swedish Orphan Biovitrum AB and Genzyme, SMEs such as Zymenex, TopoTarget and the Netherlands Health Care Insurance Board, CVZ and a member of a reference group in NICE. If you are engaged in this field, join them in these exciting discussions n





Promotion of aggregation via agitation as a Means of assessing the stability of antibody Molecules

In the process of antibody candidate selection it is important that during manufacture and shelf-life the antibody shows aggregation stability. Hence it is necessary to be able to measure and predict the propensity of aggregation of different antibody molecules in a pre-screening assay.

Mechanical stress can cause denaturation and aggregation of antibodies and is often seen as a consequence of various processes during the manufacture of antibody molecules, usually during ultrafiltration/diafiltration (UF/DF) steps involving shear stress and effects of air-liquid interaction. The aim of the aggregation assay described below was to exploit these observations by promoting aggregation using stress by agitation as a means of being able to discriminate aggregation stability of different antibody molecules.

A high-throughput assay was required which could ultimately test different antibody molecules against a range of different buffer conditions.

Aggregation propensity of antibody candidates was measured using a fluorescence-based assay in 96-well format.

Shaking stress initiated by the FLUOstar Omega and the addition of Teflon beads enabled a successful antibody screening

introductionDuring manufacture of antibody molecules, they are subjected to mechanical stress generated by processes such as pumping and filtration. This may cause denaturation and consequently aggregation due to exposure of the protein to air-liquid interfaces and shear forces, resulting in the ultimate loss of bioactivity.

Hence in the process of candidate selection, data regarding the aggregation propensity of antibody molecules in various buffer conditions

would aid in the prediction of problems that would potentially be encountered during manufacturing and shelf-life stability. Shaking stress is a convenient method to screen and compare the robustness of antibodies in different buffer conditions in manufacturing and serves to mimic the effect of stress at air-liquid interfaces1, 2.

Experiments have been performed where various antibody molecules have been stressed by vortexing in 1.5 mL tubes and the extent of aggregation measured by the change in turbidity (absorbance at 340 nm/595 nm). This involves removing aliquots at various time-points for manual analysis by a

spectrophotometer, and although this methodology is useful for screening different antibody candidates it cannot accommodate large numbers of samples, and the data collection is inefficient.

A high-throughput (96-well plate format) screening method was required which would allow continuous real-time measurement of aggregation within a convenient time window of analysis.

The FLUOstar Omega microplate reader from BMG LABTECH, equipped with shaking options (allowing for linear, orbital and double orbital continuous shaking) and with both absorbance and fluorescence detection set up in

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the kinetic mode, allowed us to explore a more efficient method for measuring aggregation propensity.

Initially, experiments were set up in 96-well format mimicking the conditions used in the vortexing experiments, but using the online absorbance detection at 340nm and 595nm to monitor any real-time change in turbidity and hence aggregation instability. However, incorporating different shaking frequencies and extending the time window of measurement resulted in negligible changes of aggregation promotion. This was also corroborated by manual spectrophotometer readings at the same wavelengths.

However, the inclusion of a Teflon bead in each well resulted in a change to the absorbance over a 24-48 h time, and caused interference of the absorbance signal so the measurement of aggregation propensity was monitored by incorporation of an in situ fluorescent dye, Thioflavin T (a benzothiazole dye that exhibits enhanced fluorescence when bound to fibrous aggregates,3. The following experiments serve to illustrate the effect of increasing the air-liquid interface of the solutions using Teflon beads and measurement of any changes of aggregation stability using an in situ fluorescent dye.

Materials and Methods• Teflon beads (Polyballs Teflon 1/8”

diameter, Polysciences)• Black 96-well microplate (Costar,

Corning, UK)• FLUOstar Omega multidetection

microplate reader from BMG LABTECH, UK

• Thioflavin T (Sigma)

Experiment 1Initial experiments had been set up where antibody solutions were shaken at various shaking frequencies and temperatures using online absorbance detection, and negligible turbidity was noted. However, it was found that adding a Teflon bead (Polyballs Teflon 1/8” diameter, Polysciences) to each well during the shaking increased the efficiency of aggregation over a shorter time window. It was impossible to measure the rate of aggregation since the presence of the beads caused ‘spiking’ in the data (not evident in the wells where no bead was present). An

alternative method for the measurement of aggregation is using Thioflavin T dye (ThT), however, since a real-time measurement of aggregation stability was required, the dye was added to the wells prior to shaking and remained in situ during the time window of the experiment.

Experiment 1 was designed to test the effect of in situ dye; that is, did the presence of the dye during the shaking promote aggregation? One antibody molecule was selected which had shown aggregation instability in previous experiments, and various conditions were tested in a 96-well format. This included wells containing antibody only (plus and minus bead) and antibody with Thioflavin T dye (plus and minus bead). Buffer controls were also set up (plus and minus ThT and beads).

The antibody molecule (in 50 mM sodium acetate/125 mM sodium chloride buffer,pH 5) was used at a final concentration of 1 mg/mL. in a Thioflavin T (ThT/2,5mM) stock solution prepared freshly on the day of use in the same buffer mentioned above, and filtered through a 0.22 um filter.

The test solutions were prepared as follows :980 µL antibody solution + 20 µL buffer980 µL antibody solution + 20 µL ThioflavinT solution980 µL buffer + 20 µL ThioflavinT solution.

150 µL of test solutions were used per well of a 96-well microplate, in the

presence or absence of one Teflon bead. A plate sealer was used to eliminate loss of sample by evaporation as the experiment was performed at 37°C and for extended times.

Instrument settings• No. of cycles: 44• Cycle time: 1810 sec• No. flashes per well: 10• Excitation: 440-10• Emission: 480-10• Shaking frequency (rpm): 1100• Shaking mode: orbital• Additional shaking time: 1800 sec

after each cycle• Temperature: 37°C.

Experiment 2In order to test the conditions tested in Experiment 1, five different antibodies which had shown different aggregation instabilities during manufacture and previous stressing experiments were chosen.

The antibody molecules were normalised by exchanging the buffer into 50 mM sodium acetate/125 mM sodium chloride, pH 5 and diluting to 1 mg/mL. All other solutions were prepared as mentioned in Experiment 1. The instrument settings for screening five different antibody molecules were as described for Experiment 1.

results and DiscussionThe first experiment was performed to establish whether inclusion of a Teflon bead could promote aggregation of an antibody molecule and to establish

Figure 1. Kinetic plot showing the effect of Teflon beads on aggregation promotion of an antibody; (+) indicates presence of bead ; (-) indicates the absence of bead. ThT=Thioflavin T. (Range set from cycle 4-40 to normalise for initial equilibration factors. Data presented as baseline corrected.)


COMPANY PROFILE

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RPN considered the key criteria for evaluating a software solution to be its capabilities regarding the scheduling of activities, the visualization of project calendars, the generation of automatic alerts, and the ability to generate detail and summary reports.

After evaluating a number of software solutions RPN chose EXTEDO’s drug regulatory activity manager (DRAmanager™). EXTEDO DRAmanager provides RPN with the following benefits:

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solution and resultsoptimized internal and external coordinationRPN uses DRAmanager to meet the following key objectives: • Internal organization and synchronization of all data from

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a client as a basis to plan upcoming maintenance activities, such as periodic safety-update report submissions, variations, and renewals.

• Single solution to manage regulatory activities

The tenant-based design of the software allows RPN to have separate database sets for each client, so that multiple collaborations are possible without any issues.

The synchronization and ease of control of all regulatory data and associated activities reduces the time and cost spent during product authorization and maintenance. Additionally, the integration with other software necessary for the preparation of eCTD, and electronic reports of pharmacovigilance, will be a further step towards global electronic regulatory affairs.

Michael Schaub, Business Development Director, RPN: “Our decision for the EXTEDO DRAmanager was based on its intuitive user interface, complete set of capabilities, as well as its wide range of customization possibilities. We appreciate EXTEDO’s focus on maintaining compatibility with the ever-increasing amount of electronic standards and processes present in regulatory affairs, such as eCTD, pharmacovigilance, and labeling.”

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about regulatory Pharma net: RPN is an international drug development and regulatory affairs consultancy in Barcelona. RPN offers a full range of services related to drug development plans, clinical and nonclinical strategy, pediatric clinical development, international registration procedures, advanced therapy medicinal products, eCTD/NeeS, as well as pharmacovigilance.

about eXteDo: EXTEDO is the key solutions and services provider in the field of eRegulatory Affairs. The complete EXTEDOsuite is unique in all that it covers: Product Registration Planning & Tracking, Submission Management, Pharmacovigilance Management, Labelling Management, and Document Management. EXTEDO provides configurable off-the-shelf products, as well as customized and integrated solutions. EXTEDO also provides EURS is Yours, the validation, review and approval system for the EMA and more than 25 Regulatory Authorities worldwide. Today EXTEDO serves more than 700 customers in 57 countries. EXTEDO operates in the following markets for human, veterinary and crop protection: Life sciences, including pharmaceutical, biotech and biopharma, generics, homeopathics and medical devices, healthcare, and public sector. EXTEDO is recognized as the worldwide leader in each of its areas of operation. For more information visit www.extedo.com.


Figure 3. Rate of aggregation of the different antibody molecules in the presence and absence of a Teflon bead

whether in situ Thioflavin T could itself promote aggregation (Fig. 1).

There was only an increase in fluorescence intensity with time when the antibody sample was in the presence of the Teflon bead. It was noted that the overall fluorescence intensity was higher where Thioflavin T was present, but there did not appear to be any aggregation promotion as a consequence of being present during the experiment.

In order to establish the effect of the Teflon bead and particularly in situ Thioflavin T, the antibody samples were also analysed by dynamic light scattering (DLS; data not shown). The DLS data illustrated that there was only generation of large particles when the protein was in the presence of the Teflon bead. There was no particle formation when the protein was shaken in the absence of the bead and in situ Thioflavin T. Hence aggregation promotion was obtained as a consequence of shaking in the presence of the Teflon bead only and not by Thioflavin T.

A second experiment was done to screen different antibody molecules. The aim of this test was to investigate if it is possible to discriminate between five different antibody molecules with respect to aggregation propensity in a set buffer condition. The results are shown in Fig. 2.

When five different antibody molecules were examined, it was possible to discriminate between them with respect to their different rates of aggregation in the buffer of interest. It was possible to calculate different rates of aggregation for each of the antibody molecules tested and to obtain a ranking order (see Figure 3). The ranking was in the order Ab3 > Ab2 > Ab5 > Ab1=Ab4, where A3 showed the greatest tendency to aggregate in the chosen buffer.

Interestingly, the ranking order for the different antibody molecules was equivalent to that obtained when aggregation was promoted by an alternative method (agitation by vortexing; data not shown).

conclusionThe FLUOstar Omega multidetection microplate reader proved successful in preliminary experiments as a suitable high-throughput screening method for the assessment of aggregation stability of different antibody molecules.

Since the mechanical stress using the shaking options of the FLUOstar Omega was gentler compared with the vortexing approach in 1.5 mL tubes, the inclusion of a Teflon bead was required. This served to introduce more turbulence and hence increased the exposure to an air-liquid interface, resulting in a faster and more efficient means of promoting aggregation n

References:1. Sluzky, V., Tamada, J.A., Klibanov,

A.M. and Langer, R. (1991) Proc.Natl. Acad. Sci., USA. 88, 9377-9381.

2. Eppler, A., Weigandt, M., Hanefield, A. and Bunjes, H. (2010) Eur. J. Pharm. Biopharm. 74, 139-147.

3. Munishkina, L.A., Ahmad,A., Fink, A and Uversky, V.N. (2008) Biochemistry 47(34), 8993-9006.

Figure 2. Effect of shaking on the aggregation propensity of different antibody molecules in the presence of a Teflon bead (in situ ThT).


Alison Turner, P r i n c i p a l Scientist.I have worked at UCB, (formerly Celltech) for the past 27 years where I have been involved in many aspects of modification and characterisation of therapeutic antibody molecules. More recently, as part of the Protein Biochemistry and Biophysics Team, I have been investigating the measurement and prediction of aggregation stability for various clinical antibody candidates.Email: [email protected]

IPI 2 9/3/09 01:29 Page 43


CLINICAL RESEARCH

Flexible Phase I Study Designs: Expediting Early Clinical Drug Development

Phase I marks a significant milestone in the development of any new medicinal product. A target has been identified, a compound has been discovered that hits the target, and has been refined to ensure it has good properties for development. In-vivo safety pharmacology and toxicology studies have been conducted and the compound has been tested in pre-clinical models of the disease. This process will have taken many years. A multi-disciplinary team has evaluated all the data, and decided to take the plunge and invest in clinical development. And now, the drug is ready to be tested in humans.

The objectives of the Phase I development plan are many. Alongside establishing the safety, tolerability and pharmacokinetics (PK) of single and multiple doses in humans and ascertaining the maximum tolerated dose, it is often important to explore at least some of the following: effect of food on exposure, potential drug-drug interactions, gender and/or age effects, alternative formulations and pharmacodynamic (PD) effects. Traditionally, this has led to sizeable Phase I packages with multiple studies which take many months to complete. However, with careful planning and protocols that are written flexibly, many objectives can be addressed under one protocol (often with many parts) which can improve efficiencies in the drug development process and speed up the time to becoming Phase II ready. This article will illustrate some of the ways in which this can be achieved.

Phase 1 Clinical Development PlanningTo maximise efficiency in Phase I development, the clinical development plan must first be considered as a whole, before considering the details of individual studies. What are the

objectives of Phase I for the compound in question? What data do the team require before they can proceed to efficacy studies in patients? Are there any potential issues from pre-clinical development that need to be addressed (e.g. QT signal, potential for drug-drug interactions)? Once all the questions are identified, the clinical team can plan which studies need to be conducted in order to answer them, look for specific ways to minimise the time taken and maximise the value of each study.

It is becoming increasingly common to combine single dose ascending (i.e. First-in Human) and repeat dose studies under one protocol1. With a single protocol written in a flexible way, this can save considerable time by cutting out the period between the end of the single dose study and the writing of the repeat dose protocol, and the time for regulatory review of the second protocol. In these combined designs, it is typical for the clinical development team to be unblinded, whilst the subjects, investigator, all staff at the study site (other than the pharmacist) and study monitors remain blinded to treatment allocation. The clinical development team will carefully review any issues of poor tolerability or adverse events at the individual level, and thus need to be fully unblind in order to make an informed choice of doses for the repeat dose phase whilst the study is ongoing. Provided an efficient process is in place for transfer of samples between the study site and the bioanalysis laboratory, and of electronic data between the study site and the study statistician and pharmacokineticist, statistical summaries of pharmacokinetic and safety data can be provided quickly throughout the course of the trial, to assist the clinical development team at each dose escalation or key decision

stage. Additional objectives can often be

easily incorporated into a combined single and repeat dose study. The possibilities here are almost limitless, but a few common examples for an orally administered drug primarily aimed at a broad cross-section of the population might be as follows:i) Assess the food effect on the PK of a

selected dose;ii) Assess relationship between PK and

PD effects (e.g. on QT interval);iii) Assessment of a potential drug-drug

interaction (e.g. effect of drug A on drug B, effect of drug B on drug A, or both);

iv) Assessment of the effect of gender and/or age on PK (if applicable to the target population);

v) Assessment of therapeutic effect, if an appropriate PD measure is available (e.g. fMRI, EEG, blood biomarker, relevant rating scales).

If the protocol is written in a flexible way, some of these may be incorporated in an opportunistic manner. For example, if the dose escalations stop earlier than planned (due to reaching the maximum tolerated dose, or achievement of higher PK exposure than anticipated), one or more of the remaining periods can be utilised to assess, for example, the food effect on a dose that has been established as being well tolerated earlier in that cohort. Optional cohorts may also be included to allow exploration of higher doses where appropriate (e.g. if the planned doses are well tolerated, and there are appropriate safety margins, for example the PK exposures are lower than anticipated). Assessments of PD effects, or drug-drug interactions, can often be built into the design of the planned cohorts, obtaining more information using the same set of subjects.

ConsiderationsProtocolWhen planning a combination study with many objectives such as those illustrated above, care must be taken to ensure that all optional aspects are clearly explained. Stopping rules at the individual, cohort and study level, and the decision rules for selection of doses and for proceeding (or not) with the optional parts of the study should be outlined. The maximum number of subjects to be included should be stated, and there must be no compromise to subject safety through the flexible nature of the study design. Ethics committees and regulators will be particularly concerned that there is an appropriate data review process in place for each key decision stage.

There may be a greater lead time required between the initiation of protocol development and the first subject first visit (due to study complexity), but provided this time is built in to the development plan it is easily accommodated. In fact, overall there will be a reduction in the development time of the drug (from efficiencies by having only one protocol to review, time savings between cohorts, and in the data management, statistical and reporting processes). Other data analysis activities (e.g. population PK) will benefit too from having data consolidated on to one database.

Data CaptureIt is important that the data required for in-stream (i.e. whilst the study is ongoing) decision making can be available for review and analysis very quickly, perhaps even within 24 hours of the assessments being performed. Therefore, some means of electronic data capture is necessary. With a multi-part study, which may include a mixture of cross-over and parallel group cohorts, the structure of the database must be carefully considered to ensure that the data from any part of the study can be extracted separately as required for reporting. Where possible, data checks should be built in at data-entry, to ensure high quality data are available for in-stream decision making, which will occur prior to database lock.

In-Stream MonitoringDuring the course of the study, there

are likely to be several data review meetings to determine the dose level or other design aspect, for the next cohort(s) of subjects. These meetings need to be planned from the outset and incorporated into the study schedule. Key points to identify upfront are:i) which data are required for decision

making (PK, adverse events, lab results, etc)?

ii) how much time needs to be built in for sample analysis and data transfer?

iii) how much time is required by the pharmacokineticist, statistician and other study team members to analyse and report the data to the team?

iv) how much time is needed between the confirmation of the next dose level and the dosing of the next subject (e.g. time needed to prepare and dispense the study medication)?

If appropriate measures are in place, it can in most cases be possible to complete ii) and iii) within a week of the last data point being recorded. Dose escalation decisions are usually made jointly between the clinical development team and the investigator, therefore during review meetings care must be taken so that any information that might reveal the treatment blind is not shared with the investigator or other study site personnel.

From all the above considerations, it can be seen that planning is key. Once everything is in place, the study can proceed efficiently through the various cohorts to completion. The resulting time saving compared to doing several separate protocols can have high

impact in terms of reducing cost and overall development timelines.

Case StudyThis case study is a randomised, double blind (investigator and subject), placebo controlled multi-part study to evaluate pharmacokinetics, safety and tolerability of single and multiple ascending doses of Compound Y in healthy volunteers, including assessment of food, drug-drug interaction (the assessment of Compound Y on the PK of Drug Z) and pharmacodynamic effects. It should be noted that at this stage the evaluation of food and drug-drug interaction effects are exploratory, and may require more robust evaluation later in development. However early assessment can provide helpful estimates of the potential effects and variability which can inform future development. The overall study design is presented in Figure 1 and more fully described as follows:

Cohort 1 and Cohort 2 will assess single ascending doses (doses A to D in Cohort 1, and E to H in Cohort 2) of Compound Y, and placebo (P). Eight subjects will be enrolled into Cohort 1, and will receive three of the four doses of compound Y and placebo. Ten subjects will be enrolled into Cohort 2, which will comprise five periods in which subjects will receive all four doses of Compound Y and placebo. The administration of placebo to two subjects in each period assists with the interpretation of safety data and maintains the study blind. Typically, doses within each period will be administered in a staggered/sequential manner2. The design of Cohorts 1 and 2 is illustrated in Figure 2.


CLINICAL RESEARCH

Figure 1. Overall Study Design

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The dose escalation meetings (to evaluate pharmacokinetics and safety) will be held on the day before the next dose is due to be administered. Statistical analysis of safety data and PK/PD (e.g. vital signs, ECG etc) modelling may help inform decisions.

Cohort 3 is an optional cohort. Cohort 3 will be used to explore doses higher than those explored in Cohorts 1 and 2. It will consist of up to five dosing periods and use a maximum of ten subjects, with the same design as Cohort 2. If dose escalation has been completed in Cohorts 1 and 2 then Cohort 3 will not be used.

In the event that the dose escalations need to stop prematurely within any cohort (e.g. because the maximum tolerated dose has been reached), then the remaining dosing periods may be used to gather more data on lower doses, or to administer a previously studied dose with food. If the latter option (food) is used, then in the period where food is administered all subjects will receive the selected dose and no subjects will receive placebo.

Cohort 4 is an optional cross-over cohort comprising two periods. Ten subjects will receive a single dose of Compound Y under fasted and fed conditions (in a randomised order). If the food effect has been explored in an earlier cohort then Cohort 4 will not be used. Cohort 4 can be run in parallel with the multiple dose cohorts.

Cohorts 5 and 6 are multiple dose cohorts, exploring the pharmacokinetics and safety of two different dose levels of Compound Y when administered daily for 28 days. The choice of dose levels will be based on evaluation of data from the single dose cohorts. In each cohort, 12 subjects will receive active compound and 4 subjects will receive placebo, in a parallel group design. Cohort 5 can typically be run in parallel to Cohort 3 (where conducted).

In Cohort 6, it is planned to include an assessment of a potential drug interaction, looking at the effect of repeated doses of Compound Y on the pharmacokinetics of a single dose of Drug Z (which is given on day -7 and day 28). For this development program, the pre-clinical data indicates the potential only for Compound Y to inhibit the metabolism of Drug Z, and no possibility that Drug Z could affect

the PK or PD of Compound Y. This is not always the case, so care needs to be taken if using this approach.

Also in Cohort 6, assessments of key PD endpoints will be made on day 1 and 27. The design of Cohorts 5 and 6 is illustrated in Figure 3. Cohort 6 can be started as soon as the data review from day 14 of Cohort 5 has been completed.

Cohort 7 is an optional cohort that may be used to explore the pharmacokinetics and safety of 28 days dosing of a further dose level of compound Y if required. If Cohort 7 goes ahead, there will be 12 subjects on active and 4 subjects on placebo and the schedule of assessments will be the same as for Cohort 5. Cohort 7 could be started once the review of data from day 14 of Cohort 6 has been completed (or, if Cohort 7 is at a lower dose than Cohort 6, it could run in parallel).

Commentary on the Case StudyThis example illustrates some of the possibilities, but many different options could have been considered3. For example, the single dose ascending cohorts (Cohorts 1 and 2) could have used an interlocking cohort pattern, which may be particularly helpful if a long half life were anticipated requiring a longer washout between doses. The slightly different designs for Cohort 1 and Cohort 2 also illustrate alternative options. In Cohort 1, it is assumed that the doses to be studied are low and not of any interest for the purposes of development. The primary objective of Cohort 1 is purely to demonstrate safety before moving on to study higher doses in the anticipated therapeutic range in Cohort 2. Therefore, the design of Cohort 1 is less statistically robust than

that of Cohort 2, in that subjects do not receive all of the dose levels, and the dose levels are completely confounded with period. However it is conducted more quickly and with fewer subjects. In Cohort 2, where the doses may cover the range of expected therapeutic benefit, a more robust design is used so that data are available for all doses for all subjects, and the dose levels are staggered to some extent across the dosing periods as illustrated in Figure 2. Cohort 3, if it proceeds, will also use doses that are of potential interest for development and so has the same robust design as Cohort 2.

There are two possibilities to assess the effect of food on Compound Y. It may be added to a later period of one of the dose escalation cohorts should a decision be taken not to escalate the dose; in this case, Cohort 4 will not be needed. However Cohort 4 is included as an option to allow the food effect to be studied if Cohorts 1-3 complete all dose escalations in each period, as planned.

For the multiple dose cohorts, it is assumed that at least two, and possibly three, dose levels will be explored. Cohort 5 covers the lowest dose, which perhaps represents the lowest dose that may be considered for future development. Hence the design for this cohort is simple. Cohort 6 is intended to cover the most likely dose for future development, and this is the reason for including the assessment of the potential drug-drug interaction and also the PD assessments in this cohort. However, PKPD modelling is more informative where a range of doses is used and thus where trial budget and practicalities allow, there would be benefit in including PD in

Figure 2. Design for Cohorts 1 and 2


CLINICAL RESEARCH

Cohorts 5 and 7 (or even the single dose cohorts), though resources for PD may be best left to studies in patients depending on the nature of the PD. For the assessment of the drug-drug interaction, Cohort 6 only considers the effect of repeat dosing of Compound Y on Drug Z. It should be noted that when measuring the effect of Compound Y on Drug Z, PK assessments are generally more relevant following repeat dosing of compound Y (so that it is at steady state) than when administering only a single dose of Compound Y, but the most appropriate design will depend on the half lives of Compound Y and Drug Z. Cohort 7 allows the option of a third dose level, and if desired could also include PD assessments.

DiscussionThis paper has provided an overview of some of the ways in which Phase I packages can be tailored to the needs of the specific compound, and conducted more efficiently using combination, flexible protocols. Considerations that need to be made at the planning stage have been outlined and the practicalities discussed so that best use can be made of emerging PK and safety data to enable informed decisions regarding study progression. The case study illustrates some of the possibilities within a combination First-in-Human and Repeat Dose design. Combination studies can also be used in different settings, for example ‘cocktail’ drug-drug interactions where probes for several CYP450 pathways are administered simultaneously, with and without the test drug, to enable the assessment of several potential drug interactions in one study.

Apart from combination studies, use

of novel statistical designs can be used to improve Phase I or other clinical pharmacology studies in other ways. For example, the use of incomplete block designs (where each subject receives a subset of the treatments under study) can enable more treatments to be tested within a cross-over study than might otherwise be thought practical. This may arise in situations where different formulations of the same compound are to be evaluated. Factorial designs can also be used to help explore several factors simultaneously in one study (e.g. for ascertaining the optimal dose levels for a combination product). For compounds where the expected variability of the pharmacokinetic parameters is high, resulting in a large sample size, the use of interim analysis or sequential designs can offer the opportunity to complete the study more quickly with fewer subjects, if the primary objective has been reached or the study looks as if it will fail to achieve it.

In conclusion, the use of combination studies, flexible protocols and novel statistical designs can significantly improve Phase I and clinical pharmacology packages, with benefits both in terms of timelines and costs n

References1. ‘Guidelines for Phase I Clinical Trials’

(2007) Association of the British Pharmaceutical Industry at www.abpi.org.uk/publications

2. ‘Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products’, Committee for Medicinal Products for Human Use (CHP), 2007 http://www.ema.europa.eu/docs

3. ‘First in Human Studies: Points to Consider in Study Placement, Design and Conduct’ (2011) Association of the British Pharmaceutical Industry www.abpi.org.uk/publications

Valerie Harding, Q u a n t i c a t e ’ s communications account director, c o n d u c t e d interviews within the Quanticate statistical consultancy team on Phase II design methodologies across a wide range of therapeutic areas. The statisticians’ group experience includes applying a variety of statistical techniques including MMRM, simulations, logistic regression, survival analysis, sample size calculations and Bayesian methods to trials in clinical development (including first-in-human, repeat dose studies, phase II, Proof of Concept, phase III) and clinical pharmacology studies for late phase/marketed compounds (also bioequivalence studies and drug-drug interaction studies). The group is adept in providing support to trial Sponsors at meetings with regulatory bodies.Email: dfontaine@ recommunication.com

Figure 3. Design for Cohorts 5 and 6

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CLINICAL RESEARCH

ePRO Technology Enables Reliable, Real-Time Suicidality Monitoring in Clinical Trials

Increasing concerns regarding treatment-emergent suicidality have prompted the US Food and Drug Administration (FDA) to issue draft guidance for prospective assessment of suicidal ideation and behaviour in clinical trials. The Columbia-Suicide Severity Rating Scale (C-SSRS), a free-form clinician-administered interview, is an accepted instrument for meeting this requirement. However, procedural variance in the way this and all clinical assessments are performed by human raters has been a shortcoming for many years, negatively impacting the reliability of results. Electronic patient reported outcomes (ePRO) solutions can effectively address this limitation. This is the approach used in the development of a fully-structured, electronic self-report C-SSRS script, the eC-SSRS. Using interactive voice response (IVR) technology the eC-SSRS has demonstrated feasibility and clinical validity for monitoring suicidality. Since its introduction, the solution has been incorporated into many clinical trials by several sponsors. This article provides an overview of the FDA draft guidance, the limitations of the C-SSRS and the benefits offered by ePRO solutions and eC-SSRS in particular. A real-life application example is also outlined to further demonstrate the advantages of this innovative approach to monitoring suicidal ideation and behaviours.

Regulatory Overview and the C-SSRSThe FDA draft guidance - “Suicidality: Prospective Assessment of Occurrence in Clinical Trials” was released in September 2010 and represents the agency’s current thinking regarding the assessment of treatment-emergent suicidality. The guidance defines prospective assessment as actively querying patients about suicidal thoughts and behaviours. The objectives

are to ensure prompt recognition and treatment of at-risk patients as well as to facilitate more complete and timely data collection to improve detection

of treatment-emergent suicidality in individual studies and through pooled data analysis. Prospective suicidality assessment is also intended to limit

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CLINICAL RESEARCH spurious signals, risks and concerns

arising from spontaneous reports.According to the draft guidance,

a suicidality assessment instrument must map to Columbia Classification Algorithm for Suicide Assessment (C-CASA) codes. The C-SSRS being the prospective counterpart to C-CASA is identified as an acceptable prospective suicidality assessment instrument. The C-SSRS is essentially a semi-structured clinical interview designed to be conducted with subjects during trials, at baseline and at each patient visit. The scale probes and documents the patient’s possible suicidal ideation and behaviours.

The Power of ePRO SolutionsInherent limitations are present when employing this and other clinician-administered assessments as these are affected by rater variability. Procedural variability and clinical reliability of assessments by human raters in clinical trials has been a long-standing concern. Even with extensive training, rater skills deteriorate over time and clinicians are influenced by prior experiences with patients. This variability decreases the reliability and accuracy of suicidality assessments. ePRO solutions have been designed to increase both the reliability and efficiency of patient data collection and analysis.

Using ePRO solutions, clinical trial investigators are able to eliminate data collection issues such as clinician bias, processing delays and the monitoring of sensitive patient data. High-quality, accurate, real-time data can be gathered directly from patients, without third party involvement, offering superior confidentiality. ePRO technology encompasses a wide range of tools, including IVR solutions, PDA solutions, web browser-based solutions and mobile phone-based solutions. The different ePRO tools present clinical trial subjects with only the questions that they are required to answer. Collecting data is simple, as subjects just make selections from a list. Patient responses are obtained, checked for validity and the data stored in an electronic database. In addition, the systems promote compliance by reminding patients to take their medications, complete diary entries and submit their data to the investigators.

Owing to their unique advantages, ePRO solutions have been traditionally employed to support key aspects of the clinical trial process, including subject recruitment, patient diaries, clinical assessments and safety monitoring and alerting. However, recent studies have demonstrated that patients tend to disclose more suicidal thoughts and behaviours to non-human computer interviews than to clinicians during an interview. This has triggered the use of ePRO tools for suicidality monitoring.

The eC-SSRSThe FDA draft guidance specifies that alternative methods for administering the C-SSRS, including self-reporting using telephones or computers, are appropriate if validated. Along these lines, a structured C-SSRS script with standardised probes, appropriate follow-up queries, error-handling routines and assessment scoring conventions has been developed for IVR administration of an electronic C-SSRS (eC-SSRS).

The eC-SSRS is an automated telephone-based C-SSRS program that can reliably and accurately identify changes in suicidality signals, thereby increasing patient safety. Contrary to traditional interview techniques, the eC-SSRS program uses specific algorithms to ensure that all relevant questions are always asked in a consistent manner. Additionally, the electronic version of the C-SSRS benefits from procedural reliability in content and delivery, scalability for delivery to thousands of patients at any one time and accurate recording, storage and documentation of patient responses.

Backed by a complete ePRO solution, the eC-SSRS enables swift reaction to suicide concerns. Certain patient-reported responses trigger alerts to the trial site via a call centre. It is important to note that this approach is not intended to replace clinical judgment but to provide clinicians with useful, unbiased information for exercising clinical discretion regarding patient safety. Clinician judgment can be combined with the eC-SSRS immediate, automated, standardised reports of the patient’s responses in order to facilitate precise, efficient and thorough assessment of suicidal ideation and behaviour, thereby

ensuring patient safety.Telephone based systems (IVR) are

simple and enable patients to report their feelings without any additional equipment to manage. Subjects use a toll-free number and enter their responses using the familiar telephone keypad. This data goes directly into the vendor’s central database, making the process simple, convenient and immediate.

Clinical Trial ApplicationA total of 14,937 administrations of the eC-SSRS were completed by August 2010 and analysed. (as of April 2011 over 30,000 have been completed and another analysis is planned) This represented ten RCTs sponsored by four different pharmaceutical companies inves¬tigating treatments for major depression, PTSD, insomnia and a methodology study evaluating assessment scales for use with epilepsy patients. The eC-SSRS reports of active ideation with intention to act, with or without a fully-developed plan, reported behaviours preparatory to a suicide attempt, and/or any reported suicide attempts were classified as positive case findings.

A total of 3,263 patients completed baseline eC-SSRS assessments regarding lifetime suicidal ideation and/or behaviours, while 11,674 follow-up assessments were also completed by 2,495 patients. The mean (± SD) time between follow-up assessments was 12.9 ± 7.8 days. This resulted in 871 (26.7%) baseline assessments and 170 (1.5%) follow-up assessments being classified as positive case findings. The mean time required to complete the eC-SSRS assessments was 3.9 ± 1.9 minutes. Positive case findings took significantly more time to complete than negative case findings during both baseline (7.8 ± 1.9 versus 3.7 ± 2.3 minutes p<.001) and follow-up assessments (7.2 ± 2.0 versus 3.6 ± 1.3 minutes, p<.001). In total, 1,509 (46.2%) baseline assessments and 10,018 (85.8%) follow-up assessments reflected a complete absence of any suicidal ideation or behaviour.

Previously published validation data(1) supported the feasibility of the eC-SSRS as a valid and effective means for prospectively assessing suicidality in clinical trial research, however those

TM

clinical laboratory

TM

clinical laboratory

data were limited with respect to the number of patients studied and the duration of the follow-up study. The present analysis includes data from more diverse patient populations participating in RCTs and monitored over longer intervals. The accumulating evidence continues to support the use of the eC-SSRS as a valid and reliable assessment of suicidal ideation and behaviours.

ConclusionIn recent years, there have been heightened concerns over the increased risk of suicidal ideation and behaviour in clinical trial subjects. This has resulted in the FDA publishing draft guidance requiring the use of a more routine and reliable method for prospectively evaluating potential suicidality. ePRO technology can facilitate the complete patient experience and can revolutionise the clinical trial process, including being used for precise, dependable and regulatory-compliant suicidality

monitoring. The newly developed eC-SSRS is a phone-based ePRO solution that enables clinical trial investigators to ask highly sensitive questions and receive replies in a non-judgmental environment. Suicidality assessments are thus facilitated, reducing the risk of false negatives and maximising signal sensitivity to evaluate the true effects of new compounds and drugs. Almost 15,000 applications of this approach have been analysed and over 30,000 have been completed to date.

Reference: 1. Methodology Study: Electronic

Administration of the Columbia-Suicide Severity Rating Scale (eC-SSRS). Mundt,JC; Greist,JH; Federico,M; Posner,K.

Michael Federico is responsible for managing all aspects of the ePRO Solutions suite at ERT, including product development, operations and sales. The ePRO group has organised ERT’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: [email protected]

COMPANY PROFILE

Benefits of Insects as a novel species in the discovery ADMET screenEntomoPharm’s solution merges the best of in vitro and in vivo ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) models, using insects as the model species to obtain fast, consistent, predictive and cost-efficient in vivo data.The insect models have several advantages:• Time- and cost-effective • Fast turnaround • No traditional animal testing• Test on stock solutions – no re-synthesis

EntomoPharm BBB ServicesEntomoPharm has found that the Locusta migratoria (Locust) grasshopper (fig. 1) blood brain barrier (BBB) has similar functionality as the vertebrate BBB and that it can discriminate vertebrate BBB permeating CNS (Central Nervous System) drugs from non-CNS permeating drugs (fig. 2).

Two EntomoPharm BBB models have been successfully tested in-house and with external customers. The models are fast and cost effective, enabling improved ADMET decision-making. The models are available to pharma and biotech customers for contract support or model in-licensing.

Ex Vivo Insect BBB: Ex vivo BBB permeability model enables BBB permeability studies of compounds with a constant exposure to the brain. The model requires a minimum amount of compound material and this reduces the need for re-synthesis. The ex vivo Locust model also allows detection of Pgp substrates (fig 3). EntomoPharm has shown that Quinidine does not enter the locust brain. However, co-administration of the Pgp-blocker Verapamil and Quinidine increases the amount of Quinidine in the locust brain (Nielsen PA et al., “Models for predicting blood-brain barrier permeation”, accepted for publication in Drug Discovery Today, Accepted).

In Vivo Insect BBB: The in vivo BBB permeability insect model enables BBB permeability studies of compounds in a living organism with elimination systems similar to vertebrates and includes possibilities for both kinetic and metabolic parameters. In addition to this, grasshoppers has no albumin in the hemolymph* which offers a clear advantage for compound permeability studies as the permeability predictions will not

be blurred by albumin-bound versus unbound effects like in vertebrates. Thus, the in vivo insect BBB model provides permeability and clearance data that can be used to select candidates for conventional vertebrate in vivo BBB studies. The insect in vivo BBB permeability model allows BBB permeability studies of compounds even with low solubility. This is a useful feature especially in the early discovery phase where the compounds frequently do not have optimal physical chemistry properties.

Other EntomoPharm focus areasIntestinal absorption model: The midgut of the Locust shows high similarities to vertebrate intestinal mucosa and EntomoPharm use this to predict intestinal absorption.

Pharmacokinetic profiling in grasshoppers: Clearance of substances from Locust hemolymph correlates strongly to corresponding observations in vertebrate experimental models and EntomoPharm use this to predict plasma elimination of test compounds in a Locust pharmacokinetic model.

Environmental models: Clearance of nano particles (NP) is executed by phagocytotic cells in the Locust grasshopper in a similar way and at the same efficiency level as in vertebrates. This is used by EntomoPharm to predict NP safety.


EntomoPharm is an early-stage contract research organization (CRO) that provides predictive, time- and cost-efficient insect models to determine ADMET properties

Fig. 1: Locusta migratoria (Locust)

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About EntomoPharmEntomoPharm was established in 2009 by experienced industry professionals. The EntomoPharm’s insect platform is cutting edge and designed to target a key problem in drug development—decreasing R&D productivity at increasing costs. ADMET failures alone count for 50-60% of late stage failures, with great consequences for the cost of drug development. EntomoPharm continually develop and optimize pre-clinical screen models in insects to provide customers with cost-efficient, quality rich data enabling informed decision making and improved cost-benefit ratio.

Key persons: Peter Aadal Nielsen is CEO at EntomoPharm. He received his Ph.D. in Computational Chemistry from University of Copenhagen. He has worked as senior scientist at AstraZeneca R&D and 7TM Pharma. During his work he has been focusing on developing computational models for prediction of ADMET properties. Email: [email protected]

Gunnar Andersson is CSO at EntomoPharm. He received his Ph.D in Animal Physiology from University of Lund. He has worked as Head of Dept. of Experimental Animal Pharmacology at various pharmaceutical companies. He has been Adj. Professor at University of Lund with main focus on cell proliferation and differentiation.Email: [email protected]

Lotte Martoft is VP of commercialization and sales at EntomoPharm. She received her PhD. Veterinary neurophysiology from Copenhagen University. She has worked in laboratory pharmacology in drug discovery at AstraZeneca R&D as line manager and drug project leader and as scientific advisor and lab animal vet at XImmune and Bavarian-Nordic. During her time in the industry her focus has been on model information- and screen process improvements.Email: [email protected]

*) hemolymph is the insect analogue to the fluids and cells making up blood in vertebrates.

For inquiries please contact:Head of salesLotte Martoft DVM PhDEmail: [email protected]

Fig. 2: Locust BBB discriminate between vertebrate CNS and non-CNS drugs. Fig. 3: Locust Pgp selection for influx of molecules to the brain


CLINICAL RESEARCH

Implementing the Voluntary Harmonization Procedure for Accelerated Clinical Trial Approval

Traditionally, clinical trial application (CTA) approval in EU member states has been subject to national legislation. As a result, the assessment of a CTA that was filed simultaneously in several member states often resulted in varying final decisions and unnecessary delays. Country-specific modifications to the application often occurred due to changes requested by the different competent authorities and ethics committees. In some cases, a clinical trial might even be approved in one member state and rejected in another. The entire procedure could be extremely time-consuming and the country-specific modifications risk jeopardising the scientific value of clinical trial results.

In response, a requirement was identified for harmonisation of the assessment of multinational clinical trial applications in the EU. This requirement was guided by the need to protect clinical trial participants, ensure high quality research and bring innovative medicines to patients as quickly as possible. In 2004, the EU Heads of Medicines Agencies (HMA) established a Clinical Trials Facilitation Group (CTFG) to coordinate the implementation of the EU clinical trials directive 2001/20 EC across the member states. In 2009, the CTFG proposed a voluntary harmonisation procedure (VHP) for assessing multinational CTAs. The latest version of this procedure streamlines the assessment of multinational CTAs to be conducted in the EU in order to enlarge the scope of the pilot phase and shorten the timelines.

To date, all EU member states have accepted and are implementing the VHP except Poland, where there are some country-specific requirements that need to be fulfilled to facilitate successful clinical trial applications. However, the clinical trial approval agency in Poland will participate in the VHP process by

the end of 2011. The VHP committee is composed of representatives of the different national agencies.

The Pharmaceutical Landscape and the VHPDespite the fact that all members of the EU (excluding Poland) have accepted the VHP as a valid approach to gaining clinical trial approval, there are still many sponsors and contract research organisations (CROs) that have yet to use it. Prior to the introduction of the VHP two years ago, it was expected that the new procedure would be immediately accepted and used across the pharmaceutical industry. While there is evidence that the VHP is being increasingly adopted, some companies have shown reluctance due to a number of factors.

Firstly, there is a perceived risk associated with the fact it is a new procedure. Sponsors are not familiar with the process and are afraid that it might not be as effective as expected. As a result, they prefer to use established processes that have been more commonly used. Another factor that has resulted in limited adoption of the VHP to date is that it is free of charge. Many sponsors believe that non-paid approval procedures are of low value compared to submissions which are subject to a fee.

The VHP would perhaps have been more widely and readily accepted if more efficient promotional activities had been conducted. However, many cases have proven that the VHP is a low-risk and highly beneficial procedure, with more than 50 successful applications

completed to date. As more concrete results come to light demonstrating the usability of the procedure and a greater understanding of its benefits and use are communicated, it can be expected that the VHP will become increasingly adopted by the industry.

Understanding the ProcedureThe VHP is realised through three straightforward and brief stages. Firstly, the sponsor must electronically submit the application form and all necessary documentation to the VHP committee, the members of which will validate the material within five working days and provide feedback. Only clinical trials involving not less than three member states are eligible to undergo the VHP.

Following validation, the VHP committee will proceed with reviewing the material and 24 working days later the sponsor will receive a consolidated list of questions. The sponsor then has eight working days to answer the questions before it is the responsibility of the VHP committee to confirm approval. As a consequence, the entire procedure takes approximately 50 working days to complete, from the day of submission to the day the VHP committee approval is granted. This is significantly less time than was required to interact with each member state agency separately in order to gain approval along with an updated protocol including the modifications required by the respective agencies, and therefore can save up to two months.

In the final stage of the process, the sponsor has approximately three weeks to submit the country-specific applications to the different agencies of the countries where the clinical trial will take place. In doing so, the sponsor must submit copies of the material submitted to the VHP committee along with the VHP approval letter and country-specific documentation. The agencies will normally respond within 10 working days and will either approve the submission, or ask additional, nationally-driven questions.

The BenefitsThe VHP provides two main advantages, namely time efficiencies and uniformity. Sponsors no longer need to interface individually with different national agencies, repeatedly answering similar

questions and losing valuable time. The procedure is fully harmonised and consolidated and all national agencies involved in the approval process of a clinical trial are simultaneously aware of the information the sponsor has provided. As a result, considerable time and effort are saved, enabling faster commencement of the clinical trial for new investigational medicinal products.

Further time savings are achieved because the VHP can be initiated very early, even when sponsors do not have all the information about the clinical trial. To obtain VHP approval, an application form containing key information about the essence of the clinical trial is sufficient. More detailed information, such as the names of the clinical trial sites and/or the clinical investigators, can be provided at a later stage when submitting the country-specific application, following VHP approval, approximately one to two months later.

An additional time-efficient characteristic of the VHP is that once the approval has been granted, any modifications to the study protocol requested by the member states and accepted by the sponsor are incorporated within the procedure and do not require the filing of a protocol amendment and awaiting its approval. Harmonising a clinical trial protocol across different countries is an extremely time-consuming process. Prior to the establishment of the VHP, sponsors wishing to introduce protocol amendments could only do so by resubmitting the amendment to the concerned agencies. However, with the new procedure, a protocol amendment will be submitted to the VHP committee and a response is received within only 20 working days.

Once a clinical trial is VHP-approved, sponsors may decide to add another EU country. In such a case, that country may accept the VHP approval already obtained and allow the sponsor to proceed with the country-specific application and get final approval 10 working days after the submission of the country-specific dossier to the agency.

ConclusionIn Europe, the voluntary harmonisation procedure (VHP) is a new method to obtain clinical trial approval across

multiple European countries in a timely manner. In comparison to the traditional standard national submissions, which must be completed in parallel and submitted to each of the different European agencies, the VHP consolidates these activities into a single submission. The procedure provides clinical trial approval of all the technical documentation in every country/agency involved and can save sponsors up to two months. The VHP has been in place in Europe for approximately two years with more than 50 successful applications. As it is anticipated to be the clinical trial application approval pathway in the future, it is recommended that both sponsors and CROs that have not yet used the VHP consider it when conducting pan-European clinical trials n

Franz Josef B u c h h o l z e r , M.Sc, PhDVice President, R e g u l a t o r y O p e r a t i o n s W o r l d w i d e , PharmaNet Dr. Buchholzer has more than 20 years of experience with international pharmaceutical companies at corporate senior management level and has been extensively involved with clinical trial applications and worldwide regulatory dossier submissions. Multilingual, he has provided strategic regulatory assistance for drug development programs and/or stand-alone services, and his regulatory portfolio includes biotech products, NCEs and other innovative products covering the following indications: anaemia, heart failure, oncology, neurology, immunology, dermatology, growth, fertility and respiratory. Dr. Buchholzer has an international regulatory network and has been a speaker at several international regulatory congresses. He is a pharmacist and holds a PhD in pharmaceutical sciences from the University of Geneva in Switzerland.E-mail: [email protected]

CLINICAL RESEARCH


CLINICAL RESEARCH

Oslo Cancer Cluster was established in 2006, and has more than 60 members from all over Scandinavia and Scotland. As a Norwegian Centre of Expertise, the Oslo Cancer Cluster maintains high standards and is fully supported by the Norwegian govern-ment. The members represent the best in academic research institutions, biotech companies, and industry, financial, regional and national development stakeholders.

The vision of the Oslo Cancer Cluster is to improve the lives of cancer patients by accelerating the development of new cancer diagnostics and medicines. To fulfil the vision the Cluster is focus-ing on four main areas; cluster collaboration and partnership, attracting capital, shortening clinical development timelines and accelerating innovation in the Oslo Cancer Cluster Innovation Park.

Cluster collaboration and partnerships

The core activity of the Cluster is to facilitate networking, col-laboration and partnering among the members and towards leading international oncology milieus. On the national level Oslo Cancer Cluster organizes meeting places for the members such as R&D Network Meetings and the annual CancerCrosslinks. On the international side we facilitate our members attendance at important international conferences as the BIO convention, AngloNordic and Epic.

Most importantly we organize and host the European Cancer Cluster Partnering (ECCP) event together with our French sister-organization the Cancer-Bio-Santé. ECCP is the oncolo-gy-partnering meeting in Europe for biotech, pharma, inves-tors, clinicians and academia. ECCP2011 will take place in Toulouse, France in mid-September, find more information here: www.ecc-partnering.com.

Attracting capital

The biotech industry is a capital-intensive industry with high risk and long development timelines. In order to increase our member’s ability to access capital, we work towards the Norwegian Government to secure international competitive frame-work conditions. We also actively promote our members towards international pharma to facilitate partnering deals and to attract the interest of phase I investors. Oslo Cancer Cluster also works to establish a Norwegian governmental seed fund for biotech.

Shortening clinical development timelines

The Clinical Cancer Research Unit at Oslo University Hospital is one of Scandinavia’s leading facilities in the field of early phase clinical trials. In order to strengthen the unit and shorten the

DEDICATED ONCOLOGY CLUSTER

1

Oslo Cancer Cluster is an oncology research and development cluster dedicated to accelerating the development of new cancer diagnostics and medicines.

2

3

clinical development timelines, we have sponsored one oncolo-gist position at the Unit. Oslo Cancer Cluster have also worked towards the Norwegian government to increase the funding of clinical cancer research, which have lead to a new national programme administrated by the Norwegian Research Council.

Oslo Cancer Cluster Innovation Park

The Oslo Cancer Cluster makes its home in the heart of Norway’s Oslo Region, where almost half of Norway’s R&D activity is located. To put real strength to the vision of the Oslo Cancer Cluster we plan to gather the oncology community in the region physically by building the Oslo Cancer Cluster Innovation Park next to the renowned Oslo University Hospital, Radium.

The Innovation Park will be unique in a number of ways, includ-ing the integration of the Ullern High School. The collabora-tion between the Oslo Cancer Cluster and Ullern will be giving students both the theoretical as well as hands on opportunity to work with Oslo Cancer Cluster members. The Innovation Park will also include Norway`s world-renowned Cancer Registry, and an incubator for oncology start-up companies.

4 Find out more: www.oslocancercluster.no

Here you may find information on how to become a member of

Oslo Cancer Cluster.

Oslo Cancer Cluster was established in 2006, and has more than 60 members from all over Scandinavia and Scotland. As a Norwegian Centre of Expertise, the Oslo Cancer Cluster maintains high standards and is fully supported by the Norwegian govern-ment. The members represent the best in academic research institutions, biotech companies, and industry, financial, regional and national development stakeholders.

The vision of the Oslo Cancer Cluster is to improve the lives of cancer patients by accelerating the development of new cancer diagnostics and medicines. To fulfil the vision the Cluster is focus-ing on four main areas; cluster collaboration and partnership, attracting capital, shortening clinical development timelines and accelerating innovation in the Oslo Cancer Cluster Innovation Park.

Cluster collaboration and partnerships

The core activity of the Cluster is to facilitate networking, col-laboration and partnering among the members and towards leading international oncology milieus. On the national level Oslo Cancer Cluster organizes meeting places for the members such as R&D Network Meetings and the annual CancerCrosslinks. On the international side we facilitate our members attendance at important international conferences as the BIO convention, AngloNordic and Epic.

Most importantly we organize and host the European Cancer Cluster Partnering (ECCP) event together with our French sister-organization the Cancer-Bio-Santé. ECCP is the oncolo-gy-partnering meeting in Europe for biotech, pharma, inves-tors, clinicians and academia. ECCP2011 will take place in Toulouse, France in mid-September, find more information here: www.ecc-partnering.com.

Attracting capital

The biotech industry is a capital-intensive industry with high risk and long development timelines. In order to increase our member’s ability to access capital, we work towards the Norwegian Government to secure international competitive frame-work conditions. We also actively promote our members towards international pharma to facilitate partnering deals and to attract the interest of phase I investors. Oslo Cancer Cluster also works to establish a Norwegian governmental seed fund for biotech.

Shortening clinical development timelines

The Clinical Cancer Research Unit at Oslo University Hospital is one of Scandinavia’s leading facilities in the field of early phase clinical trials. In order to strengthen the unit and shorten the

DEDICATED ONCOLOGY CLUSTER

1

Oslo Cancer Cluster is an oncology research and development cluster dedicated to accelerating the development of new cancer diagnostics and medicines.

2

3

clinical development timelines, we have sponsored one oncolo-gist position at the Unit. Oslo Cancer Cluster have also worked towards the Norwegian government to increase the funding of clinical cancer research, which have lead to a new national programme administrated by the Norwegian Research Council.

Oslo Cancer Cluster Innovation Park

The Oslo Cancer Cluster makes its home in the heart of Norway’s Oslo Region, where almost half of Norway’s R&D activity is located. To put real strength to the vision of the Oslo Cancer Cluster we plan to gather the oncology community in the region physically by building the Oslo Cancer Cluster Innovation Park next to the renowned Oslo University Hospital, Radium.

The Innovation Park will be unique in a number of ways, includ-ing the integration of the Ullern High School. The collabora-tion between the Oslo Cancer Cluster and Ullern will be giving students both the theoretical as well as hands on opportunity to work with Oslo Cancer Cluster members. The Innovation Park will also include Norway`s world-renowned Cancer Registry, and an incubator for oncology start-up companies.

4 Find out more: www.oslocancercluster.no

Here you may find information on how to become a member of

Oslo Cancer Cluster.


CLINICAL RESEARCH

Adaptive Designs: A Method for the Future of Cancer Research

In the past few years, we have witnessed an exponential increase in costs for research and the development of new cancer drugs: it has been estimated that the average expenditure in R&D for new drugs has doubled in the last decade. Consequently, the question pharmaceutical companies continue to face is: “How can we make a study more efficient while maintaining the validity and integrity?” Sponsors, clinical researchers and biostatisticians are becoming more interested in designs with greater flexibility than the standards and procedures that anticipate “go/no-go” decisions.

Specifically in the area of development of cancer drugs this would be an enormous advantage, because cancer trials have some special features which are different from other indications:- usually the primary endpoint is

overall survival time (OS) or time to progression (TTP), resulting in a long time of observation before the endpoint is available;

- recruitment of patients is slow, except for special indications like breast cancer, resulting in a prolonged duration of trials;

- there is high importance placed on patients’ genotype or tumour cell expression, e.g. Her-2/neu positivity;

- the treatment and clinical care of patients is very expensive and

- the use of treatment combinations and modifications of treatments during the trial.

In light of these facts, it is of utmost importance to make modifications to a study while in process on the basis of new information pulled from accumulated data.

Adaptive designs offer the opportunity to do this. Within the definition of “adaptive design” comes many different possible approaches, some simple and of relatively common use, others more sophisticated, and

in certain aspects, controversial. All of these designs, however, have in common the use of collected data to modify several aspects of a study already in progress, without compromising the validity or integrity. It should be emphasised that modifications are not a remedy for inadequate planning, but must be pre-defined and justified in the study protocol.

The possible modifications include changes in sample size, in the criteria for inclusion/exclusion, in the doses or treatment regimen, in the study endpoints, in the elimination or addition of treatment groups, in the randomisation ratio or in the early closure of the study for efficacy/futility.

Developed statistical methodologies permit the application of these modifications to a study in progress, while keeping under control the probability of error associated with hypothesis testing.

The European Medicines Authority (EMA) has also faced the topic of adaptive designs in a document “Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design” (18 October 2007), and periodically

updates this topic. While it is well known that there is a

possibility to re-estimate the number of patients needed for a study based on observed data in interim analysis, it is less known, but of great interest, that design can allow objectives to be achieved in one study that would normally require the scheduling of two distinct studies, so called “seamless Phase II/III designs”.

The seamless Phase II/III designs combine two sequential and separate studies into one study and allows the use of collected information in the first stage to adapt the design in the second stage. The advantages of this design are a reduction in the overall time in the development of a drug, fewer patients required, and the early availability of long-term safety data.

As an example of the application of designs in Phase II/III, let’s consider a recent study we are in charge of planning (Figure 1). In the first stage, corresponding to Phase II, there are three arms of treatment expected: two different experimental treatment doses, and standard treatment. In the second stage, corresponding to Phase

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III, there are only two arms of treatment expected: the experimental treatment dose, selected based on observed results in the first stage, and standard treatment.

The selection of dosage depends on the observed success rates in the treatment groups at the end of Phase II, according to a pre-specified decision rule. We can note that, in the case of a lack of efficacy of both doses of the experimental treatment, there is also the possibility to stop the study.

Another very interesting possibility of an adaptive study is to select the right target population for the drug. This is of special interest in the development of highly specific cancer drugs, which are only effective in a selected patient population, for example monoclonal

antibodies. An adaptive study in Phase II/III may allow the selection of the most promising target population in the first stage for the second stage.

The advantages of this design are that it may result in a reduction in the overall time in the development of a drug, fewer patients required and the early availability of long-term safety data.

Based on our experience, the advice we would give a pharmaceutical company that is considering this type of design is as follows:• Budget more time for the planning of

an adaptive design as compared to a standard design.

• Interact with regulatory authorities in the planning phase, especially for

Phase II/III studies.• Define the decision rules for interim

analyses and provide statistical justification to support the study design.

• Use simulations to calculate the power of the sample size and the probability of success in the study.

• Evaluate whether or not to stop the recruitment of patients for the interim analyses.

• Take into consideration the use of electronic files to manage data efficiently and rapidly for the interim analyses.

• Use independent statisticians to perform the interim analyses and independent committees to review the results of the analyses.

• Schedule frequent monitoring visits in order to provide as much data as possible for the interim analyses.

• Inform in advance those who are responsible for supplying the drug on the type of design, and take into consideration, for randomisation, the possibility of an interactive centralised system.

In conclusion, adaptive designs have the potential to change the way in which we conduct clinical research, taking into consideration, however, that the flexibility allowed in comparison to traditional designs requires a greater effort in the initial planning stage of the study.

Thomas Zwingers is the Chief Operating Officer for CROS NT, a contract research o r g a n i s a t i o n based in Verona, Italy and Augsburg, Germany. Thomas assumes the responsibility of all clinical operations and strategic planning. He has been working in the field of clinical trials since 1980 in project team management and statistical analysis. Thomas is also a member of CROS NT’s prestigious Statistical Scientific Board, a group of prominent European statisticians providing statistical consultancy for clinical trials. Email: [email protected]


CLINICAL RESEARCH

A Generic Approach to the Validation of Small Molecule LC-MS/MS Biomarker Assays

IPI Summer IFC-53.indd 35 6/9/10 19:19:51


CLINICAL RESEARCH

Dermatological Models: A Sound Basis for Early Decision-MakingWhereas the early phase of drug development for systemically acting drugs is mostly driven by the presumed relationship between safety/efficacy and concentration of drug in the systemic circulation, this relationship does not exist for topically applied drugs intended for local or regional action. For these topical drugs, systemic absorption is not desired and systemic exposure can often be kept to very low or even negligible levels by controlling the size of the treatment area. In early clinical development this ability to limit systemic exposure often allows for initial assessment of efficacy in innovative models before investment in costly safety studies.

In dermatological models, discrete evaluation of treatment effects may be possible following simultaneous application of multiple formulations/actives to small treatment areas in parallel in one individual, without risk of cross-over effects. By making intra-individual comparisons between treatments, the inter-subject variability is reduced, allowing meaningful interpretation of results with smaller panel sizes. Further, in these models non-invasive biophysical measurement and imaging methods to monitor skin function and structure provide alternative objective endpoints to support clinical evaluation, delivering additional information on structural and functional changes in the skin.

The following provides a brief overview of several established dermatological models and how they can be applied in clinical testing.

Psoriasis Plaque TestIn the psoriasis plaque test, also known as the psoriasis microplaque assay, anti-psoriatic efficacy of multiple formulations is assessed in parallel in small test areas located on stable psoriatic plaques in patients with psoriasis vulgaris. It may even be possible to test efficacy in this design as the first Phase I study, analog to an early Phase I study under an exploratory IND.

In the original test design described by Dumas and Scholtz in 19721, the efficacy of corticosteroids for treatment of plaque-type psoriasis was evaluated clinically following standardised occlusive application over several days. Test fields were graded as follows: unchanged or less than full involution (0) or complete return of epidermis to normal (+). Whereas this design is well suited for testing of strong anti-psoriatics such as potent corticosteroids, the sensitivity may not be sufficient for assessment of weaker formulations or determination of slight differences between formulations.

Meanwhile biophysical measurement methods have been used in the PPT to objectively measure the inflammatory alterations accompanying psoriasis, greatly improving the sensitivity of the test. Since one of the most important clinical endpoints in psoriasis is the extent of the psoriatic infiltrate, objective measurement of the infiltrate depth with 20 MHz sonography is probably the most relevant outcome to use as a marker for treatment effects. Other methods that have been used in the plaque test include measurement of intensity of erythema by colorimetry, skin blood flow by laser-Doppler flowmetry, skin surface characteristics by profilometry, and skin temperature2-5.

In a typical psoriasis plaque test design, patients (n=15-20) suffering from psoriasis vulgaris with stable plaques already existing for several months or years are suitable for inclusion. Plaques exhibiting spontaneous regression as well as exacerbation of psoriasis are excluded. Small test fields (e.g. 12 mm )

are treated over a 12-28 day period. The proposed mechanism of action of the active pharmaceutical ingredient (API) should be taken into consideration to determine the length of treatment. Ideally all test fields are located on a single psoriatic plaque or on two plaques located in a similar body area and of comparable severity. Prior to baseline measurements and the first treatment, scales are removed from plaques. This is necessary since it is not possible to obtain sonographic images of good quality if images are taken through thick scales. A bandage is attached to the plaque in which the test fields have been punched out (figure 1). Treatments are preferably performed in an occluded manner once daily. More rarely treatments are performed in an open manner once or twice daily. In general, occlusion is preferred as this maximises absorption of drug, shortening the necessary treatment period. The primary variable is the depth of the psoriatic infiltrate measured in sonographic images taken at defined intervals during the treatment period. The echo-poor region directly underneath the entrance echo mainly represents the inflammatory infiltrate and is readily demarcated in good quality images (figure 2). Alternatively, full skin thickness (infiltrate plus dermis) can be measured to evaluate changes in severity of psoriasis, however this method is generally less sensitive than measurement of the psoriatic infiltrate alone. Clinical improvement is assessed as a secondary variable, but it is not posssible to make the fine distinctions between treatments that are possible with

Figure 2Figure 1

Established in 1992, bioskin® is a full-service CRO dedicated to dermatology. We plan and conduct clinical trials for pharmaceuticals,medical devices, food supplements and ad-vanced/professional cosmetics.

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measurements of sonographic images. The intensity of erythema can also be

measured in the test fields by colorimetry. Even though this measurement has proven particularly useful for the evaluation of corticosteroids where vasoconstriction plays a prominent role in the measurable effect, the overall relevance of additional assessment of redness is questionable for other drug classes. Redness is the last symptom to clear in psoriasis and some residual erythema may remain after all other skin alterations have cleared1.

The psoriasis plaque test has been used to investigate efficacy of corticosteroids, vitamin D analogs, retinoids, oligonucleotides, and immunmodulators, among others. The test is very well suited for comparison of developmental candidates, alternative formulations or initial studies of dose response. Due to the maximised conditions it is to be expected that efficacy will be found if a formulation indeed possesses antipsoriatic activity.

Irritant Dermatitis ModelAcute or chronic eczematous skin reactions can be simulated by standardised repeated washing with the anionic surfactant sodium lauryl sulfate (SLS)6,7. The clinical appearance of the skin (erythema, scaling, fissuring) and biophysical parameters of skin condition (transepidermal water loss (TEWL), stratum corneum hydration, skin colour/erythema) show similarities between the irritation induced with SLS and irritant dermatitis.

In one such model used at bioskin comparable localised skin lesions are created on the forearms of healthy or atopic subjects using a highly standardised open washing procedure once daily for six days. Following this washing procedure, test fields are delineated by application of a bandage system with punched holes (figure 3). Treatments are then applied once or twice daily for up to four days. In a modification of this design the washing procedure may be continued during the treatment phase to better simulate chronic irritation.

This model is mainly suited for screening of barrier repair formulations or other anti-inflammatory formulations intended for treatment of conditions such as hand eczema. It may also be

very useful for screening of suitable moisturisers and lubricating vehicles.

UV-Induced Erythema TestThe UV-induced erythema test is an experimental model to evaluate anti-inflammatory efficacy of steroidal and non-steroidal topical formulations8,9. The model has the advantage that it is performed in healthy volunteers as opposed to patients with inflammatory skin disease. UV-induced inflammation is mediated by several possible mechanisms and involves the generation of a variety of inflammatory mediators such as prostaglandins, histamine, bradykinin, serotonin and leucotrienes.

In this model, a typical sample size is 20 to 40 subjects with Fitzpatrick skin type II to III. Since efficacy is correlated with the severity of the inflammatory response, success of the test is dependent on controlling the extent of inflammation, even in individuals with different inherent sensitivities. This is achieved by irradiating with a defined UVB dose which is a multiple of the Minimal Erythemal Dose (MED). The MED is the smallest amount of UVB light producing distinct erythema, and differs from individual to individual. The MED for each subject must be determined beforehand by parallel exposition of small fields to graduated UVB dosages.

After determination of the individual MED, test fields on the back are irradiated with the desired UVB dosages. The degree of inflammation can be varied by irradiating separate test fields with different UVB dosages, e.g. 1.25, 1.6 and 2 MED, in a single panel. Immediately after irradiation the test fields are treated for the first time with the test formulations. Since treatments are performed after irradiation, a sun protective effect can be excluded. Test products can be applied in an occlusive or open manner, however in the case of weak anti-inflammatory drugs, e.g. hydrocortisone, it may only be possible to measure an anti-inflammatory effect under occlusive conditions. The frequency of application (single or repeated applications) and the length of the treatment period (eight to 48 hours) can be varied.

The endpoint is the degree of erythema in the irradiated test fields. Diminished erythema compared to irradiated, untreated fields or vehicle-treated fields

is indicative of anti-inflammatory efficacy. Objective measurements of erythema are done using colorimetry.

Thermal Sensory AssessmentAlterations in pain perception can be quantified using a thermal sensory analyser. Using this technique a thermal diode is placed on the subject’s skin to heat or cool the skin. The subject is then asked to respond to the temperature stimuli by pressing a button when pain is first perceived or becomes intolerable.

To take this methodology one step further, thermal hyperalgesia can first be induced in test fields by setting an inflammation with UVB light to increase pain sensitivity for testing antihyperalgesic drugs10,11. To measure the heat pain threshold, the skin temperature is linearly increased using the thermode, and subjects are advised to stop the heat by pressing a button as soon as the heat becomes painful. The threshold temperature is recorded. The threshold is assessed prior to irradiation and at intervals beginning six to 12 hours following irradiation. Antihyperalgesic drugs lower the heat pain threshold.

Wound Healing ModelsAside from patients with wounds resulting from accidents or diseases, or wounds resulting from diagnostic or therapeutic measures (cryosurgical removal of skin lesions, punch biopsies


CLINICAL RESEARCH

Figure 3

Figure 4


CLINICAL RESEARCH

and post-operative wound care), there are few ethical models to examine wound healing in humans. The production of wounds is inevitably an invasive procedure that may be associated with pain, bleeding, wound infection and scarring.

There are however two good models for induction of superficial wounds in which the promotion of wound healing during the early phase of re-epithelisation can be measured.

The first is a recently developed model in which standardised abrasive wounds are induced which closely mimic the clinical picture of bagatelle abrasive wounds12. Multiple wounds are induced on the forearm by scrubbing the skin with a hard brush until punctate bleeding occurs. Healing and re-epithelisation is then followed for up to 14 days (figure 4). Panel sizes range from 10-30 subjects.

An alternative model involves making epidermal defects of defined size by raising suction blisters using negative pressure over a surgical pump. Following removal of the blister roof there is a large increase in water loss as a result of the missing epidermal barrier. It is well established that the transepidermal water loss (TEWL) is correlated with the degree of epidermal damage. The highest TEWL values are measured in fresh wounds with a continual decline until values from intact skin are reached at the end of healing. Therefore the measurement of TEWL is a suitable parameter to determine the degree of re-epithelisation. The critical phase of epithelial regeneration already occurs during the first days following experimental wound induction in this model.

Expanded Flora TestBactericidal efficacy of topical preparations can be investigated in the expanded flora test13. In this model the bacteria on the surface of the skin are multipied by occluding test fields located on the back with a plastic covering. In this way the resident cutaneous microflora can be expanded from its normal low density of about 10² colony forming units to 105-106 after 24-48 hours of occlusion14,15. Modifications of the original model allow for treatments before or after expansion of the skin’s bacteria to assess the antibacterial activity.

ConclusionThese as well as other “custom-made” models can help to make the all-important go/no go decision early in a topical product development programme. Further, test model results are valuable for planning of later therapeutic trials, for instance for sample size calculations, dose finding and ranking with comparators. These advantages should be exploited to the fullest to optimise clinical development programmes n

References:1. Dumas KJ, Scholtz JR. The psoriasis

bio-assay for topical corticosteroid activity. Acta Dermatovenerol (Stockholm) 1972; 52: 43-8.

2. Bangha E, Elsner P. Evaluation of topical antipsoriatic treatment by chromametry, visiometry and 20-Mhz ultrasound in the psoriasis plaque test. Skin Pharmacol 1996; 9: 298-306.

3. Remitz A, Reitamo S, Erkko P et al. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol 1999; 141: 103-7.

4. Harrison DK, Abbot NC, Beck JS, et al. Laser doppler perfusion imaging compared with light-guide laser doppler flowmetry, dynamic thermographic imaging and tissue spectrophotometry for investigating blood flow in human skin. Adv Exp Med Biol 1994; 345: 853-9.

5. Wolff HH, Kreusch JF, Wilhelm KP, Klaus S. The psoriasis plaque test and topical corticosteroids: evaluation by computerized laser profilometry. Curr Probl Dermatol 1993; 21: 107-13.

6. Lee CH, Maibach HI. The sodium lauryl sulfate model: an overview. Contact Dermatitis 1995; 33: 1-7.

7. Gehring W, Gloor M, Kleesz P. Predictive washing test for evaluation of individual eczema risk. Contact Dermatitis 1998; 39: 8-13.

8. Hughes-Formella BJ, Bohnsack K, Rippke F, et al. Anti-Inflammatory Effect of Hamamelis Lotion in a UVB Erythema Test. Dermatology 1998; 196: 316-22.

9. Jocher A, Kessler S, Hornstein S, et al. The UV erythema test as a model to investigate the anti-inflammatory potency of topical preparations – reevaluation and optimization of the method. Skin Pharmacol Physiol 2005; 18: 234-240.

10. Koppert W, Likar R, Geisslinger G, et al. Peripheral antihyperalgesic effect of morphine to heat, but not mechanical, stimulation in healthy volunteers after ultraviolet-B irradiation. Anesth Analg 1999; 88: 117-22.

11. Bickel A, Dorfs S, Schmelz M, et al. Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man. Pain 1998; 76: 317-25.

12. Wigger-Alberti W, Kuhlmann M, Ekanayake S, Wilhelm D, Buettner H, Callaghan T, Wilhelm KP. Using a novel wound model to investigate the healing properties of products for superficial wounds. J Wound Care 2009; 18: 123-128, 131.

13. Marples RR, Kligman AM. Methods for evaluating topical antibacterial agents on human skin. Antimicrob Agents Chemother 1974; 5: 323-329

14. Leyden JJ, Stewart R, Kligman AM. Updated in vivo methods evaluating topical antimicrobial agents on human skin. J Invest Dermatol 1979; 72: 165-170.

15. Leyden JJ, McGinley KJ, Foglia AN, Wahrman JE, Gropper, CN, Vowels BR. A new method for in vivo evaluation of antimicrobial agents by translocation fo complex dense populations of cutaneous bacteria. Skin Pharmacology 1996; 9: 60-68.

Betsy Hughes-Formella is Director of B u s i n e s s D e v e l o p m e n t and Consulting at bioskin GmbH. She received her MS and PhD in Physiology from the University of Georgia in Athens before moving to Germany to join a research team at the University Medical Center in Hamburg. In 1992 Dr. Hughes-Formella joined bioskin where she she is responsible for the coordination of business development activities and is a consultant and advisor for dermatological product development.

Email: [email protected]

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Good Clinical Laboratory Practice: An IntroductionThe regulatory environment in which clinical trials are conducted is constantly changing. Applying more rigorous controls to ensure reliability of data and to guard patient safety is now a constant focus for us all. The worldwide acceptance of the ICH Guideline for Good Clinical Practice (GCP) and the implementation of the European Union Clinical Trials Directive (2001/20/EC) are two clear indicators of this fact.

Whilst the requirements defined for the roles of the ethics committee, the investigator and the sponsor (to name a few) are clear in both the EU Clinical Trials Directive and the ICH GCP Guideline, the importance of the defining standards to be applied in the analysis of samples from clinical trials seem to have been underestimated.

The EU Clinical Trials Directive indicates clearly that guidance documents may be issued to define the various aspects of a trial and the requirements that should be satisfied for each aspect. However, at this time, the Directive is uncertain as to whether these defined requirements will include the analysis of trial samples.

Within the ICH GCP Guidelines, the most applicable references that indicate the standards required for the analysis of samples are in sections 2.13, “Systems with procedures that assure the quality of every aspect of the trial should be implemented”, and section 8, “Essential Documents”, parts 8.2.12 and 8.3.7. These do not represent a definitive description of the wide-ranging requirements of clinical trials.

What is GCLP?Good Clinical Laboratory Practice (GCLP) is a quality system for laboratories designed to provide a strong framework to those individuals and organisations that undertake the analyses of samples from clinical trials, specifically on the facilities, systems and procedures that should be

Q

COMPANY PROFILE

Qualogy Contract Regulatory Archive Service is a fast growing, secure archive providing high quality contract services to the GLP and GCP regulated industries. The archive facilities are operated to the exacting standards required by the Good Clinical Practice (GCP), Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) Regulations and the Good Clinical Laboratory Practice (GCLP) guidelines.

Founded in 1997, Qualogy Ltd began as solely an Independent consultancy company, specialising in providing expertise to organisations that are required to implement the requirements of Good Laboratory and Good Clinical Practice. The company was founded by Tim Stiles, who has worked within the regulatory arena for 30 years, including working as the Director of Quality Assurance within a large Contract Research Organisation (CRO). Tim was also involved in the inception of BARQA QA professional development courses within the UK and has lectured and trained in Europe, East Africa, India, US, Asia, South Africa and Japan on GLP and GCP topics.

In the course of the companies consultancy business the need for a secure and reliable independent contract archive storage facility for Investigator Site Files (ISFs) was identified. In response to this identified need, our archive facility was established in 2002 for the archive storage of ISFs and other GLP/GCP/GMP materials on behalf of sponsor/client organisations.

The archive facility is a secure storage area which is operated in accordance with documented standard operating procedures (SOPs) and stringent environmental and security controls. The contract archive service includes a detailed documented chain of custody from point of collection, storage in secure facilities, and rapid retrieval when required. The archive facility is managed and operated by an experienced Archivist qualified in Scientific Archive Management and with over ten years experience as an Archivist in a large CRO.

The basic principle of operation is that material is received or collected by Qualogy in sealed archive boxes. Transportation of the material from the client to the archive facility can be undertaken by the client or by Qualogy’s own dedicated courier service. Full inventories of the boxes held will be maintained and copied to the client on receipt of each new batch of material received. A full “chain of custody” for each box of material received will also be maintained from the point of collection/receipt of the material.

Services Offered Include

Archivist

If you require further information on any of the services provided by Qualogy please contact:The ArchivistQualogy LtdPO Box 6255ThrapstonNorthamptonshireNN14 4ZLTelephone: +44 (0)1234 783466Email: [email protected]

Qualogy

Q

Contract Archive Services




present to assure the quality, reliability and integrity of the work and results generated during the organisation’s/individual’s particular contribution to a clinical trial.

GCLP applies the principles established in Good Laboratory Practice (GLP) for data generation used in regulatory submissions which are relevant to the analyses of samples from a clinical trial, whilst concurrently ensuring that all GCP principles, and the objectives and purpose of the trial, are satisfied. By combining these principles a high level of regulatory security is achieved.

To properly put the GCLP framework into context, it is important to define the core elements that have been amalgamated to create the GCLP quality system, namely GLP and GCP.

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects, provided by the International Conference on Harmonization (ICH). Compliance with this standard provides public assurance that the rights, safety and wellbeing of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, developed by the World Medical Association (WMA). Many countries have implemented the ICH GCP Guideline as part of their own regulations.

Good Laboratory Practice (GLP) is intended to promote the quality and validity of non-clinical test data. It is a managerial concept covering the organisational process and the conditions under which laboratory studies are planned, performed, monitored, recorded and reported. (OECD GLP Guideline).

GCLP applies those most relevant aspects of GCP and GLP to a quality system that is a useful tool for ensuring the integrity of clinical data.

The DocumentThe guidance document is intended for use by any organisation analysing samples generated during the conduct of a clinical trial. The principles can be applied equally to the analysis of a blood sample for routine safety screening of volunteers (haematology/biochemistry)

as to pharmacokinetics or the process of analyses of ECG traces.

The GCLP document is designed to provide a unified global framework that inspires confidence in the data generated by the clinical trials from all around the world. With this in mind it is important to reiterate that the framework outlined in the GCLP document is just that - a framework. It is important to note this because, as already mentioned, GCLP can be applied across a diverse set of disciplines involved in the analysis of samples from clinical trials. Therefore the GCLP document has been designed so its application is open to interpretation, allowing it to be used in the work of all the many varying organisations that undertake analyses that must have the quality of every aspect of the work that they perform assured.

AccreditationThe GCLP Laboratory Accreditation scheme is an inspection process that provides laboratories, and the users of such services, with assurance of the standards in operation. The scheme has been designed expressly for laboratories worldwide that analyse samples from clinical trials and provides a high level of assurance as to the standards operated by the laboratory by using the principles of GCLP.

The scheme is aimed at those laboratories who wish to demonstrate to sponsors of clinical trials and government agencies worldwide that their clinical laboratory operates to a standard that assures the reliability, quality and integrity of the work and results and protects the rights of subjects/patients.

The standard against which the compliance is monitored is Good Clinical Laboratory Practice, as published in the BARQA guideline document, first produced in March 2003 and reviewed in 2011, (ISBN 978-1-904610-00-7).

The scheme employs assessors to evaluate the level of compliance with the defined standard. They will possess a number of years’ experience in either GLP or GCP and will be trained in GCLP assessment procedures.

The type of laboratories involved in the scheme is extremely varied. They include hospital laboratories, central laboratories, company laboratories

and investigator site laboratories. These laboratories perform various assays including pharmacokinetic (PK), screening, routine haematology, biochemistry and urinalysis, non-routine sample analysis, sample processing and many other activities involved in the collection, transportation, analysis and reporting of results from clinical trial samples. The scheme is open to any laboratory, in any part of the world that meets the schemes qualification criteria.

About Qualogy LtdQualogy Ltd is a fast-growing independent consultancy company. Founded in 1997, Qualogy specialises in providing expertise to organisations that are required to implement the exacting requirements of Good Laboratory and Good Clinical Practice. The company operates globally and has specialism in Good Clinical Laboratory Practice (GCLP). In addition to providing advice, training and guidance to organisations on how to implement GLP, GCP and GCLP, the company also operates a Contract Regulatory Archive, which offers a uniquely personal service to its clients.

Tim Stiles is a Director of Qualogy Ltd (www.qualogy.co.uk), an internat ional ly-r e n o w n e d consultancy firm that provides assistance to organisations implementing GCP and GLP regulations and GCLP guidelines. As a company, Qualogy provides training courses, contract archive services and compliance services to those organisations working to the global GLP and GCP regulations. Tim has worked in organisations operating in compliance with GLP and GCP for the past 30 years. Tim has lectured and trained in Europe, Africa, India, US, Asia, and Japan on GLP and GCP topics. He co-authored the GCLP Guidelines for the British Association of Research Quality Assurance (BARQA), where he is a former chairman.Email: [email protected]



It’s a Risky Business

As a child you don’t really understand that one of the universal constants in life is that of risk. In the big, wide world there may be many things attempting to hurt you - other kids trying to beat you up, and the odd wasp flying around to sting you. The chances are that you won’t care too much, because what’s important is getting to play with your friends, getting a high score on your games console, and eating fast food. For most kids, the worst that might happen is that your ball goes over the fence into next door’s garden, or your mum stops you playing an 18-rated shoot-em-up.

As you grow a little older then, hopefully, you begin to apply what your maiden aunt might term common sense and look out for things coming to get you. You don’t push beans up your nose anymore, you don’t feel a need to taste everything within reach, and you might put someone on watch when you are doing something vaguely illicit, to see if an adult is coming to stop you. The world may come to an end because you’ve used up your text allocation for the month.

Then we reach adulthood. Risk becomes about much bigger things: will your car tyres pass the MOT? Can you persuade the bank manager that you are a good financial risk to get a loan or a mortgage? Will the chicken in the back of the fridge give you salmonella if you eat it two days after the use by date? Your adult self should recognise that the safety signs put up in every office, warehouse and building site are there for good reason.

The pharmaceutical industry has gone through all these stages over the last twenty years or so, and whilst it used to be considered acceptable to put clinical supplies in a box with some gel packs, and cross your fingers, now not only is pre-qualified packaging a necessity, but also using a temperature monitor for almost every shipment.

Increasingly risk management, the identification, assessment, and prioritisation of risks, is required in

advance of shipping. The regulators are increasingly expecting not just consideration to be made of risk, but a process to be in place to make this assessment, and documented evidence

of the process and the conclusions to be available.

Risk assessment has become a tool not just to ensure the compliance of companies with health and safety, its

A) Evaluation Scale “Failure Probability”

Probability Description Numerical Value

High will appear permanently 6

Moderate likely to appear frequently

3

Low appears seldom 1

b) Evaluation Scale “Impact”

Impact Description Numerical Value

High critical failure, process not mastered, service/product quality completely lost, loss of business likely

6

Moderate major failure, process not securely mastered, service/product quality very weak, customer complaint, service/product not competitive on the market

3

Low minor failure, process not well mastered, service/product quality with weaknesses, customer not satisfied, service/product quality below average

1

Decision criteria based on initial risk

Unacceptable risk 18-36 Preventive actions are mandatory. If the risk cannot be lowered then proceed only with approval of client AND senior manager

Acceptable under specific conditions

6-9 Preventive actions desirable. If no risk reduc-tion is possible, authorisation requires case by case decision by senior manager or designate

Acceptable risk 1-3 Preventive actions not required, but should be performed where feasible

High (6) Moderate (3) Low (1)

36 18 6

18 9 3

6 3 1

Probability

High (6)

Moderate (3)

Low (1)

Consequence

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traditional use, but is increasingly used to assess the competence of shipping departments, freight forwarders, couriers and third party logistics (3PLs) prior to sending high value pharmaceuticals. This is particularly the case for clinical trial items with their tight temperature ranges, limited stability data and limited resupply options. It is also universally

used by actuaries and therefore insurers to decide upon premiums.

If we apply the teenage view and some common sense then let’s look at an example from a few years ago regarding delays in transit:

Potential problems: • Airline requirements not considered

• Flight delays • Airline mishandling• Clearance problems • Site personnel unprepared for arrival• Weekends / holidays

The considered response was: • Airline choice • Reputable courier or freight forwarder

No. Description of Activity

Failure Probability

Impact Risk Existing Control Measures

General Use of Envirotainers Unit Load Devices (ULD) for E1 and T2 type containers

1 Selection of the appropriate type of container e.g. E1 or T2.

1 6 6 Only individuals with spe-cific training are permitted to handle Envirotainer moves.

2 Damaged container being supplied.

3 6 18 All containers are inspected on delivery and subjected to a 24-hour running test. Pickup checklist completed includes cleanliness, seals and temperature test.

3 Requirement for adequate air circulation inside the unit.

3 3 9 Pallets must be used for all shipments to ensure adequate circulation or air.

4 Handling errors by the airline can jeopardise the integrity of the product inside the container.

1 6 6 The airline handling at origination and destination must be closely monitored by the local office.

5 Placement inside refrigerators can jeopardise shipment integrity and cause failure of the unit and freezing.

1 6 6 Shipment should be maintained as close to room temperature (15-25°C) as possible. ULD is labelled at collection with “Do not refrigerate / freeze” labels in local language if appropriate. This information is shown on the MAWB.

• Pre-alerting consignee • GPS tracking of packages• Work backwards from required delivery

time • Clear chain of custody at site

At the time this was considered to be perfectly adequate, and addressed the concerns of auditors and regulators alike, backed up with existing standard operating procedures (SOPs) for controlling how each step of the process was managed.

Whilst it is expected that those common sense principles will still be applied, what does the extra requirement of risk assessment provide, and given the universal acceptance of risk management, how best can we apply it to transportation?

Risk assessment requires an evaluation of all the parts of a process flow, in this case each step along a transport chain, and each potential area of concern. It can be useful to brainstorm all the elements of the transport chain, bringing in multiple disciplines.

The following stages can be used: 1. Identify possible risk areas and

threats2. Evaluate the risks of failure probability

and the resultant impact3. Identify control measures to reduce

the risks 4. Prioritise remaining risk reduction

measures based on a strategy

1. Evaluation CriteriaThe criteria for analysing the overall risk are the failure probability and the failure impact. Some examples are given below. A high weighting is given to high probability and impact.

Calculation The risk will be calculated with the formula:Probability x Impact = RiskThe resulting numerical values (Risk Number 1 to 36) correlate with a risk assessment matrix and three decision criteria.

So let’s look at an example for shipping large quantities of product in an Envirotainer:

It can be seen that every single step of the process can be considered in this way, and by using this format of report,

each department can give input on both the risks and the control measures which should be put in place. One of the benefits of adopting a risk management strategy is that, used well, it empowers employees to give their assessment of likely problems and solutions. Over time this results in a risk-aware culture and encourages participation at all levels. This multi-level approach brings to light small things which may not be readily obvious but can have a significant effect on the transport chain.

Using this approach can be particularly useful when sending materials into the newer emerging destinations: Latin America, Asia Pacific and Sub-Saharan Africa. These offer considerable opportunities for patient recruitment, but there are new and interesting risks associated with them. A lot of these are cultural, or involve specific local regulatory requirements. For example, China has different food and drug administrations in Beijing and Shanghai who operate slightly differently. When sending into India, airports have temperature-controlled areas for storage during customs clearance but the available temperatures will depend upon the city, airport and which airline the shipment flew in on.

These risks can be mitigated by having local knowledge, local representation and local staff, or by working in close partnership with a company with extensive experience.

And then there are the very unlikely events. This is not to say that these are unforeseeable; with enough people in a brainstorming session it is entirely feasible that a volcanic explosion in Iceland might be mooted, but not necessarily that air stoppages of up to a month across Europe would result. We can expect unusual amounts of snow in the winter, earthquakes around the Pacific Rim, petrol strikes, and air traffic control strikes, all of which have occurred during the last year. Companies can and should have contingency plans in place for all those events, with clear responsibilities and chain of command for when events such as these continue for extended periods.

If you want to know more about risk management, then there are a number of applicable standards which can be mined for information, including ISO 31000, and the London-based Institute

of Risk Management offers a variety of certificates and diplomas which may become de rigueur in the fullness of time for pharmaceutical professionals.

Risk is a part of life, and will never go away, as we might tell the small child finding out what happens if he sticks his fingers into the electric socket. However, we should remember that if companies decided to take no risks at all then the world of commerce would grind to a halt. It is possible to circumvent almost anything if you are prepared to spend a great deal of money on shipping, chartering flights, driving to the other side of Europe, using hand-carriers and flying people to remote destinations, but these are normally extreme measures. Perfection can be achieved but is a very expensive commodity, and so a balance must be struck. We should consider the advice of General Patton, who said: “Take calculated risks. That is quite different from being rash.” n

Sue Lee has a background in M i c r o b i o l o g y and has worked for World Courier for 17 years. As Manager BioPharm Systems, Research and Development at World Courier in London she oversees the logistics for multinational clinical trials controlled from the United Kingdom. Her office supports approximately 500 projects through Europe and the rest of the World. Sue provides consultation and technical expertise to shippers, sponsors, labs and World Courier working groups on training, BioPharm shipping, and dangerous goods. She is a qualified DGSA for road and rail and IATA trained for shipping Dangerous Goods including Radioactives, and is a member of the Institute of Freight Professionals (Grad.)Email: [email protected]



The challenges of pharmaceutical logisticsIf you are going to outsource non-core business like

freight management, then you want to know that it is

going to be done right. Your industry is facing

enormous pressure to reduce global logistics costs. At

the same time, increased outsourcing to countries such

as India and China means that total supply chain

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strategies. We have a proven pharmaceutical track

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Global control tower and e-service transparencyFreight management is all about maintaining full control

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Full control. Every step of the way.

Tailored solutions to ensure pharmaceutical compliance

Introducing Geodis Wilson Geodis Wilson is a leading global freight management company. With 6,000 employees in more than 50 countries it delivers tailor-made,

integrated solutions to customers, therefore enabling them to operate as ‘best in class’. Geodis Wilson manages sea and air cargo across

five continents, making supply chains transparent and flexible to handle. As the freight forwarding division of the Geodis Group, Geodis

Wilson grew out of the merger between Geodis Overseas, TNT Freight Management and Rohde & Liesenfeld. In November 2008, the

company became part of the French rail and freight group SNCF. With its now 50,000 employees located in 120 countries, SNCF Geodis

ranks among the top six companies in its field in the world. Visit Geodis Wilson online: www.geodiswilson.com

Teams dedicated to your industryGeodis Wilson is strategically located across the

world with teams committed and dedicated to the

pharmaceutical industry. We monitor changes in

regulatory EMEA and FDA standards. Our superior

account management and strong network can match

the needs of even the largest global companies.

We take full responsibility from start to finish.

A total pharmaceutical solution tailored to your needsGood Distribution Practice is at the core of any

pharmaceutical logistics solution. We provide the

most optimal sea, air or land route throughout the

entire supply chain to provide the best cost/quality

ratio for your business. We are experts in raw material

management and ‘just-in-time’ solutions, as well as

pharmaceutical packing, export services and

temperature-controlled stock management. Not only

will you receive services tailored to your specific

requirements, but we will also use our Cost Analysis

Tool to highlight potential process improvements

throughout your supply chain, which can lower your

overall costs considerably. It is a continuously

customized solution tailored to your increasingly

regulated industry, from a partner who understands

the challenges you face.

At Geodis Wilson we think that partnership is what it’s

all about.

Tailored solutions to ensure pharmaceutical compliance

When it comes to pharmaceutical supply chains, cost pressures are merging with shifting production, and time-to-market is becoming more challenging than ever. Geodis Wilson’s Martin Svantesson believes that the answer lies in global solutions, and he says that interaction between freight forwarders and pharmaceuticals has never been greater.

Challenges of the cool chainThe distribution demands of pharmaceutical products

are more stringent than for many other types of

products. End-to-end logistics solutions in this market

segment must maintain ‘cool chain’ ambient

temperature requirements of between 2 and 25 degrees

Celsius. As a result, pharmaceutical companies,

manufacturers and distribution providers are

constantly working together to develop better ways of

securing optimal temperature control for all shipment

modes – air, sea and road – to create the most

successful supply chain.

A secure process at all hubs in the chainMode of transport is really not the driver for

pharmaceutical companies. Instead, the challenge lies in

securing the right type of equipment for specific product

requirements for specific markets. In other words, the

choice of mode is linked to a company’s supply chain

strategy for a specific market or region.

Pharmaceuticals are predominately high value goods. As

such, they demand a safe process at all hubs in the

chain. Security measurements must be harmonized and

rigorously checked across the operating lanes, and

definitely at sub-warehouses and on/off loading places,

which should be kept to a minimum. In fact, the

importance of minimizing on/off loading places and

transport mode changes of is one of best ways to create

time-effective and secure solutions.

Narrowing costs between pharmaceutical and regular shipmentsWhen it comes to the costs of distributing

pharmaceuticals, the gap between regular air or sea

freight shipments and pharmaceutical shipments has

narrowed. The pharmaceutical industry has put two

focus areas on their internal map:

The changing challenges of supply chain performance

divisional activities and increasingly centralized

decision making.

review of the costs of the full supply chain. These

days, companies understand more than ever what

they are paying for.

Time-to-market increases in importance These key changes are good for the pharmaceutical

industry. But they also provide an opportunity for

logistics providers – interaction between these two

groups has never been greater. As patents expire for

the blockbusters, fierce competition from generic

companies is making time-to-market the most

important success factor going forward. At the same

time, the pharmaceutical industry is seeking to

outsource non-core activities. There is room for an

innovative solution provider that is willing to go

beyond general freight management.

Today’s market now demands global solutions, and

customers want the ability to lower inventory levels

while ensuring correct quantities. As orders become

smaller, production and order profiles change. While

this is obviously a challenge for distribution, it also

greatly increases the value of consolidation

possibilities that can meet the lead time demands of

end customers.

Pharmaceutical companies move to their marketsBrutal re-organizations are currently underway to

restore profit margins. Sales forces are being reduced.

Production sites are closing. The production of high

and low value pharmaceuticals is now moving to

emerging markets. This of course has an impact on

solution providers – they need to be where the

industry is, so their network infrastructure needs to

expand while meeting GDP requirements, and local

compliance and competence regulations.

Global harmonization brings supply chain optimization to its fullest potentialGlobal harmonization therefore enhances the

possibility of maximizing effects in a supply chain. It is

this type of harmonization and interaction between

pharmaceutical companies, freight forwarders and

carriers that helps ensure supply chain success.

Martin Svantesson – Director Vertical [email protected] Phone: +46-31-42 98 58


MANUFACTURINg

Recent Trends in Manufacturing Deals and Alliances

Outsourced manufacturing has long been a key component of the pharmaceutical industry, whether it is to overcome internal capacity issues or exploit external expertise and cost advantages. In recent years, the trend towards outsourcing manufacturing to India and China has increased, enabling significant cost savings. However, manufacturing is often just a component of a wider deal where the product or technology is being developed and future manufacture for clinical or commercial use is anticipated within the agreement. Broadly speaking, from a deal-making perspective, there are two types of manufacturing deal; arms-length contract manufacturing, and partnering deals that include manufacturing as a component of the deal.

Attributes of Pure Manufacturing Deals:• Pure manufacturing deals tend to occur

when the product is already marketed or at registration phase.

• Manufacturing deals are agreed in order to enable a primary marketer to extend its capabilities in order to respond to a growing or uncertain market for a product. In effect, the manufacturer is acting as a flexible outsourced contract manufacturer, providing product on demand.

• Some manufacturing agreements may be put in place between a marketer and manufacturer to provide a contingency cover in the event that demand outstrips capacity, or as cover for any failure in the primary manufacturing capacity. This may particularly be the case where a product has a short shelf life, and therefore the ability to warehouse stocks of finished product is limited.

• Some companies may seek to outsource in entirety the manufacture of a product to a certain market, either due to a preference for a virtual business model which does away with the need for internal infrastructure requirements, or because import of the product from overseas into a market is prohibited, either by regulatory or cost constraints.

• Pure manufacturing agreements almost always result in implementation between the parties as it forms the basis for the signing of the deal in the first instance.

Example Manufacturing Deal: Dendreon-GlaxoSmithKline, September 2010A recent example of such a deal is the manufacturing and supply agreement between GlaxoSmithKline and Dendreon for the antigen used in the manufacture of Provenge, dated September 2010. The deal obliges GSK to commence manufacture of the product in commercially reasonable amounts for Dendreon at an agreed price.

Specifically: (a) Upon completion of the Process Implementation Phase, GSK shall commence the Manufacturing Phase. During the Manufacturing Phase, GSK shall manufacture Product in accordance with all applicable regulatory requirements necessary to support the approval of DENDREON’S BLA and maintain the BLA in accordance with applicable quality standards for the Product as set forth in the Quality Agreement (attached hereto as Schedule 3.1A); applicable health and safety requirements; and the Specifications. GSK shall manufacture Product for both commercial sale and for use in any human clinical trials initiated by DENDREON in the Territory, respectively. DENDREON may request Product be manufactured for use in clinical trials and/or commercial sale outside the Territory, and the Parties will in good faith discuss the requirements and costs associated therewith. Any such changes to the Territory would be defined and mutually agreed upon in a Scope Change document, outlining the requirements and specifications, and any additional cost. (b) In no event shall GSK be required

to manufacture more Product than commercially possible based on the demonstrated Process capability or forecasted by DENDREON and accepted by GSK. From time to time, due to significant unforeseen circumstances, DENDREON may deliver to GSK an order for Product volumes in excess of those specified in any Firm Order. Upon DENDREON’s written request, GSK shall use its Commercially Reasonable Efforts to provide DENDREON with such additional Product volumes, but shall not be obligated to do so if accommodating DENDREON would adversely impact GSK.Details of the deal including the source contract at Current Agreements: http://bit.ly/m2WFC7 The pure manufacturing deal is generally well understood, so the remainder of this article will look at partnering deals where manufacturing is a component of the deal.

Attributes of Multi-Component Manufacturing Deals:• It can often be a precondition of a

partnering deal that a licensee has its product manufactured by the licensor once the product is launched. This is because the licensor is seeking to control product quality, enhance margins, benefit from manufacturing efficiencies, and prevent manufacturing know-how from falling into the hands of competitors.

• The manufacturing expertise may be considered one of the core value added components offered by a licensor, for example in drug delivery.

• Many multi-component deals allow

Figure 1. The following figure provides an overview of manufacturing deal frequency since 2005 Source: Current Agreements, May 2011

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MANUFACTURINg

for manufacture of product for clinical trials as well as, or instead of, launched product manufacture.

• The majority of earlier stage multi-component manufacturing deals do not come to fruition. This is because product supply never reaches relevance due to earlier product failure.

Reasons for Including Manufacturing Options in a Multi-Component DealMulti-component deals are often signed in anticipation that the candidate drug or device will reach the market at some point in the future. Obviously, companies would not sign deals for products they did not anticipate reaching market. Therefore, the agreement is seeking to anticipate the future as well as retain rights for certain parties to the deal.

There are a number of reasons why a company would include a manufacturing or supply option in a multi-component partnering deal. These are summarised below:• The licensor may have certain

manufacturing or product acquisition capabilities that the licensee wishes to retain or exploit.

• The licensor may have certain manufacturing or product acquisition capabilities that the licensor wishes to protect, whether it be know-how, intellectual property, manufacturing/product purchasing efficiencies, or control of product quality.

• The licensee may wish to retain a right over the licensor to ensure that a secure source of finished product is available should the product reach market, without having to invest in manufacturing finished product themselves.

• The licensee may wish to retain rights to obtain product supply from the licensor for use in clinical trials, without the need to outsource or invest internally.

• Certain rights in the agreement may be used as bargaining chips at a later stage where a product reaches market. What had relatively low value at signing may now have a lot of value to the other party now the product has realised its potential.

• In the event that an option exists in the agreement, this may allow either party to require the other to manufacture or supply product. For the licensor, this may be that they wish to retain a future

option to invest in and become a manufacturer of their licensed product. This may be especially true if they have retained rights to the product in core markets to their business.

Example Partnering Deal with Manufacturing Component: Eisai–Arena Pharmaceuticals, July 2010A recent example of such a deal is the licensing, marketing and supply agreement for lorcaserin to treat obesity and weight loss. Eisai will market lorcaserin for obesity and weight management in the United States following FDA approval under the terms of a marketing and supply agreement between Arena Pharma and Eisai. As part of the deal Arena will manufacture lorcaserin at its facility in Switzerland and sell finished product to Eisai for marketing and distribution in the United States. Specifically: 6.1. Manufacture and Supply Commitment. In accordance with the terms and conditions of this Agreement, Arena shall use Commercially Reasonable Efforts to supply, or cause to be supplied, to Eisai the amounts of the Initial Product and each Additional Product, in each case supplied as Finished Product, ordered by Eisai in accordance with the forecasting and ordering provisions of Section 6.2. Eisai shall purchase all of its requirements for Finished Products for Commercialization in the Territory from Arena under the terms of this Article 6. If requested by Arena, the Parties shall discuss in good faith Arena’s manufacturing capacity in light of forecasts provided by Eisai under Section 6.2(a). Subject to Section 6.6, if either Party anticipates that demand for any Finished Product would exceed Arena’s actual manufacturing capacity, such Party shall promptly notify the other Party, and the Parties shall meet and discuss in good faith a plan for addressing such demand, which may include capital expenditures on a reasonable time frame and/or increasing Second Source manufacturing capacity. Details of the deal including the source contract at Current Agreements: http://

bit.ly/jEEBmE

The Future of Manufacture as Part of Partnering DealsThe number of partnering deals with manufacture elements has dropped in recent years. It is likely that this steady decrease will plateau or begin to increase again as the need for product manufacture and supply, whether for clinical trials or marketing, increases. This is because there is an increased tendency towards multi-component deals where one or more of the technologies involved requires ongoing partner expertise and know-how for its future production. This is likely to be the case in drug delivery-enabled biological products and companion diagnostic deals where use of a diagnostic is paired with a therapeutic product.

About Current AgreementsCurrent Agreements is an industry leader in providing access to comprehensive deal metrics and actual contract documents covering deals, alliances and M&A since 2000.Current Agreements is a premium subscription database providing comprehensive business information and intelligence with access to thousands of contract documents, giving coverage of all deals and alliances across the life sciences sector. More details and subscription information: http://www.currentagreements.com. The Manufacturing and Supply Partnering Terms and Agreements in Pharma, Biotech and Diagnostics, 3rd edition report provides comprehensive understanding and unprecedented access to the manufacturing and supply agreements entered into by the world’s leading biopharma companies – more details: www.currentpartnering.com/reports/1067

By Steve Poile of Wildwood Ventures Ltd

A) Evaluation Scale “Failure Probability” Source: Current Agreements, May 2011

Year Pure manufacturing deals Partnering deals with a manufacturing component

2005 39 39

2006 39 71

2007 20 47

2008 11 42

2009 12 32

2010 13 27

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IPI Volume 3 Issue 1 54-OBC.indd 38 22/2/11 21:40:29



In-Line QC - The Key to ‘Zero Fault’ Pharma Packaging Production

Until five or ten years ago, companies supplying packaging to the pharmaceutical industry delivered their cartons several days or weeks before they were needed. The cartons went into the stores at the packing and filling plant, where white-coated quality control (QC) people would descend on the job to check that they met with the brand specifications. But this all changed with the arrival of leaner than lean, just-in-time manufacturing. Nowadays the same packaging is delivered not to a warehouse but straight to the filling line itself, and not days or weeks in advance but instead when it is actually needed, almost to the minute. So with no time to analyse in detail what they have been sent, the checks that the packer-fillers’ QC people can carry out are minimal at best, so the delivery has to be not only ‘on time in full’, but also has to be ‘zero fault’.

In effect, packer-fillers have put the onus on the packaging maker to carry out a large chunk of their own quality assurance (QA) process, with the packaging manufacturer needing to supply Certificates of Analysis and Certificates of Conformity, along with batch samples, before their delivery will be accepted. The emphasis is on the packaging manufacturer to prove that every carton they supply is perfect, and what this has meant in practice is that the packaging maker has to have very robust QA throughout their production, along with thorough testing before dispatch. In manufacturing terms this means that the plant’s folder-gluer lines are now the process that the cartons go through, and so they are the last lines of defence against non-conforming product being manufactured. Folder-gluers, if you are not familiar with them, are the ‘long, funny-looking’ machines

at the end of the carton manufacturing process – the ones that fold and glue the printed, foiled, hologrammed, embossed, and die-cut blank into a recognisable carton ready for the filling line.

Typically, a folder-gluer will run at several hundred metres a minute, often churning out in excess of a hundred thousand straightline cartons, or many tens of thousands of crash-locks, during each hour of production. Long before ‘zero fault’ packaging contracts became so popular, folder-gluer lines had been supplemented by simple detection systems which monitored the correct application of the adhesive they use to glue the carton flaps prior to their folding. These systems allowed

operators to rectify a problem if there was one and to remove any poorly glued or unglued cartons. Over the years, these glue detection systems have become ever more sophisticated, allowing the user to identify tiny variations in gluing patterns or the amounts applied, on a wide range of substrates.

These adhesive monitoring systems have also proved to be the perfect platform on which to piggy-back additional QC checks. Add-ons to adhesive monitoring systems have been developed which can check that two cartons have not fed together; that the carton has the correct pharma codes and barcodes printed on it; that it has a film window, if there should be one; and even its print-to-cut registration if

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the sheet was not diecut on a machine with a dynamic register system. Modern folder-gluers integrate or interface with such systems, and many lines offer ‘flipper ejectors’ which instantly remove non-conforming cartons from the line without affecting production speed.

The two latest developments in these add-on systems are Braille scanning and print quality checking. Both of these are key determinants in ensuring that every carton reaching the filling line is in compliance with the specifications the brand owner has laid down.

Launched at the end of last year, systems such as Braille-Scan read every carton passing through a folder gluer and check the Braille that has been applied against a reference sample, ejecting any non-conforming examples. Capable of scanning every single carton in a run, even at the high running speeds of modern folder-gluers, Braille-Scan also translates the Braille on the carton into the operator’s own language, displaying it on a monitor so that they can double-check its correctness. Braille-Scan can be used to check the quality of Braille regardless of whether it was embossed using an in-line rotary process or on a die-cutter.

The latest development when it comes to in-line QC is the scanning and checking of the print on cartons as they pass through the folder-gluer, way beyond the simple checking of bar and pharma codes. In many ways this has become the ‘holy grail’ of these in-line processes, offering the prospect of independent, automatic and auditable checking of the print on every carton that leaves the plant. In a batch of 150,000 cartons there may only be one bad one, but if the end user comes across that single carton then the whole delivery may be sent back to the carton maker. Automated QC like this is the last chance the packaging manufacturer has of removing bad product without resorting to hand-sorting.

At Bobst, we already produce systems which check the print on every sheet produced by the flexographic presses we manufacture for the printing of corrugated board. These ‘iQ300’ devices have been developed and built on the experience gained from many years creating sophisticated register control systems for our web-fed gravure presses. Using two high-definition

Registron® cameras, the iQ300 systems on our flexo presses scan the entire printed sheet. The analysis system, which is designed for the ultra high rate of data flow received from the cameras during production, then checks for any differences between the scan and the reference image for that job. Depending on the settings defined for the run - which areas of the sheet are high priority, which are low, what sizes and types of defect are permissible or not, etc., - the defective sheet can be automatically ejected in real time, without affecting production. Whether ejected or not, defects are recorded for later analysis.

Taking technology designed to scan a 2100mm by 1300mm sheet running at 12,000 sheets an hour and adapting it to scan a pharma carton, which is tiny by comparison but runs ten times faster, is a huge challenge. But by the middle of this year we are confident that we will be delivering fully-featured print-scanning QC modules that can be retro-fitted to many of the huge installed base of folder-gluers in the field. This will bring even

closer the packaging manufacturers’ ultimate aim of being able to supply truly ‘zero fault’ packaging to their customers. That ‘funny-looking’ machine at the end of the carton-making process is turning out to be perhaps the most important in the packaging manufacturing plant! n

Marco LideoOriginally a graduate nuclear e n g i n e e r , Marco Lideo joined Bobst, the Swiss-headquartered multinational packaging equipment manufacturer, in 2001. Here he has undertaken a variety of roles and also gained his MBA. Marco is currently Marketing & Sales Director for folder-gluer products worldwide, and is in particular responsible for the introduction to the market of the latest innovations.Email: [email protected]

Trademarks are the property of West Pharmaceutical Services, Inc. in the U.S. and other jurisdictions. Copyright ©2011 West Pharmaceutical Services, Inc.

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What’s the Buzz on Pharmaceutical Packaging?

An important – if not essential - part of any pharmaceutical product is its packaging. Nevertheless, it has almost always been seen as an outsourcing need, due to its distance from the core business of pharmaceutical companies. This is ever more present if one takes into consideration that in the development of a new drug, the production of the drug itself, regulatory concerns and its marketing and commercialisation, there are already many physical infrastructures, human resources and other investment involved, which in turn form very heavy and costly structures.

This fact has originated an entire market dedicated to the packaging of pharmaceutical products, a market which is very distinct from other packaging markets, due to its regulatory constraints, high quality standards and the need for very tight environmental controls. The companies which operate in this market are very focused on supplying the pharmaceutical market, either by being solely directed to it or by creating specialised business units for that purpose.

Consider that, after all, any drug is a top of the line item, the result of a very long-term investment, with high added value and a need for stability of the surrounding environment like no other product. This need for environmental stability even dictates changes between packaging systems for different geographical areas, as there is a direct link between packaging and the future efficiency of the drug, due to the potential for degradation resulting from the closed environmental effects that drugs may be exposed to, such as light and humidity.

Desiccant usage and special barrier walled bottles solve most of these issues in bottles and jars, as well as in some

high-end blister solutions, but for some more sensitive products, innovative packaging is needed that ensures the drugs are effective for an extended period of time. As a result, a wide array

of solutions has been developed by the packaging industry to fit each drug’s needs and its intended market. The fact is that pharmaceutical technology is changing as well as creating even more

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dispensing solutions, like the ones tied to the bio-pharmaceutical drugs, which often cannot be administered in the regular oral way.

Marketing also needs to drive the choice for new packaging, from the standard shelf-awareness requirements to new obstacles novel products present, like the full integration of drug and device in many new pharmaceutical applications. This has been an area of high growth, even though the adoption of new drug-delivery methods has been slower than initially thought. Nevertheless, this kind of packaging product already represents a profitable segment in pharmaceutical packaging that is expected to grow even further as bio-pharmaceuticals – which, as stated before, often do not perform well in pill or tablet form – grow their way into the supply offer.

A number of new companies are addressing this market, which has very high technological requirements and thus provides opportunities for smaller companies, due to the fact that high-tech is the key to success and not economies of scale. These companies are seen as the trend-setters in the pharmaceutical packaging market, due to their high growth in a previously unexplored market, and due to the fact that they deal with the specific and unmet needs of the most cutting-edge drugs.

On the other hand, convenience and ease of use for the patient will be ever more central to the development of new – or improvements to existing – drug packaging, as the end patient plays a more important role in the drug choice. From a wide array of formulations and products the physician will choose the drug that allows for the best compliance of the patient to the treatment. That is the reason senior-friendly and child-proof packaging are making their way into most products, either due to requirements of an ever-growing elderly population or for safety reasons, as a means to restrict the misuse of pharmaceuticals by children. Combining both solutions into one effective package is one of the challenges most companies face these days.

Compliance with the treatment is also of great concern for public health. Increased resistance to antibiotics or other types of drug resistance, infectious

diseases, or the price of some specific products, like oncology medicines, are just a few examples of daily practice problems that physicians need to have addressed to improve the public’s wellbeing. The reasons stated before have led to some innovative packaging products that have been launched in recent years that even register the intake of the drug, through RFID systems on blisters or mechanical systems on bottle caps.

These systems, often referred to as intelligent packaging, are still considered to be too expensive to be used on regular or generic pharmaceuticals, but for some applications - where correct usage/dosing of a drug is essential - they will surely grow as an added compliance factor. Even more, as digitalisation of the healthcare systems of the western world progresses, tools to connect the drugs to the ERP systems in health centres will be needed, and the pharmaceutical packaging will surely have a role to play in that situation.

Another application of RFID, and one which has a more visible impact to pharmaceutical companies, is its ability to fight counterfeiting and improving supply chain management. Wholesale companies are already pushing the adoption of this technology to their suppliers, and the pharmaceutical industry will soon have to follow. The constant reduction of RFID costs will also ease the adoption of this technology, and as counterfeiting is on the increase RFID will surely have a role to play. Furthermore, in countries where most medicines are already provided on retail chains this will be a driving force to early adoption of this technology.

Despite all the recent evolutions in packaging technology, the economic aspect of these solutions has been the key factor in their early adoption, and on their rate of success. In fact, due to the economic crunch, cost control has been the ruling trend observed over the last two years. Pharmaceutical companies have suffered from it as has every other market, and they have forced the cost reduction on their suppliers as well.

As a result, process optimisation has been a ruling trend in pharmaceutical packaging organisations, as their customers seek ever more cost-effective products. It is expected that the pressures on the end price of the

finished product will increase even further, due to generics proliferation and healthcare reforms in practically every western country. As such, packaging producers have been forced to evolve into more streamlined organisations and adopt more effective technologies on their production lines.

However, the alternative for SMEs will be to identify market niches and provide value-added solutions that will enable the development and adoption of many technologies described above, through partnership with pharmaceutical companies and other health providers that have similar strategies. This connection between players will have to become a reality, as the end result will mean better medicines, more compliance and better health with more cost-effective performance. Packaging could play an important part in this process, as it is present throughout all the phases of the process, from production to distribution to delivery, but only if it is acknowledged a fundamental part of the process and not a minor feature of the complex product that a drug is.

The future of pharmaceutical packaging holds many promises, but even so it will only do well for as long as their customers, the pharmaceutical companies, will. That is why solid relations with the developers, producers, prescribers and end-users of pharmacological products is vital for packaging companies who want to strive and operate in this market. Only by listening to the needs of all these groups will a company make a stand in this evolving market n

Gonçalo Poças is the Marketing Manager at Neutroplast and the Director of Neutrodevices, the company’s innovation business unit. Having worked with the company’s group for the past seven years, he has a university degree in Media Studies and a post-grad degree in Marketing and Business Intelligence.Email: [email protected]


PACKAgINg

Innovative Protection Against Counterfeiting: A Q&A with Richard Burhouse at Payne Security

1) Can you provide a brief history of Payne Security?Payne Security is one of the world’s leading companies in the fields of brand protection, document authentication and personal ID solutions. Established in 2005, Payne Security was created during the merger of three Filtrona businesses - PP Payne, Morane and Laminex - and has been involved in the security industry for over 30 years. The combination of companies provided strength in the security and packing industry to continue to focus on the development of innovative products, deliver quality and service, and continue to develop strong relationships with our partners, customers and suppliers.

2) You were awarded the Queen’s Award for Innovation for your covert authentication technology. Can you explain what the system does?The Payne Security covert authentication solution delivers a unique system for discreetly authenticating pharmaceutical products and detecting illicit and counterfeit drugs, allowing the government and companies to protect consumers and government revenues simply and efficiently. The technology adds a completely invisible chemical marker to inks and lacquers used to print product packaging, which is only detectable via the unique Payne Security handheld reader device. The technology provides a failsafe method of authentication to protect the market and minimise the risk of counterfeit products and documents.

3) You mentioned the use of a patented handheld reader; can you explain in more detail what this product is?

The handheld reader is a cost-effective, lightweight verification tool that enables quick and easy authentication of a security taggant. The handheld reader uses a detection method to analyse a specific property of the taggant pigment. The unique taggant pigment does not need to rely on a visible fluorescent emission from the taggant particle, so is not affected by any background colour or lighting conditions. Without the Payne Security handheld reader, it is impossible for counterfeiters to detect the chemical marker – it’s a lock and key relationship.

4) This is the second time Payne Security has received the Queen’s Award. What does the award mean to the company? The Queen’s Award for Enterprise recognises the achievement and innovation of UK businesses. We are very proud the award has recognised Payne Security’s achievement for a second time for unparalleled innovative methods of protection against counterfeit fraud. The award puts Payne at the forefront of security and counterfeit protection in a range of industries, including pharmaceutical product security.

5) How big a problem is counterfeiting in the pharmaceutical industry?As the drug counterfeit trade continues to grow, global pharmaceutical companies are at an increasing risk of drug counterfeiting. According to The World Health Organization (WHO) the counterfeiting trade is estimated at a value of £75 billion and is set to increase at around 13% a year. Counterfeiting criminals are continuously discovering more refined ways around government legislation, creating the need for maximum security of pharmaceutical

packaging. Not only do issues stand against the manufacturing of replica drugs, but the seizure of authentic drugs which are diverted by criminals to other markets is something of concern.

6) What makes taggant technology a unique product within the marketplace? Existing comparable solutions are not truly covert as they give a visible response under certain conditions, meaning counterfeiters can detect the presence of the taggant. The Payne Security taggant technology materials are based on special chemistry, which is visibly undetectable and can only be authenticated by the use of our detection equipment. Existing materials have been used in authentication solutions for a number of years and are widely available from a number of sources, adding risk to the supply chain. The Payne Security technology is proprietary and is a next generation development - a more sophisticated secure technology.

7) How can covert technologies work in conjunction with overt technologies such as holograms? Using both covert and overt technologies is a valuable means of enhancing the security of pharmaceutical packaging. Overt technologies, such as holograms and colour shift inks, allow for instant authentication and fast validation of packaging without the need for expert knowledge. The use of this technology combined with covert technologies such as infra red (IR) and ultra violet (UV) inks, increase validation of authentication and make it more difficult for counterfeiters to replicate packaging. This added security allows global pharmaceutical companies to be more sure of the source and genuine drugs.

PACKAgINg

About Payne SecurityPayne Security (www.payne-security.com) is one of the world’s leading companies in the fields of brand protection, document authentication and personal ID solutions. Overt, covert and forensic technologies can be applied to a wide variety of consumer goods, packaging, national identity documents and tax stamps using inks to lacquers, laminates to labels, tear tapes to threads. Payne Security’s document authentication expertise gives a unique advantage in creating some of the most secure ID card (and other document authentication) solutions. From the latest Magicard ID card printers and sophisticated IDPro7 software to secure smart card production and volume fulfilment, Payne Security is able to meet

all personal identification needs.Payne Security (www.payne-security.

com) is a part of the Coated & Security Products division of Filtrona plc, the international market-leading speciality plastic and fibre products supplier. Operating as four companies – Payne, Payne Security, FractureCode & BP Labels – we provide creative and secure packaging, identity and security solutions to our customers and markets of choice, and continually invest in our production facilities and quality procedures to ensure the highest standards of manufacture. Coated & Security Products operates from ten sites in eight countries worldwide and employs 371 people.www.payne-security.com

Neil Ivey is the Sales Development Manager, North & South America for Payne Security, a division of Filtrona, PLC. His responsibilities in this role include working with the Private and Public sectors to combat widespread counterfeit issues involving documents and consumer products. Mr. Ivey has been involved applying security solutions for Brand Protection for over 10 years.



EVENTS PREVIEwS & REVIEwS

Clinical Trial Logistics 2011, a roaring successSMi’s 5th annual conference on Clinical Trial Logistics, took place in London on the 16th & 17th May; with over 100 attendees from across the world, the event was rated by attendees as the best yet.Delegates discussed the latest developments from across the industry as the conference presented crucial updates on the logistical issues in traditional markets with a focused overview of the experiences pharma companies faced in moving their operations to the emerging marketsThis high level conference programme included presentations from leading industry speakers including:• Sylvie Noirault, Packaging and Distribution Demand Management Head, Sanofi Aventis• Elizabeth Foster, Global Trade Compliance Manager, Novartis Pharmaceuticals• Annegreat Van der Aa, Clinical Trial Manager, Galapagos• Sue Lee, Manager BioPharm Systems R&D, World Courier• Mick Bradshaw, Global Sales and Marketing Director, Biocair International Ltd• John Randria, Head of Clinical Supply Chain, Pfizer France• Rick Mann, Associate Director, Clinical Trial Material Management, Sunovion• Tony Wright, Managing Director, Exelsius Cold Chain Management• Sharon Grimster, Director, in2phase Ltd• Evelyn Edwards, Supply Chain Consultant, in2phase Ltd• Tim Saint, Business Development Manager, Marken• Marcelo Reggiardo, President, OCASA Logistics Solutiosn• VSevolod Shimokhin, General Director, IMP Logistics• Jane Maureen Valentin, Logistics and Shipping Analyst, Novo Nordisk A/SAnd covered a wide range of topics including:• Customs, trade and risk management for supply chain modelling• Understanding the role of specialist logistics providers in your supply chain• Clinical logistics in the Far East• Comparator sourcing strategies

With a busy and vibrant exhibition running alongside, delegates were able to view the latest technologies and developments from companies including:ADAllen Pharma, Aerortrim, Almac Group, B&C Group, Biocair, Creapharm, ELPRO, IMP Logistic, Marken, Ocasa, Penn Pharmaceuticals, QuickSTAT, Sensitech, World Courier and Yourway Transport. Continuing on from this year’s success, SMi can announce that Clinical Trial Logistics 2012 will take place on the 16th and 17th May in London. Preparations for the 2012 event are well underway, to keep up-to-date with the latest developments visit www.smi-online.co.uk

SMi Group are delighted to also announce the launch of Pharmaceutical and Clinical Trial Logistics Asia Pacific. Taking place on the 18th & 19th July in Singapore, this event will provide delegates and sponsors alike with a great forum to discuss opportunities and strategies for compliance, risk, forecasting and supply, CRO-pharma-logistics partnerships, site management, staff training and more. For more information visit www.clinical-trial-logistics.com/asia

For more information, please contact TOPRA via email: [email protected] or tel: +44 (0) 20 7510 2560 or go to www.topra.org/eCTDadvanced

CRED eCTD Advanced6* hoursLifelong Learning (LLL) *For more information please visit www.topra.org/lifelonglearning

eCTD AdvancedWho should attendThis workshop is designed for all industry professionals who have a basic understanding of eCTD or who have attended the TOPRA eCTD Basics course and who are presently, or planning to be, involved with the development of eCTD submissions. This includes professionals in: Medical Writing, Regulatory A�airs, Dossier and Document Management, IT and Data Management, Compliance, Publishing and Submission Management.

Topics include● Regional di�erences within Europe and other

regions of the world - e.g. Swiss and Australian DTD● European Variation legislation and the use of

Grouping and Worksharing in both Centralised and MRP/DCP

● Impact of Regulatory procedures (Centralised, Decentralised and Mutual recognition) on eCTD structure

● Available Validators and the new Validation Criteria.

Book online now at www.topra.org/eCTDadvanced

All data correct at time of print.

Date:Thursday 16 June 2011

Venue: TOPRA Office, Bellerive House, 3 Muirfield Crescent, E14 9SZ, London, UK

TOPRA – The Organisation for Professionals in Regulatory Affairs Reference: eCTD-2

CTDTraining designed with you in mind



Conference Review 7th HIC/RPC Bioseparation Conference in Estoril, Portugal

The HIC/RPC Bioseparation Conference series, which alternates between Europe and the US, provides a unique forum for in-depth discussions on downstream bioprocessing. It is focused on the better understanding of the hydrophobic nature of biological targets, such as biopharmaceuticals, and their chromatographic isolation and purification based on this understanding. The 7th HIC/RPC Bioseparation Conference was held from March 21-24, 2011 at the Hotel Palacio in Estoril, Portugal. The 101 attendees enjoyed the conference in a beautiful surrounding on the the Atlantic coastline under fantastic spring weather. This conference followed the successful 6th HIC/RPC meeting at the Silverado Resort in Napa Valley, CA. Traditionally the conference seeks to maintain an optimal balance of fundamental science and industrial Advances and Applications.

The scientific committee of the 7th HIC/RPC Bioseparation conference, headed by Alois Jungbauer, University of Natural Resources and Applied Life Sciences, Vienna, Austria, composed a striking programme of 24 lectures, accompanied by poster presentations and a round table discussion. Following its tagline ‘Advancements, Applications, and Theory in Downstream Processing’ the conference traditionally focuses on bioprocess applications and on fundamental research on hydrophobically influenced modes of chromatography. Today the emphasis of the conference shifted towards hydrophobic interaction (HIC) and mixed mode chromatography (MMC), as the importance of reversed phase chromatography for the purification of biotherapeutics has declined over the past years.

Traditionally the conference

commences with a keynote lecture on a current trend or a new development in biotechnology. Accordingly this year, Florian Rüker from the University of Natural Resources and Applied Life Sciences, Vienna, Austria, a co-founder of f-star, gave an insight into latest developments in antibody scaffolds. f-star is a company developing therapeutic antibodies and antibody fragments based on its proprietary ‘Modular Antibody Technology’. This technology can be used to engineer additional binding sites into antibodies without changing the natural antibody format. In the keynote lecture two antibody-derived constructs were presented, Fcab and mAB2. Fcabs - Fc fragments with engineered antigen binding sites - may be used as stand-alone entities (Fcab: Fc antigen binding), representing molecules with the full functionality of antibodies but only one-third the size of a complete antibody.

Fcabs can also be used as building blocks in the context of complete antibodies, so-called mAb2, which are fully functional bispecific IgG molecules displaying antigen binding sites in the Fab arms as well as in the engineered Fc region. A second keynote lecture, held by Andreas Premstaller, head of technical development at Sandoz, Kundl, Austria, gave an overview of the opportunities and challenges for biosimilars process development and for the confirmation of biosimilarity by appropriate analytical, biological, preclinical and clinical studies.

The fundamentals sessions provided interesting data on modeling of chromatographic systems for both hydrophobic interaction and mixed mode chromatography, in order to examine the relevant interactions in these systems. Lectures covered various aspects of biomolecule adsorption onto hydrophobic surfaces, e.g. the folding of



proteins upon adsorption and refolding upon desorption or surface energetic of protein adsorption. Christian Frech, University of Applied Science, Mannheim, Germany explained his studies of the interplay between ionic and hydrophobic interactions when using multi-modal stationary phases. Egbert Müller, Tosoh Bioscience, Stuttgart, Germany, presented interesting results on the use of mixed electrolyte mobile phases for modulation of binding capacity and selectivity in HIC.

A round table discussion of all members of the scientific committee covered various aspects of HIC/RPC/MMC-related downstream processing, ranging from the interplay between science and industry - e.g. the problems of intellectual property issues preventing the further use of some applications or resins for certain target molecules and the duty of industry to share results in order to increase knowledge - to the heretical question ‘does industry still need HIC in times of fixed purification platforms?’. There was a consensus that hydrophobically-influenced modes will always be part of the purification toolbox but will have to prove their value, e.g. during scale-up or for the purification of E. coli-derived targets.

Most industrial case studies and applications presented were related to antibody purification processes. In some platform approaches HIC or MMC is used after protein A and ion exchange capture/intermediate steps for the final removal of aggregates and residual host cell proteins. Jie Chen, Dyax Corp., Cambridge, USA, who attended the conference for the third time, presented comparison studies for capture step

strategies. Some case study examples with monoclonal antibodies revealed the critical role capture technology choice plays in relation to the corresponding adaption of established platforms methodology and its impact on overall process efficiency and product quality. Tim Breece from Xoma, Berkeley, USA demonstrated that an HIC polishing step in an antibody purification process can also result in an additional viral clearance. Several presentations showed how parameter optimisation for platform solutions can be supported by applying design-of-experiments (DoE) strategies and high-throughput screening (HTS) devices. Other aspects of industrial use of HIC or MMC, such as industrial scale column packing and new process column technology, were presented too. DoE and HTS were also the standard techniques presented in the Quality-by-Design session. According to the ICH guidelines the pharmaceutical industry is encouraged to generate a deep and full process understanding of drug product manufacturing. Stefan Lohninger from Sandoz GmbH, Kundl, Austria presented as an example the characterisation strategy for a reversed phase chromatography step applied in a peptide purification process. Relevant process parameters were classified based on DoE studies and then applied to establish proven acceptable ranges. Based on a qualified scale-down model the experiments were executed in terms of DoE, on-off studies, worst case runs and a cleaning-in-place (CIP) study.

The Journal of Chromatography A will publish a special edition on the conference. In addition to the scientific programme the conference offered

several opportunities to network with colleagues. The Portuguese landscape, the beautiful conference venue, tasty meals and an excursion to the famous city of Lisbon including a visit to the UNESCO world heritage Jeronimos Monastery and a dinner in the Bica do Sapato restaurant further contributed to making this conference an unforgettable event for all participants. The biannual HIC/RPC Bioseparation Conference series alternates between Europe and the US. Tosoh Bioscience is the sole sponsor of this conference series and provides support for logistics and organisation for the scientific committee. The 8th HIC/RPC Bioseparation Conference will be organised by Tosoh Bioscience LLC and will take place in the United States in 2013.

Here’s what the attendees said about the conference: “Very good opportunities for networking. Good mixture of academic and industry related topics”

“I have attended ISPE, IBC, Prep etc. but this is by far the best meeting I have attended - good mix of research and industry topics, excellent networking”

“Very good networking. Good mix academic/industry. Good mix theory/reality”

“Well organised. Pleasant mixture of events and talks”

Regina Römling is Marketing Manager at Tosoh Bioscience GmbH, with responsibility for the marketing of separation products such as HPLC columns and process resins. Prior to joining the Tosoh team in 2007 she was product specialist for HPLC systems at Shimadzu. Her background includes five years of research work in molecular biology and genetic engineering at the University Hospital Münster, and about 15 years experience in liquid chromatography and mass spectrometry. Email: [email protected]


CLINICAL FORUMBASEL 201110-12 October 2011 Congress Center Basel | Basel, Switzerland

5 T H A N N U A L

Cross Functional Working for Better Results

The Clinical Forum brings together industry leading thinking and practices across the key disciplines of data management, clinical operations, drug safety and medical communication as they relate to the practical and operational aspects of drug development.

The programme chair and committee have crafted an exciting and stimulating programme that will have fi ve concurrent tracks over two full days.

CLINICAL FORUM THEMES

EXHIBITIONExhibiting at the Clinical Forum 2011 provides a valuable opportunity to interact with a truly global audience of qualifi ed professionals.

Register now and take advantage of the €200 early-bird discount, available until 29th August 2011 – by emailing [email protected], or by calling +41 61 225 51 51.

Alternatively, visit www.diaeurope.org/ClinicalForum2011



FlandersBio Organised the 7th Edition of its Annual Life Sciences Convention Knowledge for Growth at the ICC Ghent Knowledge for Growth 2011 focused on Biotech meets global needs, improving people’s lives. The Flemish biotech industry has experienced significant growth in recent years. Some companies have products on the market for the first time; others have signed key partnerships that will have a significant impact on their continued growth. These important evolutions create a new commitment with patients and consumers, but also with financial stakeholders and other partners. KfG 2011 focused on the significance of these and other recent developments.

More than 1000 individual participants registered for the convention and about 330 companies and organisations active in life sciences were present at KfG 2011. This makes Knowledge for Growth Europe’s largest regional biotech event.

The principal ingredients of Knowledge for Growth are networking, keynote science and business talks (more than 40), a trade and poster exhibition (89 posters have been presented) and a job fair (156 jobseekers submitted their CV for this job fair). For the 2011 edition, we also organised a dedicated financial programme - Finance for Biotech - giving a clear insight into biotech financing - from venture capitalists (VCs) to a profitable exit.

During the science and business talks, Knowledge for Growth highlighted the importance of the life sciences industry addressing the global needs that make the difference for our society. The exciting speakers presented how their businesses can address the major future challenges our society is facing, such as:• Improving the quality of life of people

through, e.g., therapeutic vaccines for cervical cancer, non-invasive treatment of retinopathies, improved treatments of blood clotting, rheumatoid arthritis and constipation, increasing life expectancy of Pompe patients, repairing joint damage, early diagnostics by companies & organisations such as ThromboGenics, Ablynx, Galapagos, Shire-Movetis, Genzyme, Tigenix, Biocartis, PharmaNeuroBoost, the Center for Medical Innovation, the Drug Development Cluster, reMYND, MSD and Philips Research.

• Addressing the needs of the ageing population, e.g., slowing down or even stopping the progression of Alzheimer’s and Parkinson’s disease, detecting prostate cancer early at a moment it can still be treated,

by companies such as Janssen Pharmaceutica, UCB , reMYND…

• Ensuring that we can supply food to an ever-growing population through rice and corn varieties with better yields by companies such as Devgen, Keygene and CropDesign.

• Providing alternative solutions to become a more carbon-efficient society through, e.g., the use of alternative biomaterials for bioenergy and the creation of novel industrial crops by companies such as Quinvita.

All these presentations made Knowledge for Growth 2011 a very successful edition. We hope to welcome you all to Knowledge for Growth in May 2012. More info will be available soon on www.knowledgeforgrowth.be.

FlandersBio Organised the 7th Edition of its Annual Life Sciences Convention Knowledge for Growth at the ICC Ghent

www.icsexpo.com

Medical Devices

Exhibitor query: [email protected]

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“The place to meet all the relevant manufacturers/suppliers together with a high number of industry colleagues and others in one place at one time in an environment conducive to exploring and undertaking mutual business.”

2010 ICSE Visitor Survey

Join 28,897 Fellow Pharmaceutical Professionals from 125 CountriesVisit ICSE: The world’s only dedicated Contract Services event!

ICSE connects the pharmaceutical community with outsourcing solution providers, offering a forum for business development, networking and education.

Co-located with CPhI Worldwide for pharma ingredients, P-MEC Europe for pharma machinery, equipment and technology and InnoPack for pharma packaging, ICSE is the must attend networking event for any business or individual in the contract services sector.

Dedicated Zones and Pavilions for Easy Navigation

CRO & Clinical Trial Zone: a dedicated area where you can find companies offering Clinical Trials, Pre-Clinical, Clinical Research, Phase 1-4 Clinical Trials and Contract Research services

New Exhibitor Zone: a zone where you can find first-time exhibitors at ICSE; companies that might offer just what you need

USA Zone: a dedicated zone where you’ll find Outsourcing service providers from the USA

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General Floor: here you can build partnerships with companies that provide a wide range of contract services

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ECCP2011 Toulouse, France September 14th – 16thBuilding Partnerships to Accelerate Innovation in Cancer Treatment

Cancer-Bio-Santé Cluster and Oslo Cancer Cluster invite you to the third European Cancer Cluster Partnering event: the oncology-partnering meeting in Europe for biotech, pharma, investors, clinicians and academia.

We invite you to join us in making this third ECCP as successful as the two previous ones. ECCP2009 and ECCP2010 gathered clinicians, researchers, SMEs and major (bio)pharmaceutical companies from 22 countries, resulting in more than 1000 one-to-one meetings which led to a significant number of business negotiations.

Gathering the Whole Oncology CommunityThe ECCP event is the oncology-partnering meeting in Europe for biotech, pharma, investors, clinicians and academia. ECCP offers a vital networking arena for the oncology community in Europe, and is the direct result of the close collaboration between two of Europe’s strongest cancer clusters: the French Cancer-Bio-Santé, and the Norwegian Oslo Cancer Cluster. The main goal of the conference is to build partnerships to accelerate innovation in cancer treatment. The ECCP events succeed in gathering the entire oncology value chain: biotech, diagnostic, medical device and drug delivery companies, international biopharmaceutical industries, immunotherapy and vaccine companies, university hospitals and cancer centres, venture capital, public investors and international clusters will meet to present and discuss their assets and build new partnerships.

Two New PartnersOslo Cancer Cluster and Cancer-Bio-Santé have invited both a new European partner and a US partner to further develop the European Cancer Cluster for this year’s ECCP taking place in Toulouse: Medicon Valley Alliance will organise an oncology-focused Technology Showcase with more than 100

participants in conjunction with the conference. As part of the ABC Europe initiative this showcase will allow all European universities, research centres, technology transfer offices and SMEs to present innovative technologies within cancer research to an international business community. Maryland Biotechnology Centre has also teamed up with ECCP 2011. Together with US biotech companies as well as speakers from the NCI and the FDA, Maryland Biotechnology Centre will join the event to strengthen the collaboration between Europe and the US in oncology business development.

Exciting ProgrammeIn addition to focused partnering opportunities, the ECCP 2011 will present a broad programme with an international range of speakers addressing the key issues in translational oncology through company presentations, case studies and panel discussions. We warmly invite you to Toulouse for ECCP2011 – join us to build new partnerships and to share your ideas. Please find more information on the ECCP2011 homepage: www.ecc-partnering.com.

About Oslo Cancer ClusterOslo Cancer Cluster is an oncology research and development cluster dedicated to accelerating the development of new cancer diagnostics and medicines. Oslo Cancer Cluster was established in 2006, and has more than 60 members from all over Scandinavia. Our members comprise small biotechnology companies, large pharmaceutical companies, university hospitals, biobanks and registries, technology transfer offices and academic research institutions. Our strategy: we will accelerate the development of new cancer diagnostics and medicines through: cluster collaboration and partnership, attracting capital, decreasing clinical development timelines and accelerating innovation in the Oslo Cancer Cluster Innovation

Park. Learn more about the Oslo Cancer Cluster on our website, www.oslocancercluster.no.

About Cancer-Bio-SantéCancer-Bio-Santé Cluster, located in Toulouse, is the French cluster fully dedicated to the fight against cancer, through a broad continuum approach involving prevention, diagnostics, therapeutics and patient monitoring. CBS supports companies from the Midi-Pyrénées and Limousin regions, which develop innovative products in the fields of food and health, diagnostics, biomarkers, medical devices, immunotherapy, therapeutics, bioproduction, biotechnologies and telemedicine. The mission of the Cancer-Bio-Santé cluster is to support companies to develop innovative products by synergising public and private research and clinical research actors. The mains activities of Cancer-Bio-Santé are the following; accreditation of R&D projects, research of public funds for accredited R&D projects, follow-up of R&D projects, supporting innovation, promotion of CBS members during international events, and organisation of workshops. Learn more about Cancer-Bio-Santé on our website: www.cancerbiosante.fr/fr/

Andersen is working as a communications advisor for the Oslo Cancer Cluster, and has been with the Cluster since January 2011. Before that she worked as a consultant for the Cluster, as well as with a Norwegian communication company. She is a trained biologist and journalist, and also has a background as a science journalist for various Norwegian media. E-mail: [email protected]

Early Bird Registration Is Open: 10th ScanBalt Forum - Towards a Balanced Regional Development and Smart Specialization in the Baltic Sea RegionThe ScanBalt Forum is one of the three international conferences of the Eco4Life project. ScanBalt BioRegion is celebrating its 10th anniversary in 2011. Ten years after the first round table discussion in Teschow, the ScanBalt Forum will again take place in the German State of Mecklenburg/Vorpommern – this time on the Pomeranian Island of Usedom. Key topics of the Forum will be:• ScanBalt Health Region – the Health Flagship in the EU

Strategy for the Baltic Sea Region (BSR)• The Green Valley – Environmental projects and activities in

BSR and the Barents Sea• Cross-border cooperation - Challenges and opportunities

in the Baltic Sea RegionWelcome to Mecklenburg-Vorpommern in September 2011 – the opportunity to meet leading experts and stakeholders within Life Sciences in Northern Europe!The registration is open from the 8th of May. Use your chance to get fee allowance with the early bird registration until the 30th of June. Visit the website www.scanbaltforum2011.eu for more information about the stakeholder conference.

Compact, powerful, and energy-efficient:Bürkert presents new TwinPower actuation technology in media-separated minimum-size solenoid valvesWith the TwinPower technology, the fluid technology specialist Bürkert presents a novel actuator design for solenoid valves. The power density is increased by means of two coils – that is how solenoid valves can be made considerably more compact while retaining the same power. The new actuator design is being used for the first time in the types 6624 and 6626 TwinPower media-separated minimum-size solenoid valves. Smaller terminal devices for patient-oriented diagnostics. The types 6624 and 6626 TwinPower media-separated minimum-size solenoid valves have been designed mainly for use in the areas of life science, clinical diagnostics, medical technology, and environmental analysis. They are characterised by high reliability, long working life, an easy-clean diaphragm concept, and a fluid technology which is easily adaptable to individual customer requirements. For these applications, thanks to the space-saving TwinPower technology, the new Bürkert valves enable the design of terminal devices which are even more compact or mobile, and this simplifies point-of-care diagnostics in clinics or medical practices. Source: Burkert


NEwS


Optibrium Announces Free Models to Predict Toxicity of CompoundsStarDrop’s Glowing Molecule Provides Visual Link between Chemical Structure and Predicted Toxicities

CAMBRIDGE, UK, May, 25, 2011 – Optibrium™, a provider of software solutions for drug discovery, announces the availability of a range of models to help predict the toxicity of potential new compounds. Optibrium has generated a range of Quantitative Structure Activity Relationship (QSAR) models of key toxicity endpoints, based on data made available by the US Environmental Protection Agency (EPA) as part of its Toxicity Evaluation Software Toolkit (T.E.S.T.). The toxicity prediction models were built with the Auto-Modeller™ module of the newly launched StarDrop™ 5 and are available to all StarDrop users free-of-charge. To find out more and download the models please visit Optibrium’s on-line community at www.optibrium.com/community.

The toxicity prediction models conform to the Organisation for Economic Cooperation and Development (OECD) principles for validation of QSAR models for regulatory purposes and have also been found to perform equivalently or better than the EPA T.E.S.T. models on the same validation sets. All models were built automatically with StarDrop’s Auto-modeller module, illustrating that the Auto-Modeller is capable of building models that compare favourably with those created with more ‘manual’ methods. For further information please visit Optibrium’s on-line community at http://www.optibrium.com/community.

Pfizer teams with Parexel in CRO sector’s latest strategic dealUS firms Pfizer and Parexel have teamed up in the latest Big Pharma CRO strategic partnership. Under the collaboration, terms of which have not been disclosed, Parexel will provide the US drug major with a range of clinical development services in a five-year agreement that is due to start early next month. In a press statement released today John Hubbard, SVP of Worldwide Development at Pfizer said: “This new strategic partnership model is part of a comprehensive program to sharpen our research focus at Pfizer, and creates a more flexible cost base through outsourcing of certain research and development services.” Josef von Rickenbach, Parexel CEO, said: “We are focused on applying best-practice operational models, supported by a combination of our eClinical solutions and clinical processes, to help Pfizer reduce the time and cost of development. Pfizer has been cutting in-house R&D capacity in recent years in a bid to reduce costs with the most recent example of this approach being its decision to close its facility in Sandwich, Kent in the UK. At the time company spokesman Andrew Widger told this site’s sister publication, in-Pharmatechnologist.com, that: “Like all of our industry peers, Pfizer is challenged with insufficient productivity and an unsustainable model for innovation.” He added that: “We intend to create novel and flexible partnerships to externalize R&D services.” As a result, Pfizer’s decision to outsourcing to Parexel is not unexpected. Source: PAREXEL

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Sanofi and DNDi - Drugs for Neglected Diseases initiative - Sign an Innovative Agreement Sanofi (EURONEXT: SAN and NYSE:SNY) and Drugs for Neglected Diseases initiative (DNDi) announced a three-year research collaboration agreement for the research of new treatments for nine neglected tropical diseases (NTDs), listed by the World Health Organization (WHO) for which new, adapted, and efficient tools are urgently needed to treat patients in endemic countries. This agreement is built upon a history of successful collaboration between Sanofi and DNDi.

In the framework of this agreement, Sanofi will initially bring molecules from its libraries into the partnership, while DNDi and Sanofi collaborate in research activities on innovative molecular scaffolds. The core of the agreement lies in the innovative management of intellectual property generated through the collaboration. The rights to results produced by this partnership will be coowned by Sanofi and DNDi. The partners will facilitate publication of the results to ensure access to the wider community of researchers focusing on NTDs. The public sector will benefit from the drugs developed through this agreement under the best possible conditions to ease access for patients in all endemic countries, irrespective of their level of economic development.

“Sanofi is committed to bringing therapeutic solutions to those most affected and exposed to neglected tropical diseases (NTDs),” said Dr. Elias Zerhouni, President, Global Research & Development, Sanofi. “In this new research collaboration with DNDi, we have taken a firm step towards greater flexibility in the sharing of knowledge to produce new medicines.”

“This agreement is a major milestone in our access to molecules that can help combat neglected diseases,” said Dr. Bernard Pécoul, Executive Director of DNDi. “We believe that this level of private-sector involvement in open-research collaboration to deliver appropriate medicines as public goods is vital to addressing the needs of the most vulnerable populations of the world. The agreement allows DNDi to continue making science work more efficiently for the patients who need it most. We encourage and commend such engagement.” Source: World Pharma News, TUESDAY, 31 MAY 2011

DA approves linagliptin tablets for the treatment of type 2 diabetes Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced that the U.S. Food and Drug Administration (FDA) has approved linagliptin tablets, a prescription medication used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.(1) The FDA has approved linagliptin as a monotherapy or in combination with other commonly prescribed medications for type (2) diabetes—such as metformin, sulphonylurea and pioglitazone - to reduce haemoglobin A1c (HbA1c or A1c) levels by a mean of up to -0.7 percent (compared to placebo).(2) HbA1c is measured in people with diabetes to provide an index of blood sugar control for the previous two to three months. It is used as a marker of efficacy of antihyperglycaemic therapies.Linagliptin belongs to a class of prescription medications called

dipeptidyl peptidase-4 (DPP-4) inhibitors and is the first member of its class to be approved at one dosage strength (5 mg, once daily).(1) With linagliptin, no dose adjustment is recommended for patients with kidney or liver impairment. Linagliptin is a tablet that can be taken with or without food. Linagliptin lowers blood sugar in a glucose-dependent manner by increasing incretin levels (GLP-1), which increase insulin levels after meals and throughout the day.Source: Boehringer Ingelheim, THURSDAY, 05 MAY 2011

Evotec earns milestone payment from Boehringer IngelheimEvotec has received a milestone payment of EUR2m from Boehringer Ingelheim, following the advancement of a back-up compound into a Phase I clinical trial under a multi-year, multi-target drug discovery collaboration.

The milestone triggers from the initiation of a Phase I clinical trial of an experimental compound by Boehringer Ingelheim for the treatment neuropathic pain.

Previously, Evotec had entered into the collaboration with Boehringer Ingelheim to jointly identify and develop preclinical development candidates for the treatment of various disease areas including CNS, inflammation, cardiometabolic and respiratory diseases.

The tie up allows Boehringer Ingelheim for the full ownership and global responsibility for clinical development, manufacturing and commercialisation of the compounds identified.

Evotec CEO Werner Lanthaler said they continue to enjoy a rewarding partnership at both scientific and commercial levels with Boehringer Ingelheim.IPI Staff Writer

Mylan to rebrand Matrix subsidiary for entry in Indian marketMumbai, May 27 : US-headquartered USD 5.5 billion revenue multinational generic and specialty pharmaceutical company, Mylan Inc is set to rebrand its Hyderabad, India-based subsidiary Matrix Laboratories Limited as ‘Mylan’, purchased by it in 2007.

Matrix Laboratories is one of the world’s largest suppliers of active pharmaceutical ingredients (API) with products in anti-asthmatic, antibacterial, antifungal, antiretroviral (ARV), cardiovascular, CNS, gastrointestinal and pain management segments.

The Hyderabad company, founded in 2001, also offers a growing line of finished dosage form products, most of which are generic ARV therapies for the treatment of HIV/AIDS, including both adult and pediatric therapies.

This rebranding is part of Mylan’s strategy to lay groundwork for its entry into the Indian commercial market with its own prescription pharmaceuticals within the next 12 months, the company said here today. The planned name change is subject to approval of the Registrar of Companies in India. Mylan expects to retain the Matrix name for the institutional ARV franchise, serving NGOs and other alliances.


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